Superior outcomes with Argatroban for heparin-induced thrombocytopenia: a Bayesian network meta-analysis

Background Argatroban, lepirudin, desirudin, bivalirudin, and danaparoid are commonly used to manage heparin-induced thrombocytopenia related complications. However, the most suitable drug for this condition still remains controversial. Aim of the review This Bayesian network meta-analysis study compared the most common anticoagulant drugs used in the management of heparin-induced thrombocytopenia. Method All clinical trials comparing two or more anticoagulant therapies for suspected or confirmed heparin-induced thrombocytopenia were considered for inclusion. Studies concerning the use of heparins or oral anticoagulants were not considered. Data concerning hospitalisation length, thromboembolic, major, and minor haemorrhagic events, and mortality rate were collected. The network analyses were made through the STATA routine for Bayesian hierarchical random-effects model analysis with standardised mean difference (SMD) and log odd ratio (LOR) effect measures. Results Data from a total of 4338 patients were analysed. The overall mean age was 62.31 ± 6.6 years old. Hospitalization length was considerably shorter in favour of the argatroban group (SMD: - 1.70). Argatroban evidenced the lowest rate of major (LOR: - 1.51) and minor (LOR: - 0.57) haemorrhagic events. Argatroban demonstrated the lowest rate of thromboembolic events (LOR: 0.62), and mortality rate (LOR: - 1.16). Conclusion Argatroban performed better overall for selected patients with HIT. Argatroban demonstrated the shortest hospitalization, and lowest rate of haemorrhages, thromboembolisms, and mortality compared to bivalirudin, lepirudin, desirudin, and danaparoid

Recapitulating thyroid cancer histotypes through engineering embryonic stem cells

Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. The cell subpopulation in the lineage hierarchy that serves as cell of origin for the different TC histotypes is unknown. Human embryonic stem cells (hESCs) with appropriate in vitro stimulation undergo sequential differentiation into thyroid progenitor cells (TPCs-day 22), which maturate into thyrocytes (day 30). Here, we create follicular cell-derived TCs of all the different histotypes based on specific genomic alterations delivered by CRISPR-Cas9 in hESC-derived TPCs. Specifically, TPCs harboring BRAFV600E or NRASQ61R mutations generate papillary or follicular TC, respectively, whereas addition of TP53R248Q generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas mature thyrocytes have a very limited tumorigenic capacity. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. Tissue Inhibitor of Metalloproteinase 1 (TIMP1)/Matrix metallopeptidase 9 (MMP9)/Cluster of differentiation 44 (CD44) ternary complex, in cooperation with Kisspeptin receptor (KISS1R), is involved in TC initiation and progression. Increasing radioiodine uptake, KISS1R and TIMP1 targeting may represent a therapeutic adjuvant option for undifferentiated TCs

Geoarchaeology and Heritage Management:Identifying and Quantifying Multi-Scalar Erosional Processes at Kisese II Rockshelter, Tanzania

Natural and anthropogenically induced soil erosion can cause serious loss of the archaeological record. Our work shows the value of multi-scalar geoarchaeological study when excavating and re-excavating rockshelters in a highly dynamic sedimentary environment where erosion is prominent. Here we present our work on Kisese II rockshelter, Tanzania, originally excavated in the 1950s and largely unpublished, that preserves an important Pleistocene-Holocene archaeological record integral to understanding the deep history of the Kondoa Rock-Art World Heritage Center. Unlike rockshelters in quiescent tectonic settings, like much of central Europe or South Africa, Kisese II exists in highly dynamic sedimentary environments associated with the active tectonics of the Great Rift Valley system exacerbated by human-induced environmental and climate change. We report on our 2017 and 2019 exploratory research that includes integrated regional-, landscape-, and site-scale geoarchaeological analyses of past and present sedimentary regimes and micromorphological analyses of the archaeological sediments. Historical records and aerial photographs document extensive changes in vegetation cover and erosional regimes since the 1920s, with drastic changes quantified between 1960 and 2019. Field survey points to an increased erosion rate between 2017 and 2019. To serve future archaeologists, heritage specialists, and local populations we combine our data in a geoarchaeological catena that includes soil, vegetation, fauna, and anthropogenic features on the landscape. At the site, micromorphological coupled with chronological analyses demonstrate the preservation of in situ Pleistocene deposits. Comparison of photographs from the 1956 and 2019 excavations show a maximum sediment loss of 68 cm in 63 years or >10% of >6-m-thick sedimentary deposit. In the studied area of the rockshelter we estimate ∼1 cm/yr of erosion, suggesting the ongoing removal of much of the higher archaeological sediments which, based on the coarse stratigraphic controls and chronology of the original Inskeep excavations, would suggest the loss of much of the archaeological record of the last ∼4000 years. These multi-scalar data are essential for the construction of appropriate mitigation strategies and further study of the remaining stratigraph

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer. © 2011 Macmillan Publishers Limited All rights reserved

URBAN CENTER. Una casa di vetro per le politiche urbane.

Nella cultura di governo della città, il termine "Urban Center" (o "Casa della città") designa una serie di strutture il cui denominatore comune risiede nello svolgimento di attività di servizio per le comunità urbane ai fini di soddisfare la crescente domenda di democrazia partecipativa e deliberativa nei processi di trasformazione degli insediamenti. Traendo spunto dalla storicizzazione del fenomeno e dal confronto tra i consolidati modelli statunitensi e le recenti esperienze in Italia, il volume si interroga sulla maturazione delle missioni dell' "Urban Center" nel passaggio da asettico spazio di informazione a luogo provilegiato per la costruzione trasparente di politiche urbane condivise. Il percorso logico del volume si sviluppa seguendo un fil rouge articolato in quattro parti. Il primo blocco si apre con due tematiche che costituiscono dialetticamente la cornice di riferimento entro cui può essere correttamente collocata la questione degli UC: l’urbanistica partecipata e il marketing urbano. Nella seconda parte attraverso lo studio di casi si ricostruisce il quadro delle articolate declinazioni statunitensi di Urban Center, consolidatesi in diversi decenni di storia. Sono strutture fortemente caratterizzate e autonome per stile, missioni, obiettivi, priorità, modalità operative, ma allo stesso tempo accomunate da un equilibrato mix di passione civile e pragmatismo professionale. Il terzo gruppo di saggi è dedicato alla condizione attuale e di prospettiva degli UC in Italia, delineando criticamente una sorta di “mappa dinamica” delle diverse strutture attivate e in divenire, caratterizzate per soggetti ispiratori, missioni “stili” e protagonismo degli attori coinvolti. Il cerchio delle riflessioni si chiude nella quarta parte discutendo la questione dell’innovazione di metodo per la costruzione di un UC sia attraverso la dimensione teoretica che le potenzialità operative. Testi in italiano e inglese di B. Monardo (curatore), M.C. Bizzarri, E. Carmagnani, M. Carta, F. Ceci, P. Colarossi, L. De Bonis, A. Dina, A. De Rossi, D. Filippi, A. Giorgi, P. Laconte, F. Lovato, L. J. Osmond, R. Shiffman, O Tommasi, A. Uttaro; postfazione di M. Ricci

One-Step Preservation of Phosphoproteins and Tissue Morphology at Room Temperature for Diagnostic and Research Specimens

BACKGROUND: There is an urgent need to measure phosphorylated cell signaling proteins in cancer tissue for the individualization of molecular targeted kinase inhibitor therapy. However, phosphoproteins fluctuate rapidly following tissue procurement. Snap-freezing preserves phosphoproteins, but is unavailable in most clinics and compromises diagnostic morphology. Formalin fixation preserves tissue histomorphology, but penetrates tissue slowly, and is unsuitable for stabilizing phosphoproteins. We originated and evaluated a novel one-step biomarker and histology preservative (BHP) chemistry that stabilizes signaling protein phosphorylation and retains formalin-like tissue histomorphology with equivalent immunohistochemistry in a single paraffin block. RESULTS: Total protein yield extracted from BHP-fixed, routine paraffin-embedded mouse liver was 100% compared to snap-frozen tissue. The abundance of 14 phosphorylated proteins was found to be stable over extended fixation times in BHP fixed paraffin embedded human colon mucosa. Compared to matched snap-frozen tissue, 8 phosphoproteins were equally preserved in mouse liver, while AMPKβ1 Ser108 was slightly elevated after BHP fixation. More than 25 tissues from mouse, cat and human specimens were evaluated for preservation of histomorphology. Selected tissues were evaluated in a multi-site, independent pathology review. Tissue fixed with BHP showed equivalent preservation of cytoplasmic and membrane cytomorphology, with significantly better nuclear chromatin preservation by BHP compared to formalin. Immunohistochemical staining of 13 non-phosphorylated proteins, including estrogen receptor alpha, progesterone receptor, Ki-67 and Her2, was equal to or stronger in BHP compared to formalin. BHP demonstrated significantly improved immunohistochemical detection of phosphorylated proteins ERK Thr202/Tyr204, GSK3-α/β Ser21/Ser9, p38-MAPK Thr180/Tyr182, eIF4G Ser1108 and Acetyl-CoA Carboxylase Ser79. CONCLUSION: In a single paraffin block BHP preserved the phosphorylation state of several signaling proteins at a level comparable to snap-freezing, while maintaining the full diagnostic immunohistochemical and histomorphologic detail of formalin fixation. This new tissue fixative has the potential to greatly facilitate personalized medicine, biobanking, and phospho-proteomic research