Comatose Within 6 Weeks, but Still Alive After 3 Years, Creutzfeldt‐Jakob Disease With Unusual Progression

Creutzfeldt‐Jakob disease (CJD) should still be considered in a patient presenting with rapidly progressive dementia and negative CSF 14‐3‐3 protein and RT‐QulC. Treatable causes of encephalopathy must be ruled out. Neurodegenerative diseases must also be considered

Crown ether decorated silicon photonics for safeguarding against lead poisoning

Lead (Pb2+) toxification in society is one of the most concerning public health crisis that remains unaddressed. The exposure to Pb2+ poisoning leads to a multitude of enduring health issues, even at the part-per-billion scale (ppb). Yet, public action dwarfs its impact. Pb2+ poisoning is estimated to account for 1 million deaths per year globally, which is in addition to its chronic impact on children. With their ring-shaped cavities, crown ethers are uniquely capable of selectively binding to specific ions. In this work, for the first time, the synergistic integration of highly-scalable silicon photonics, with crown ether amine conjugation via Fischer esterification in an environmentally-friendly fashion is demonstrated. This realises a photonic platform that enables the in-situ, highly-selective and quantitative detection of various ions. The development dispels the existing notion that Fischer esterification is restricted to organic compounds, laying the ground for subsequent amine conjugation for various crown ethers. In this work, the platform is engineered for Pb2+ detection, demonstrating a large dynamic detection range of 1 - 262000 ppb with high selectivity against a wide range of relevant ions. These results indicate the potential for the pervasive implementation of the technology to safeguard against ubiquitous lead poisoning in our society

Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome Atlas (TCGA) (n = 414) and EMBL-EBI (n = 53), CLEAR score demonstrated both superior prognostic estimates and inverse correlation with anti-angiogenic tyrosine-kinase inhibition in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score. Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated that average intertumoral heterogeneity exceeded intratumoral expression heterogeneity. Wider investigation of cancer biology using continuous approaches may yield insights into tumor heterogeneity; single cell analysis may provide a key foundation for this approach

Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome Atlas (TCGA) (n = 414) and EMBL-EBI (n = 53), CLEAR score demonstrated both superior prognostic estimates and inverse correlation with anti-angiogenic tyrosine-kinase inhibition in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score. Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated that average intertumoral heterogeneity exceeded intratumoral expression heterogeneity. Wider investigation of cancer biology using continuous approaches may yield insights into tumor heterogeneity; single cell analysis may provide a key foundation for this approach

A Daphnane Diterpenoid Isolated from Wikstroemia polyantha Induces an Inflammatory Response and Modulates miRNA Activity

MicroRNAs (miRNAs) are endogenously expressed single-stranded ∼21–23 nucleotide RNAs that inhibit gene expression post-transcriptionally by binding imperfectly to elements usually within the 3′untranslated region (3′UTR) of mRNAs. Small interfering RNAs (siRNAs) mediate site-specific cleavage by binding with perfect complementarity to RNA. Here, a cell-based miRNA reporter system was developed to screen for compounds from marine and plant extracts that inhibit miRNA or siRNA activity. The daphnane diterpenoid genkwanine M (GENK) isolated from the plant Wikstroemia polyantha induces an early inflammatory response and can moderately inhibit miR-122 activity in the liver Huh-7 cell line. GENK does not alter miR-122 levels nor does it directly inhibit siRNA activity in an in vitro cleavage assay. Finally, we demonstrate that GENK can inhibit HCV infection in Huh-7 cells. In summary, the development of the cell-based miRNA sensor system should prove useful in identifying compounds that affect miRNA/siRNA activity

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Rigor prophylaxis in stage IV melanoma and renal cell carcinoma patients treated with high dose IL-2

Abstract Background Rigors are a significant adverse event during interleukin-2 (IL2) therapy for metastatic melanoma and renal cell carcinoma. Meperidine has been a mainstay for rigor prophylaxis but there is a paucity of data regarding possible alternatives. Methods Ninety one patients receiving IL2 therapy for metastatic renal cell carcinoma and melanoma at Huntsman Cancer institute (HCI), Utah from May 2009 to October 2016 were retrospectively evaluated for rigor prophylaxis. Forty two patients received meperidine and 49 received tramadol. Rigors were tabulated using the proxy of number of doses of as needed (PRN) rigor medications and normalized by IL2 doses. Other outcomes of fever, hypotension, and renal insufficiency were noted on a binary scale and normalized by cycles. Statistical analysis was performed utilizing univariate and multivariate negative binomial models. Results Ninety one patients were identified with metastatic melanoma or RCC who received high dose IL2 therapy. Forty two received meperidine and 49 received tramadol prophylaxis for rigors. Univariate negative binomial analysis shows incidence rate ratios (IRR): fever 0.41 (95% CI 0.28–0.62, p-value < 0.001), hypotension 1.7 (95% CI 1.11–2.61, p-value 0.015), renal insufficiency 0.58 (95% CI 0.35–0.98, p-value 0.041), rigors per all PRN meds 1.01 (95% CI 0.79–1.28, p-value 0.964), and rigors via opioid PRN meds 0.85 (95% CI 0.67–1.07, p-value 0.168). Multivariate negative binomial analysis shows IRR: fever 0.59 (95% CI 0.28–1.24, p-value 0.163), hypotension 0.93 (95% CI 0.43–2.03, p-value 0.864), renal insufficiency 1.1 (95% CI 0.52–2.32, p-value 0.807), rigors per al PRN meds 0.92 (95% CI 0.67–1.26, p-value 0.604), and rigors via opioid PRN 0.9 (95% CI 0.65–1.26, p-value 0.554). Conclusion Univariate models indicated meperidine pre-treatment was associated with significantly lower rates of fever and renal insufficiency whereas tramadol was associated with significantly lower rate of hypotension. However, when controlled for demographics and other treatment differences, these differences were no longer significant

Monsoonal variation of the marine phytoplankton community in Kota Kinabalu, Sabah

Monsoon-driven changes of environmental factors have been reported to be significantly variable and affects the phytoplankton community in tropical waters. This study examined the monsoonal changes of environmental parameters and the coastal phytoplankton community, including potential harmful algal bloom species, in the waters of Kota Kinabalu, Sabah, Malaysia. Bi-weekly observations were conducted from August 2017 to January 2019, covering the Southwest Monsoon (SWM), Northeast Monsoon (NEM), and inter-monsoon periods (IMPs). Sea surface temperature, salinity, and daily average photosynthetic active radiation (PAR) were significantly different between the SWM and the NEM. Total phytoplankton densities were significantly higher in the SWM with median cell densities of 1.12 × 104 cells L−1 compared to the NEM with 3.98 × 103 cells L−1. Nutrient measurements indicated that the waters were mesotrophic, with low phosphate (P) levels (1) and Si:P ratios (>16Si:1P) indicated that silicate was not limiting, a condition favourable for diatom growth. Phytoplankton dynamics shifted from a dinoflagellate-dominant community (Protoperidinium spp. and Prorocentrum spp.) to a diatom-dominant community (Leptocylindrus spp. and Dactyliosolen spp.) during the NEM, which was preceded by a peak in silicate and nitrate. Later, Chaetoceros spp. became dominant during the second SWM. The presence of intermittent increases in Margalefidinium polykrikoides and Pyrodinium bahamense var. compressum cell densities may trigger future blooms in these waters. Canonical Correspondence Analysis suggests that the dinoflagellate-dominant community was driven by changes in PAR and Si:N while changes in N:P and salinity shaped the diatom-dominant community. The shifts of the phytoplankton community composition in relation to the different monsoonal periods suggests that the monsoons function as environmental drivers which structure the phytoplankton community of this coastal ecosystem