Protein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase A.

BACKGROUND: Protein arginine methylation has emerged a pivotal role in cancer progression. However, the role of protein arginine methyltransferase 3 (PRMT3) in hepatocellular carcinoma (HCC) remains unknown. METHODS: The expression pattern of PRMT3 in HCC was analysed using quantitative real-time-polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry assays. Loss- and gain-of-function experiments were carried out to determine the oncogenic role of PRMT3 in HCC. Glucose consumption and lactate production assays, seahorse bioscience, mass spectrometry, co-immunoprecipitation, metabonomic analysis and site-specific mutation experiments were used to explore the underlying molecular mechanisms. Furthermore, a xenograft mouse model was established to investigate the effects of PRMT3 and its inhibitor, SGC707, treatment on tumour growth in vivo. RESULTS: The expression of PRMT3 was significantly upregulated in HCC, with high expression of which correlated with poor prognosis. PRMT3 knockdown led to the decrease in proliferation, glycolysis of HCC cells and tumour growth, whilst its overexpression showed opposite results. The catalytic activity of PRMT3 was important in mediating these biological processes. Mechanistically, our data showed that PRMT3 interacted with and mediated asymmetric dimethylarginine (ADMA) modification of lactate dehydrogenase A (LDHA) at arginine 112 (R112). Compared with LDHA-wild-type (LDHA-WT) cells, LDHA-R112K-mutant-expressing HCC cells exhibited a decrease in lactate dehydrogenase (LDH) activity, HCC cell glycolysis and proliferation. Furthermore, the administration of SGC707, a selective inhibitor of PRMT3, disrupted the PRMT3-mediated LDHA methylation and abolished PRMT3-induced HCC glycolysis and tumour growth. CONCLUSIONS: Our results suggested a novel oncogenic role of PRMT3 in HCC, and it could be a promising therapeutic target for HCC by linking post-translational modification and cancer metabolism.

Adverse Histological Features of Differentiated Thyroid Cancer Are Commonly Found in Autopsy Studies: Implications for Treatment Guidelines.

Background: While the popularity of lobectomy for differentiated thyroid cancer (DTC) has increased since the 2015 ATA (American Thyroid Association) guidelines, recent studies reported that adverse histological features (minimal extrathyroidal extension [mETE], multifocality, vascular invasion, and lymph node [LN] metastases) may be found in 30-60% of lobectomy specimens, questioning the validity of this approach. Aim: To assess the prevalence adverse histological features in occult DTC detected in autopsy studies. Methods: Meta-analysis of autopsy studies of the thyroid in subjects without known history of thyroid cancer. Results: Twenty-nine studies including 8750 subjects fulfilled the inclusion criteria, with incidentally discovered DTC in 740 autopsies (8.5%). Age was reported in 17 studies, with a median age of 61 years (range 41-68 years). Multifocality was reported in 27 studies with a calculated event rate of 28.2% ([CI 23.1-33.8], I2 = 46.3%), with bilateral involvement in 18% [CI 12.6-25.1]. mETE was reported in 5 studies, with an event rate of 24.5% ([CI 9.3-50.7], I2 = 88.5%), and the presence of LN metastases were reported in 13 studies with an event rate of 11% ([CI 6.1-19.1], I2 = 69.5%). Vascular invasion was reported in seven studies with an event rate of 16% ([CI 4-47], I2 = 86.8%). Of 25 studies with whole body autopsies (722 subjects), 3 cases of distant metastases were reported, of which 2 had fatal metastatic disease (where thyroid origin was not diagnosed before death), and 1 had occult disease. Conclusions: Adverse histological features including mETE, LN metastases, multifocality, and vascular invasion are common in occult DTC. When minimal in size, these adverse histological features do not seem to be markers of aggressive disease and may not be an indication for completion thyroidectomy or radioiodine therapy.

Reporting regression in primary cutaneous melanoma. Part 2: prognosis, evaluation and management.

The effect of histological regression on patient prognosis for primary cutaneous melanoma is controversial. Some authors hypothesize that regression indicates a robust systemic immune response and may decrease risk of metastasis. Others argue that histological regression calls into question a T0 diagnosis because there may have been an invasive component of the melanoma that is no longer visible but is still active. The literature to date does not suggest that histological regression is associated with increased risk of positive sentinel lymph node status, metastasis or increased risk of mortality. Thus, the presence of histological regression should not change patient staging, evaluation or management. The criteria used for reporting regression have varied dramatically across studies, and standardized reporting is needed to foster evidence-based practices in the future.

The changing face of adult posttransplant lymphoproliferative disorder: Changes in histology between 1999 and 2013.

Posttransplant lymphoproliferative disorder (PTLD) typically presents with either polymorphic or monomorphic histology. While both are the end result of immunosuppressive therapies, their origins are felt to be different with different prognoses and responsiveness to therapy, resulting in 2 different malignancies. We attempted to confirm reports suggesting that the relative frequency of these 2 histologies is shifting over time. We analyzed 3040 adult PTLD cases in the UNOS OPTN database from 1999 to 2013. Changes in PTLD cases over time were analyzed for histology, time from transplant to diagnosis, and patient EBV serostatus. We found that the relative proportion of polymorphic versus monomorphic histology has changed with an increase in the proportion of monomorphic cases with time (1999-2003, 54.9% vs. 45.1%; 2004-2008, 58.3% vs. 41.7%; 2009-2013, 69.7% vs. 30.3%; P = <.001). The change is driven by a gradual increase in the number of monomorphic PTLD with a steady number of polymorphic PTLD. The change is most strongly seen in transplant recipients who were EBV serostatus positive at the time of transplant. Potential causes are changes in immunosuppressive regimens with increased tacrolimus use (P = .009) and increased survival among transplant patients leading to later occurrence of PTLD (P = .001) that have occurred during the time frame analyzed. As organ transplantation has evolved over time, PTLD has coevolved. These changes in histology have important implications regarding the origin and clinical management of PTLD.

[Impact of the pathology in modern medicine]. / Représentation en sciences du vivant (9) émergence d'une spécialité médicale nouvelle : la pathologie.

In this review, the authors emphasize the pivotal role of the pathology in the setting of a revolution which progressively transforms medical sciences into basic sciences. Several key aspects of this specialty will be discussed together with the main perspectives in the fields of oncologic disorders.

Real-time histology with the endocytoscope.

Endoscopic Imaging has progressed tremendously over the last few decades. Novel imaging technologies such as high-resolution and high-magnification white light endoscopy, narrow band imaging, optimal band imaging, autoflourescence imaging and optical coherence tomography not only aid the endoscopist in detecting malignant or pre-malignant lesions but also assist in predicting histology. Recently, the introduction of Endocytoscopy (EC) and Confocal Endomicroscopy has taken us into a new realm of diagnostic endoscopy. With the ability to magnify up to 1000 ×, cellular structures can be visualized in real-time. This advance in technology could potentially lead to a paradigm shift negating the need to obtain biopsies. EC is, however, still in the early stages of development and further research needs to be carried out before it can be accepted as standard practice. This review will focus on the diagnostic utility of the Endocytoscope.

Will the "new biology" affect the future of histopathology?

The technologies used in histopathology are changing as a consequence of the current revolutionary progress in several areas of biology. It is likely that general cancer management will improve because of the impact of molecular techniques and immunohistochemistry on tumor diagnosis and classification and on the determination of prognosis and response to therapy. Moreover, as therapies are starting to be modelled after the distinctive molecular characteristics of a specific tumor, the availability of molecular tests to all patients will become a matter of great importance.

Tumores intracraneales en nuestro medio / Intracraneal tumors in our practice

Se describe el tipo histologico de 140 tumores intracraneales, estudiados en los hospitales Nro.1 CNS (1965-1985) y Metodista (1967-1985) de La Paz, incluidos los tuberculomas. Los resultados revelan que los adenomas pituitarios son los mas frecuentes con un 23.17 por ciento ; seguidos de los astrocitomas (22.14 por ciento ); los meningiomas (15 por ciento ); los tuberculomas (13.57 por ciento ) y los tumores metastasicos (7.14 por ciento ).

[Experimental histology and the problems of the evolution of tissues]. / Eksperimental'naia gistologiia i problemy évoliutsii tkanei.

Trends in modern histology have been reviewed. The role of evolutionary concepts (hypotheses) in analysis of experimental data has been stressed. Several problems of onto- and phylogenesis of hemopoiesis have been discussed. They include evolution of structure of hemopoietic system; origin of fibroblasts and correlation of hemal (mobile) and desmal (fixed) mesenchymal cells; immunological approaches to studies of evolution of hemopoietic cell.