Citations

Voltage-gated Ca2+(CaV) channels are expressed in endocrine cells where they contribute to hormone secretion. Diverse chemical messengers, including epidermal growth factor (EGF), are known to affect the expression of CaVchannels. Previous studies have shown that EGF increases Ca2+currents in GH3 pituitary cells by increasing the number of high voltage-activated (HVA) CaVchannels at the cell membrane, which results in enhanced prolactin (PRL) secretion. However, little is known regarding the mechanisms underlying this regulation. Here, we show that EGF actually increases the expression of the CaVα2δ-1 subunit, a key molecular component of HVA channels. The analysis of the gene promoter encoding CaVα2δ-1 ( CACNA2D1) revealed binding sites for transcription factors activated by the Ras/Raf/MEK/ERK signaling cascade. Chromatin immunoprecipitation and site-directed mutagenesis showed that ELK-1 is crucial for the transcriptional regulation of CACNA2D1 in response to EGF. Furthermore, we found that EGF increases the membrane expression of CaVα2δ-1 and that ELK-1 overexpression increases HVA current density, whereas ELK-1 knockdown decreases the functional expression of the channels. Hormone release assays revealed that CaVα2δ-1 overexpression increases PRL secretion. These results suggest a mechanism for how EGF, by activating the Ras/Raf/MEK/ERK/ELK-1 pathway, may influence the expression of HVA channels and the secretory behavior of pituitary cells.

Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with recognized variability in clinical outcome, genetic features, and cells of origin. To date, transcriptional profiling has been used to highlight similarities between DLBCL tumor cells and normal B-cell subtypes and associate genes and pathways with unfavorable outcome. Given the genetic heterogeneity in DLBCL, there are likely to be subsets of tumors with different pathogenetic mechanisms and possible treatment targets. To identify DLBCL subtypes that were sufficiently robust to be captured by multiple methods, we analyzed the profiles of 176 newly diagnosed DLBCLs using three different clustering algorithms (hierarchical clustering (HC), self-organizing maps (SOM), and probabilistic clustering (PC)), the top 5% of genes with the highest reproducibility across duplicate samples and largest variation across patient tumors, and a resampling-based method (consensus clustering) that automatically selects the most stable numbers of clusters with each algorithm. Three discrete subsets of DLBCLs -- “Oxidative Phosphorylation” (OxPhos), “B-cell Receptor/Proliferation” and “Host Response” (HR) -- were identified, characterized using gene set enrichment analysis and confirmed in an independent series of newly diagnosed DLBCLs with available array data. There was an association between cluster membership and examined genetic abnormalities in DLBCL. BCL2 translocations were more common in the OxPhos cluster whereas BCL6 translocations were more frequent in the BCR/proliferation cluster. Translocations of either type were uncommon in the HR cluster. Patients with HR DLBCLs were also significantly younger than those with OxPhos or BCR/proliferation tumors; HR patients also had a significantly higher incidence of splenic and BM involvement. The unique characteristics of HR tumors - fewer known genetic abnormalities and prominent host immune and inflammatory cell transcripts -prompted us to assess host immune cells in study tumors using morphologic and immunohistochemical approaches. HR DLBCLs contained significantly higher numbers of morphologically distinct CD2+/CD3+ tumor-infiltrating lymphocytes and interdigitating S100+/GILT+/CD1a-/CD123- dendritic cells. The HR cluster shared features of histologically defined T-cell/histiocyte-richBCL, including fewer known genetic abnormalities, younger age at presentation and frequent splenic and bone marrow involvement. The current study identifies tumor microenvironment and host inflammatory response as defining features in DLBCL, provides insights into the nature of the host immune response in a major DLBCL subtype and suggests rational treatment targets in newly identified tumor groups.

Abstract Background and study aims Colonoscopy is an effective tool to prevent colorectal cancer. Social media has emerged as a source of medical information for patients.YouTube (a video sharing website) is the most popular video informative source. Therefore, we aimed to assess the educational quality of colonoscopy videos available on YouTube. Methods We performed a YouTube search using the keyword “colonoscopy” yielded 429 videos, of which 255 met the inclusion criteria. Colonoscopy Data Quality Score (C-DQS) was created to rate the quality of the videos (–10 to +40 points) based on a colonoscopy education video available on the Ameican Society of Gastrointestinal Endoscopy (ASGE) website. Each video was scored by six blinded reviewers independently using C-DQS. The Global Quality Score (GQS) was used for score validation. The intraclass correlation coefficient (ICC) was used to assess the similarity of the scores among reviewers. Results Professional societies had the highest number of videos (44.3 %). Videos from professional societies (6.94) and media (6.87) had significantly higher mean C-DQS compared to those from alternative medicine providers (1.19), companies (1.16), and patients (2.60) (P < 0.05). Mean C-DQS score of videos from healthcare providers (4.40) was not statistically different than other sources. There was a high degree of agreement among reviewers for the videos from all sources (ICC = 0.934; P < 0.001). Discussion YouTube videos are a poor source of information on colonoscopy. Professional societies and media are better sources of quality information for patient education on colonoscopy. The medical community may need to engage actively in enriching the quality of educational material available on YouTube.

SummaryImmunoglobulin light‐chain (AL) amyloidosis is a clonal plasma cell disorder characterised by production and deposition of misfolded monoclonal light chains in vital organs with potential to cause irreversible organ damage. The treatment of AL amyloidosis has evolved along the lines of multiple myeloma (MM) owing to clonal plasma cells being at the root of both disease processes. Treatment with melphalan and autologous haematopoietic cell transplantation, as well as proteasome inhibitors and immunomodulatory agents, are the standard of care for AL amyloidosis. While these treatment modalities are highly effective against the neoplastic plasma cells, patients often relapse and those with advanced disease may be unable to tolerate these treatments due to side‐effects. Immunotherapy with monoclonal antibodies, bispecific antibodies, antibody–drug conjugates and chimeric antigen receptor T cells have revolutionised the treatment armamentarium for MM. These novel immunotherapy agents are in the early phases of evaluation and clinical development for patients with AL amyloidosis. The present review aims to discuss the role of novel immunotherapies currently in development and their potential for use in the treatment of AL amyloidosis.

AbstractIntroductionRadiologically inserted gastrostomy (RIG) placement in patients with amyotrophic lateral sclerosis (ALS) carries risks related to periprocedural sedation and analgesia. To minimize these risks, we used a paravertebral block (PVB) technique for RIG placement.MethodsWe retrospectively reviewed patients with ALS undergoing RIG placement under PVB between 2013 and 2017.ResultsNinety‐nine patients with ALS underwent RIG placement under PVB. Median (range) age was 66 (28 to 86) years, ALS Functional Rating Scale—Revised score was 27 (6 to 45), and forced vital capacity was 47% (8%–79%) at time of RIG placement. Eighty‐five (85.9%) patients underwent RIG placement as outpatients, with a mean postanesthesia care unit stay of 2.3 hours. The readmission rate was 4% at both 1 and 30 days postprocedure.DiscussionPVB for RIG placement has a low rate of adverse events and provides effective periprocedural analgesia in patients with ALS, the majority of whom can be treated as outpatients.

SNAP‐25, a synaptosome associated exocytosis protein of 25 kDa plays an important role in the secretory activity of several endocrine cells. In the present study, we investigated 15 PRL, 10 GH, 5 ACTH, 5 TSH, 15 FSH/LH/ alpha subunit producing, and 5 null cell adenomas. Surgically removed, formalin‐fixed and paraffin embedded human pituitary tumors were used. Sections were immunostained by the streptavidin‐biotin‐peroxidase complex method. The results showed that 10 PRL producing adenomas were strongly immunoreactive for SNAP‐25. The immunopositive material was located mainly on the plasmalemma. The nuclei were immunonegative, the cytoplasm was mildly immunopositive in several cells. Treatment of patients with dopamine agonists before surgery decreased markedly SNAP‐25 immunopositivity in 5/10 cases. In GH producing adenomas SNAP‐25 was seen in 5 cases. Immunopositivity was mild‐ moderate, membrane bound and cytoplasmic. Somatostatin analogs caused no marked reduction in immunopositivity (5 cases). Other adenoma types were practically immunonegative. Among human pituitary adenomas only PRL producing tumors release their secretory granules via exocytosis as was demonstrated by electron microscopy. This observation is concordant with our results. In dopamine agonist treated patients, decreased SNAP‐25 expression in PRL producing adenoma cells is consistent with reduction of blood PRL levels.

Introduction . The triglyceride and glucose (TyG) index has been described as a biochemical marker of insulin resistance (IR); however, its diagnostic accuracy remains uncertain. Objective . To summarize the evidence assessing the diagnostic accuracy of the TyG index regarding IR. Methods . A comprehensive search in MEDLINE, EMBASE, Web of Science, and Scopus was performed without any language restriction. Studies assessing the diagnostic accuracy of the TyG index against the hyperinsulinemic-euglycemic clamp (HIEC) or any other IR biochemical were assessed independently and in duplicate. Diagnostic accuracy measures (sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios) were extracted independently and in duplicate. The QUADAS-2 tool was used to assess the risk of bias of independent studies. Results . We identified 15 eligible studies with 69,922 participants and an overall quality of low to moderate. The TyG index was evaluated by HIEC and HOMA as reference tests. The highest achieved sensitivity was 96% using HIEC, and the highest specificity was of 99% using HOMA-IR, with a cutoff value of 4.68. AUC values varied from 0.59 to 0.88. Cutoff values for IR were variable between studies, limiting its comparability. Conclusion . In this systematic review, we found moderate-to-low quality evidence about the usefulness of the TyG index as a surrogate biochemical marker of IR. Due to the lack of a standardized IR definition and heterogeneity between studies, further validation and standardized cutoff values are needed to be used in clinical practice.

Extramedullary multiple myeloma is defined by the presence of plasma cell infiltration outside of the bone marrow. It is associated with a poor prognosis and resistance to therapy and is often associated with high-risk cytogenetics. Aggressive relapsed and refractory extramedullary multiple myeloma is often treated with salvage infusional chemotherapy to achieve rapid disease control. Commonly used regimens include DCEP, CVAD, and VTD-PACE. While VTD-PACE contains bortezomib and thalidomide which have potent antimyeloma activity, the advent of novel agent therapy with proteasome inhibitors and immunomodulatory agents being used in the first-line setting has resulted in many patients being refractory to bortezomib by the time they are treated with VTD-PACE. Herein, we discuss two cases of aggressive relapsed, high-risk, bortezomib-refractory extramedullary multiple myeloma treated with KRD-PACE and review the available clinical data on salvage chemotherapy regimens used in relapsed refractory myeloma.

Despite the evolution of the therapeutic arsenal for the treatment of multiple myeloma (MM) over the past decade, autologous stem-cell transplantation (ASCT) remains an integral part of the treatment of patients with both newly diagnosed and relapsed MM. The advent of novel therapies, such as immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies, has led to unprecedented levels of deep hematologic responses. Nonetheless, studies show that ASCT has an additive effect leading to additional deepening of responses. As the therapeutic agents for MM continue to evolve, the timing, duration, and sequence of their use in combination with ASCT will be crucial to understand to obtain the deepest response and survival benefit for patients with MM. This review aims to discuss the role of ASCT for the management of MM, with a particular focus on the role of ASCT in the context of novel therapies and minimal residual disease.