There is still no standard treatment for non‐clear cell renal cell carcinomas. Sunitinib is the most examined drug because of its effectiveness in retrospective studies and clinical trials, and is ...the preferred first‐line drug in the National Comprehensive Cancer Network guideline. Temsirolimus is an option as a first‐line drug, especially for poor‐risk non‐clear cell renal cell carcinoma patients. Everolimus, pazopanib, axitinib and nivolmab might also be viable options. Clinical trials are still required to gather evidence regarding non‐clear cell renal cell carcinoma treatment. Because each non‐clear cell renal cell carcinoma has a different genetic background and molecular features, specific treatment for each non‐clear cell renal cell carcinoma should be established. From the results of a Japanese multicenter study, tyrosine kinase inhibitors might be better used for metastatic papillary renal cell carcinoma in both first‐ and second‐line settings. Both tyrosine kinase inhibitors and mammalian target of rapamicin inhibitors are effective for metastatic chromophobe renal cell carcinoma, but the preferred first‐line drug has not been determined. Platinum‐based chemotherapies are currently recommended for metastatic collecting duct carcinoma, and anti‐angiogenic drugs are effective in some cases. Tyrosine kinase inhibitors, especially sunitinib, appear to be effective for X11.2 translocation renal cell carcinoma among the microphthalmia‐associated transcription family of translocation renal cell carcinomas. Evidence is still lacking regarding the treatment for other rare non‐clear cell renal cell carcinomas. Appropriate sequential therapies using antivascular endothelial growth factor therapies, mammalian target of rapamicin inhibitors and immuno‐oncology drugs should be established for each non‐clear cell renal cell carcinoma.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Components of transcriptional machinery are selectively partitioned into specific condensates, often mediated by protein disorder, yet we know little about how this specificity is achieved. Here, we ...show that condensates composed of the intrinsically disordered region (IDR) of MED1 selectively partition RNA polymerase II together with its positive allosteric regulators while excluding negative regulators. This selective compartmentalization is sufficient to activate transcription and is required for gene activation during a cell-state transition. The IDRs of partitioned proteins are necessary and sufficient for selective compartmentalization and require alternating blocks of charged amino acids. Disrupting this charge pattern prevents partitioning, whereas adding the pattern to proteins promotes partitioning with functional consequences for gene activation. IDRs with similar patterned charge blocks show similar partitioning and function. These findings demonstrate that disorder-mediated interactions can selectively compartmentalize specific functionally related proteins from a complex mixture of biomolecules, leading to regulation of a biochemical pathway.
Display omitted
•Disorder-mediated selective partitioning regulates gene activation•Disordered regions are necessary and sufficient for selective partitioning•Charge patterning in disordered regions is required for specificity of partitioning•Disordered regions with similar patterning have similar partitioning and function
Charge patterning in disordered regions of transcriptional regulators mediates selective partitioning into MED1IDR condensates for gene activation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We previously demonstrated a genetic evidence of the progression from seminoma to embryonal carcinoma in mixed testicular germ cell tumors (TGCTs). This process, the “reprogramming” of seminoma ...cells, is crucial for pathological tumorigenesis and should be kept in mind while designing clinical therapeutic strategies. We hypothesized that a comparison between pure-type seminomas and seminoma components in mixed tumors (mixed-type seminomas) could reveal early changes in the reprogramming process. In the present study, we performed gene expression microarray analysis of six pure-type and six mixed-type seminomas. Hierarchical clustering analysis properly grouped each type of seminomas into a separated cluster. Supervised analysis between pure-type and mixed-type seminomas revealed 154 significantly dysregulated genes (Storey-adjusted
q
< 0.05). The genes with the highest overexpression in mixed-type seminomas compared with the pure-type seminomas included
MT1
isoforms,
PRSS8
,
TSC22D1
, and
SLC39A4
; downregulated genes included
DEFB123
,
LMTK2
, and
MYRF
. Functional annotation analysis of the differentially expressed genes revealed that the top-ranked functional categories were related to cellular zinc metabolism and consisted of
MT1
isoforms and
SLC39A4
, the results of which were validated using quantitative polymerase chain reaction and immunohistochemical analysis. In conclusion, this research provides further evidence that pure and mixed types of seminomas are molecularly different, which may contribute to elucidate the reprogramming mechanism in the progression of TGCTs.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Background Periostin is an extracellular matrix protein that has been known to be implicated in fibrillogenesis and cell migration, including cancer metastasis. Periostin overexpression in cancer ...cells and/or intervening stroma is usually related to tumor progression and poor patient outcomes in various human cancers; however, its role in urothelial carcinoma, especially upper urinary tract urothelial carcinomas (UTUCs), remains inconclusive. Methods Samples from 126 consecutive cases of invasive UTUC (69 renal pelvic cancers and 57 ureteral cancers) were histologically reviewed and analyzed for periostin expression using immunohistochemistry. The intensities of immunoreactivity and the fraction of positive cancer cells and stroma (i.e., epithelial and stromal expression, respectively) were classified into four categories each (intensity, 0-3; fraction, 0-25% = 1; 26-50% = 2; 51-75% = 3; and > 75% = 4). The overall score was determined by multiplying both scores, and overall scores greater than or equal to 6 were considered to indicate high periostin expression. Results Among 126 UTUCs, 55 (44%; 27 renal pelvic and 28 ureteral cancers) showed high stromal periostin expression. None of the cases were considered to have high epithelial periostin expression. High stromal periostin expression was associated with non-papillary gross findings, higher pathological T category, lymphovascular invasion, concomitant carcinoma in situ, subtype histology, lymph node metastasis, positive surgical margins, high tumor budding, and high tumor-associated immune cell status. Multivariate analysis revealed that high stromal periostin expression was an independent predictor of overall survival (p = 0.00072, hazard ratio = 3.62), and lymphovascular invasion and high stromal periostin expression were independent predictors of cancer-specific survival (p = 0.032 and 0.020, hazard ratio = 2.61 and 3.07, respectively). Conclusions Stromal periostin expression was often observed in invasive UTUCs with adverse clinicopathological factors and may be a useful predictor of patient outcomes. Keywords: Urothelial carcinoma, Upper urinary tract, Periostin, Immunohistochemistry
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The current study aimed to investigate the plausible histopathological factors that affect the detectability of prostate cancers on multiparametric magnetic resonance imaging (MP-MRI). This ...retrospective study included 59 consecutive patients who had undergone MP-MRI and subsequent radical prostatectomy. The cases were standardized according to the tumor size ranging from 10 to 20 mm on the final pathological diagnosis. Histopathological review and semi-automated imaging analysis were performed to evaluate the relative area fractions of the histological components, including cancer cells, stroma, and luminal spaces. Among the 59 prostatectomy specimens, no case showed two or more foci of cancer that matched the size criteria. Of the 59 lesions, 35 were MRI-detectable Prostate Imaging Reporting and Data System (PIRADS) score of 3 or greater and 24 were MRI-undetectable (PIRADS score of 2 or less). No significant differences were observed in Gleason Grade Group, percentage of Gleason pattern 4, and predominant subtype of Gleason pattern 4 between MRI-detectable and MRI-undetectable cancers. On the other hand, significantly higher mean area fraction of cancer cells (60.9% vs. 42.7%, P < 0.0001) and lower mean area fractions of stroma (33.8% vs. 45.1%, P = 0.00089) and luminal spaces (5.2% vs. 12.2%, P < 0.0001) were observed in MRI-detectable cancers than in MRI-undetectable cancers. In a multivariable analysis performed upon exclusion of area fraction of stroma due to its multicollinearity with that of cancer cells, area fractions of cancer cells (P = 0.0031) and luminal space (P = 0.0035) demonstrated strong positive and negative correlation with MRI-detectability, respectively. Changes in cancer cells, stroma, and luminal spaces, rather than conventional histological parameters, could be considered one of the best predictors to clinical, in vivo MRI-detectability of prostate cancer.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A supercontinuum (SC) light source enables multispectral photoacoustic imaging at excitation wavelengths in the visible-to-near-infrared range. However, for such a broad optical wavelength range, ...chromatic aberration is non-negligible. We developed a multispectral optical-resolution photoacoustic microscopy (MS-OR-PAM) setup with a nanosecond pulsed SC light source and a reflective objective lens to avoid chromatic aberration. Chromatic aberrations generated by reflective and conventional objective lenses were compared, and the images acquired using the reflective objective were not affected by chromatic aberration. Hence, MS-OR-PAM with the reflective objective was used to distinguish red blood cells from melanoma cells via spectral subtraction processing.
Hepatoblasts, hepatic stem/progenitor cells in liver development, have a high proliferative potential and the ability to differentiate into both hepatocytes and cholangiocytes. In regenerative ...medicine and drug screening for the treatment of severe liver diseases, human induced pluripotent stem (iPS) cell-derived mature functional hepatocytes are considered to be a potentially good cell source. However, induction of proliferation of these cells is difficult ex vivo. To circumvent this problem, we generated hepatic progenitor-like cells from human iPS cells using serial cytokine treatments in vitro. Highly proliferative hepatic progenitor-like cells were purified by fluorescence-activated cell sorting using antibodies against CD13 and CD133 that are known cell surface markers of hepatic stem/progenitor cells in fetal and adult mouse livers. When the purified CD13(high)CD133(+) cells were cultured at a low density with feeder cells in the presence of suitable growth factors and signaling inhibitors (ALK inhibitor A-83-01 and ROCK inhibitor Y-27632), individual cells gave rise to relatively large colonies. These colonies consisted of two types of cells expressing hepatocytic marker genes (hepatocyte nuclear factor 4α and α-fetoprotein) and a cholangiocytic marker gene (cytokeratin 7), and continued to proliferate over long periods of time. In a spheroid formation assay, these cells were found to express genes required for mature liver function, such as cytochrome P450 enzymes, and secrete albumin. When these cells were cultured in a suitable extracellular matrix gel, they eventually formed a cholangiocytic cyst-like structure with epithelial polarity, suggesting that human iPS cell-derived hepatic progenitor-like cells have a bipotent differentiation ability. Collectively these data indicate that this novel procedure using an in vitro expansion system is useful for not only liver regeneration but also for the determination of molecular mechanisms that regulate liver development.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
