Heteroannular dilithiation of trovacene, (η 7 -C 7 H 7 )V(η 5 -C 5 H 5 ) (1 • ), and subsequent reaction with the respective dichlorosilane yielded the [1]silatrovacenophanes (η 7 -C T 7 H 6 )V(η 5 -C 5 H 4 S UiR 2 ) (2 • , R ϭ Ph; 3 • , R ϭ Me) and the [2]silatrovacenophane (η 7 -C T 7 H 6 )V(η 5 -C 5 H 4 SiMe 2 S UiMe 2 ) (4 • ). Structural studies by X-ray diffraction revealed sandwich tilt angles of 17.3°(2 • ) and 3.8°(4 • ), respectively, and considerable strain in the ring-link-ring region. EPR spectroscopy responds to these distortions in that the g-tensor is tetragonal (g x ϭ g y ϶ g z ) for 4 • but rhombic (g x ϶ g y ϶ g z ) for 2 • and 3 • . With increasing tilt, ϽgϾ increases slightly towards g fs ϭ 2.0023 and a( 51 V) decreases, the latter response to tilting being Trovacenchemie. 10 [1] Die [1]-und [2]Silatrovacenophane (η 7 -C T 7 H 6 )V(η 5 -C 5 H 4 S UiR 2 ) und (η 7 -C T 7 H 6 )V(η 5 -C 5 H 4 SiR 2 S UiR 2 (R ‫؍‬ Me, Ph): Synthese, Struktur und Ringöffnung Inhaltsübersicht. Heteroannulare Dilithiierung von Trovacen, (η 7 -C 7 H 7 )V(η 5 -C 5 H 5 ) (1 • ), und anschließende Reaktion mit den entsprechenden Dihalogensilanen lieferte die [1]Silatrovacenophane (η 7 -C T 7 H 6 )V(η 5 -C 5 H 4 S UiR 2 ) (2 • , R ϭ Ph; 3 • , R ϭ Me) und das [2]Silatrovacenophan (η 7 -C T 7 H 6 )V(η 5 -C 5 H 4 SiMe 2 S UiMe 2 ) (4 • ). Strukturuntersuchungen mittels Röntgenbeugung ergaben Sandwich-Kippwinkel von 17.3°(2 • ) und 3.8°(4 • ) und beträchtliche Spannung im Ring-Brücke-Ring-Bereich. Die EPR-Spektren zeigen diese Verzerrungen an, indem der g-Tensor für 4 • tetragonal (g x ϭ g y ϶ g z ), für 2 • und 3 • hingegen rhombisch (g x ϶ g y ϶ g z ) ist. Mit zunehmender

A microbial polysaccharide (glucuronoxylomannan (GXM)) exerts potent immunosuppression by direct engagement to immunoinhibitory receptor FcγRIIB. Activation of FcγRIIB by GXM leads to the recruitment and phosphorylation of SHIP that prevents IκBα activation. The FcγRIIB blockade inhibits GXM-induced IL-10 production and induces TNF-α secretion. GXM quenches LPS-induced TNF-α release via FcγRIIB. The addition of mAb to GXM reverses GXM-induced immunosuppression by shifting recognition from FcγRIIB to FcγRIIA. These findings indicate a novel mechanism by which microbial products can impair immune function through direct stimulation of an inhibitory receptor. Furthermore, our observations provide a new mechanism for the ability of specific Ab to reverse the immune inhibitory effects of certain microbial products.

T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological disorder that results from the clonal transformation of T‐cell precursors. Phosphatidylinositol 3‐kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β‐catenin signaling pathways play a crucial role in T‐cell development and in self‐renewal of healthy and leukemic stem cells. Notably, β‐catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T‐ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β‐catenin pathway through ICG‐001, a CBP/β‐catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK‐474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T‐ALL cells. ICG‐001 and ZSTK‐474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/β‐catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐ALL settings.

The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

The isolation of four new variants or serotypes of avian infectious bronchitis virus in Italy is reported. The antigenic characteristics of these strains were investigated by cross-neutralization tests with the new isolates, Fa 6881/97, AZ 27/98, AZ 20/97, and BS 216/01; two of the most common European serotypes, AZ 23/74 and CR 88121 (793B); and the classic Massachusetts M41 serotype in association with a panel of 17 specific antisera. On the basis of the results obtained, the new isolates show relevant serologic differences. In fact, the four isolates were not neutralized by antisera against the most common European and American serotypes; the AZ 20/97 isolate was partially neutralized by FA 6881/97 antiserum but not reciprocally. The closely related Fa 6881/97 and AZ 27/98 isolates can be considered rather diffused in our country because they have been isolated over 20 times in the last 3 yr in different parts of Italy. On the contrary, the AZ 20/97 and BS 216/01 isolates were reported only once so far. The reverse transcription-polymerase chain reaction showed that Fa 6881/97 isolate is related to 793B isolate, whereas AZ 27/98 and BS 216/01 isolates appeared not to be related to the most common European and Massachusetts serotypes.

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that comprises 10–15% of pediatric and ~25% of adult ALL cases. Although the curative rates have significantly improved over the past 10 years, especially in pediatric patients, T-ALL remains a challenge from a therapeutic point of view, due to the high number of early relapses that are for the most part resistant to further treatment. Considerable advances in the understanding of the genes, signaling networks, and mechanisms that play crucial roles in the pathobiology of T-ALL have led to the identification of the key drivers of the disease, thereby paving the way for new therapeutic approaches. PTEN is critical to prevent the malignant transformation of T-cells. However, its expression and functions are altered in human T-ALL. PTEN is frequently deleted or mutated, while PTEN protein is often phosphorylated and functionally inactivated by casein kinase 2. Different murine knockout models recapitulating the development of T-ALL have demonstrated that PTEN abnormalities are at the hub of an intricate oncogenic network sustaining and driving leukemia development by activating several signaling cascades associated with drug-resistance and poor outcome. These aspects and their possible therapeutic implications are highlighted in this review.

SummaryA purified microbial capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan (GXM), induces Fas ligand (FasL) upregulation on macrophages and, as a consequence, apoptosis of lymphocytes. The mechanisms that lead to lymphocyte apoptosis in both in vitro and in vivo systems were investigated by cytofluorimetric analysis and Western blotting experiments. Caspase 8 cleaves caspase 3 in two different pathways: directly as well as indirectly by activation of Bcl-2 interacting domain, which initiates caspase 9 cleavage. Therefore, the caspase 8 and caspase 9 pathways cooperate in an amplification loop for efficient cell death, and noteworthily we provide evidence that they are both activated in one single cell. Furthermore, both activation of GXM-mediated caspase 8 and apoptosis were also found in in vivo systems in an experimental model of murine candidiasis. Collectively, our data show that GXM-induced apoptosis involves, in a single cell, a cross-talk between extrinsic and intrinsic pathways. Such a finding offers opportunities for the therapeutic usage of this polysaccharide in appropriate clinical settings for taming T-cell responses.