Brief Communication on MAGE-A4 and Coexpression of Cancer Testis Antigens in Metastatic Synovial Sarcomas: Considerations for Development of Immunotherapeutics.

Therapeutic options for synovial sarcoma (SyS) have not evolved for several decades and the efficacy of second-line treatments is very limited. The expression of a large family of proteins known as cancer testis antigens (CTAs) in SyS has spurred the development of targeted T-cell therapies currently in clinical trials, such as those aimed at melanoma-associated antigen (MAGE)-A4 and New York esophageal squamous cell carcinoma 1 (NY-ESO-1), which have shown promising clinical efficacy. Extensive knowledge of the prevalence of expression and coexpression of CTAs is critical to design T-cell therapies with optimal coverage of the patient population.

Investigating the prognostic impact of NY-ESO-1 expression and HLA subtypes in metastatic synovial sarcoma.

Background: To better understand the importance of the New York esophageal squamous cell carcinoma 1 (NY-ESO-1) and human leukocyte antigen (HLA) subtypes in treatment decision-making, further investigation of their prevalence and prognostic impact among patients with metastatic synovial sarcoma (mSS) is needed.

Patients And Methods: This was a retrospective clinico-biological cohort study of adults with mSS. Patient data were collected from the French Sarcoma Group NetSARC database and supplemented by electronic medical records.

Neuropilin 2 and soluble neuropilin 2 in neuroendocrine neoplasms.

Neuropilin 2 (NRP2), a transmembrane non-tyrosine kinase receptor, has been described as a potential critical player in the tumourigenesis of several solid cancers and particularly in neuroendocrine neoplasms (NENs). A soluble form of NRP2 (sNRP2) has been previously described and corresponds to a truncated splice isoform. Its prognostic value has never been studied in NEN.

Comprehensive Immune Profiling Unveils a Subset of Leiomyosarcoma with "Hot" Tumor Immune Microenvironment.

To investigate the immune biomarker in Leiomyosarcoma (LMS), which is rare and recognized as an immune cold cancer showing a poor response rate (<10%) to immune checkpoint inhibitors (ICIs). However, durable response and clinical benefit to ICIs has been observed in a few cases of LMS, including, but not only, LMS with tertiary lymphoid structure (TLS) structures. We used comprehensive transcriptomic profiling and a deconvolution method extracted from RNA-sequencing gene expression data in two independent LMS cohorts, the International Cancer Genome Consortium (ICGC, N = 146) and The Cancer Genome Atlas (TCGA, N = 75), to explore tumor immune microenvironment (TIME) in LMS.

Refining Prognosis in Localized Gastrointestinal Stromal Tumor: Clinical Significance of Phosphatase and Tensin Homolog Low Expression and Gene Loss.

Purpose: To investigate the use of PTEN biomarker to improve prognostic stratification in patients with localized gastrointestinal stromal tumor (GIST).

Methods: PTEN expression and genomic analysis were performed on two independent GIST-60 (n = 60) and GIST-100 (n = 100) cohorts, respectively.

Results: PTEN expression was significantly lower in patients with local and metastatic recurrent tumor compared with those with no recurrence ( = .

SELNET clinical practice guidelines for bone sarcoma.

Bone sarcoma are infrequent diseases, representing < 0.2% of all adult neoplasms. A multidisciplinary management within reference centers for sarcoma, with discussion of the diagnostic and therapeutic strategies within an expert multidisciplinary tumour board, is essential for these patients, given its heterogeneity and low frequency.

Neuropilin-2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors.

The identification of novel regulators of tumor progression is a key challenge to gain knowledge on the biology of small intestinal neuroendocrine tumors (SI-NETs). We recently identified the loss of the axon guidance protein semaphorin 3F as a protumoral event in SI-NETs. Interestingly the expression of its receptor neuropilin-2 (NRP-2) was still maintained.

Volatile element evolution of chondrules through time.

Chondrites and their main components, chondrules, are our guides into the evolution of the Solar System. Investigating the history of chondrules, including their volatile element history and the prevailing conditions of their formation, has implications not only for the understanding of chondrule formation and evolution but for that of larger bodies such as the terrestrial planets. Here we have determined the bulk chemical composition-rare earth, refractory, main group, and volatile element contents-of a suite of chondrules previously dated using the Pb-Pb system.

Combinatorial Treatment with mTOR Inhibitors and Streptozotocin Leads to Synergistic and Antitumor Effects in Insulinoma Cells.

Streptozotocin-based chemotherapy is the first-line chemotherapy recommended for advanced pancreatic neuroendocrine tumors (pNETs), whereas targeted therapies, including mTOR inhibitors, are available in second-line treatment. Unfortunately, objective response rates to both treatments are limited. Because mTOR pathway activation, commonly observed in pNETs, has been reported as one of the major mechanisms accounting for chemoresistance, we investigated the potential benefit of mTOR inhibition combined with streptozotocin treatment in a subset of pNETs, namely insulinomas.

Early formation of planetary building blocks inferred from Pb isotopic ages of chondrules.

The most abundant components of primitive meteorites (chondrites) are millimeter-sized glassy spherical chondrules formed by transient melting events in the solar protoplanetary disk. Using Pb-Pb dates of 22 individual chondrules, we show that primary production of chondrules in the early solar system was restricted to the first million years after the formation of the Sun and that these existing chondrules were recycled for the remaining lifetime of the protoplanetary disk. This finding is consistent with a primary chondrule formation episode during the early high-mass accretion phase of the protoplanetary disk that transitions into a longer period of chondrule reworking.

mTOR inhibitors activate PERK signaling and favor viability of gastrointestinal neuroendocrine cell lines.

mTOR and Unfolded Protein Response (UPR) are two signaling pathways frequently activated in cancer cells. The mTOR pathway has been shown to be up-regulated in most gastroenteropancreatic neuroendocrine tumors. In contrast, little is known about the UPR status in neoplastic neuroendocrine cells.

Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma.

Objective: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy.

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling.

The complex biochemical effects of RAF inhibitors account for both the effectiveness and mechanisms of resistance to these drugs, but a unified mechanistic model has been lacking. Here we show that RAF inhibitors exert their effects via two distinct allosteric mechanisms. Drug resistance due to dimerization is determined by the position of the αC helix stabilized by inhibitor, whereas inhibitor-induced RAF priming and dimerization are the result of inhibitor-induced formation of the RAF/RAS-GTP complex.

Pb-Pb dating of individual chondrules from the CB chondrite Gujba: Assessment of the impact plume formation model.

The CB chondrites are metal-rich meteorites with characteristics that sharply distinguish them from other chondrite groups. Their unusual chemical and petrologic features and a young formation age of bulk chondrules dated from the CB chondrite Gujba are interpreted to reflect a single-stage impact origin. Here, we report high-precision internal isochrons for four individual chondrules of the Gujba chondrite to probe the formation history of CB chondrites and evaluate the concordancy of relevant short-lived radionuclide chronometers.

Prediction of response to everolimus in neuroendocrine tumors: evaluation of clinical, biological and histological factors.

Objectives Several targeted therapies are available for metastatic neuroendocrine tumours (NETs) but no predictive factor of response to these treatments has been identified yet. Our aim was to identify and evaluate clinical, biological, histological and functional markers of response to everolimus. Methods We retrospectively reviewed 53 patients with NETs treated with everolimus (68 % in clinical trials).

The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors.

Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs.

Mechanisms of local invasion in enteroendocrine tumors: identification of novel candidate cytoskeleton-associated proteins in an experimental mouse model by a proteomic approach and validation in human tumors.

Small-intestinal neuroendocrine tumors (SI-NETs) are defined as locally invasive only after extension to the muscularis propria. To gain further insight into the molecular mechanisms, we applied a proteomic approach to an orthotopic xenograft model to identify candidate proteins evaluable in human SI-NETs. After grafting STC-1 neuroendocrine tumor cells on the caecum of nude mice, comparative proteomic studies were performed between the pre-invasive and the invasive stages, respectively 2 and 8 weeks after grafting.

Antitumor effect of everolimus in preclinical models of high-grade gastroenteropancreatic neuroendocrine carcinomas.

Background/aims: While the range of therapeutic options for well-differentiated gastroenteropancreatic neuroendocrine tumors has recently increased with the emergence of targeted therapies, such as mTOR inhibitors, there is no recent progress in the treatment of poorly differentiated neuroendocrine carcinomas (PDNECs). Since PDNECs have been shown to strongly express mTOR pathway components, the aim of the present study was to assess the antitumor effect of the mTOR inhibitor everolimus in preclinical models of PDNECs.

Methods: The expression of mTOR pathway components and their response to everolimus were assessed in two neuroendocrine cell lines: STC-1 and GluTag.

Preservation of mucus in situ in rat colon.

Mucus, a hydrated complex consisting mainly of glycoproteins, forms a layer over the epithelial surface of the gastrointestinal tract. The usual preparative procedures for histological and scanning electron microscopic examination of the gut result in the loss or distortion of this mucus layer. Careful evaluation of two new methods reported to stabilize the mucus layer showed that acrolein vapor did not provide adequate fixation, but application of heat-inactivated antiserum raised in rabbits against rat colon mucus reliably preserved a continuous layer closely adherent to the epithelium.

Location of bacteria in the mid-colon of the rat.

The distribution of microorganisms in the mid-colon of the rat was studied by light and scanning electron microscopy. An antiserum against rat colon mucus was used to stabilize the mucus in situ. In samples not incubated with antiserum, the mucus disintegrated and contracted into patchy strands only partly covering the luminal surface of the colon.