Uterine Sarcomas: An Updated Overview Part 2: Endometrial Stromal Tumor

Uterine sarcomas (USs) account for 3–9% of uterine malignant neoplasia and about 5% of all gynaecologic malignancies. Despite their low prevalence, these tumors stimulate a great interest because of their aggressiveness, poor prognosis and high mortality rate. According to the last world health organization (WHO) classification and the International Federation of gynecology and obstetrics committee (FIGO) staging, USs are categorized as pure mesenchymal tumors (endometrial stromal sarcoma, leiomyosarcoma and undifferentiated uterine) and mixed tumors (carcinosarcoma and adenosarcoma). Due to their non-specific signs and symptoms, USs are commonly diagnosed in advanced stage, more often after surgery for a suspected leiomyoma. Although surgery followed by adjuvant therapies represent the common choices for USs, they show poor efficacy due to the early occurrence of metastasis, and the high resistance of tumors to radio-and chemotherapy. Presently, specific expression profiles and new cytotoxic agents are under investigation. In these reviews, we summarized clinical and pathological features, imaging characteristics, therapeutic approaches, genomic and molecular aberration associated with smooth muscle neoplasia (Part 1) and endometrial stromal neoplasia (Part 2); the goal is to understand the biology and the molecular signature of these tumors, in order to focus on their best management

Uterine Sarcomas: An Updated Overview. Part 1: Smooth Muscle Tumors

Uterine sarcomas (USs) account for 3–9% of uterine malignant neoplasia and about 5% of all gynaecologic malignancies. Despite their low prevalence, these tumors stimulate a great interest because of their aggressiveness, poor prognosis and high mortality rate. According to the last World Health Organization (WHO) classification and the International Federation of Gynecology and Obstetrics Committee (FIGO) staging, USs are categorized as pure mesenchymal tumors (endometrial stromal sarcoma, leiomyosarcoma and undifferentiated uterine), and mixed tumors (carcinosarcoma and adenosarcoma). Due to their non-specific signs and symptoms, USs are commonly diagnosed in advanced stage, more often after surgery for a suspected leiomyoma. Although surgery followed by adjuvant therapies represent the common choices for USs, they show poor efficacy due to the early occurrence of metastasis, and the high resistance of tumors to radio-and chemotherapy. Presently, specific expression profiles and new cytotoxic agents are under investigation. In these reviews, we summarized clinical and pathological features, imaging characteristics, therapeutic approaches, genomic and molecular aberration associated with smooth muscle neoplasia (Part 1) and endometrial stromal neoplasia (Part 2); the goal is to understand the biology and the molecular signature of these tumors, in order to focus on their best management

Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit

BubR1 kinase is essential for the mitotic checkpoint and also for kinetochores to establish microtubule attachments. In this study, we report that BubR1 is phosphorylated in mitosis on four residues that differ from sites recently reported to be phosphorylated by Plk1 (Elowe, S., S. Hummer, A. Uldschmid, X. Li, and E.A. Nigg. 2007. Genes Dev. 21:2205–2219; Matsumura, S., F. Toyoshima, and E. Nishida. 2007. J. Biol. Chem. 282:15217–15227). S670, the most conserved residue, is phosphorylated at kinetochores at the onset of mitosis and dephosphorylated before anaphase onset. Unlike the Plk1-dependent S676 phosphorylation, S670 phosphorylation is sensitive to microtubule attachments but not to kinetochore tension. Functionally, phosphorylation of S670 is essential for error correction and for kinetochores with end-on attachments to establish tension. Furthermore, in vitro data suggest that the phosphorylation status of BubR1 is important for checkpoint inhibition of the anaphase-promoting complex/cyclosome. Finally, RNA interference experiments show that Mps1 is a major but not the exclusive kinase that specifies BubR1 phosphorylation in vivo. The combined data suggest that BubR1 may be an effector of multiple kinases that are involved in discrete aspects of kinetochore attachments and checkpoint regulation

First constraints of dense molecular gas at z~7.5 from the quasar P\=oniu\=a'ena

We report the detection of CO(6-5) and CO(7-6) and their underlying continua from the host galaxy of quasar J100758.264+211529.207 (P\=oniu\=a'ena) at z=7.5419, obtained with the NOrthern Extended Millimeter Array (NOEMA). P\=oniu\=a'ena belongs to the HYPerluminous quasars at the Epoch of ReionizatION (HYPERION) sample of 17 $z>6$ quasars selected to be powered by supermassive black holes (SMBH) which experienced the fastest mass growth in the first Gyr of the Universe. The one reported here is the highest-redshift measurement of the cold and dense molecular gas to date. The host galaxy is unresolved and the line luminosity implies a molecular reservoir of $\rm M(H_2)=(2.2\pm0.2)\times 10^{10}$ $\rm M_\odot$, assuming a CO spectral line energy distribution typical of high-redshift quasars and a conversion factor $\alpha=0.8$ $\rm M_{\odot} (K\,km \, s^{-1} \,pc^{2})^{-1}$. We model the cold dust spectral energy distribution (SED) to derive a dust mass of M$_{\rm dust} =(2.1\pm 0.7)\times 10^8$ $\rm M_\odot$, and thus a gas to dust ratio $\sim100$. Both the gas and dust mass are not dissimilar from the reservoir found for luminous quasars at $z\sim6$. We use the CO detection to derive an estimate of the cosmic mass density of $\rm H_2$, $\Omega_{H_2} \simeq 1.31 \times 10^{-5}$. This value is in line with the general trend suggested by literature estimates at $z < 7$ and agrees fairly well with the latest theoretical expectations of non-equilibrium molecular-chemistry cosmological simulations of cold gas at early times.Comment: Submitted to ApJ Letter

Accurate dust temperature and star formation rate in the most luminous z>6z>6 quasar in the HYPerluminous quasars at the Epoch of ReionizatION (HYPERION) sample

We present ALMA Band 9 continuum observation of the ultraluminous quasi-stellar object (QSO) SDSS J0100+2802, providing a $\sim 10\sigma$ detection at $\sim 670$ GHz. SDSS J0100+2802 is the brightest QSO with the most massive super massive black hole (SMBH) known at $z>6$, and we study its dust spectral energy distribution in order to determine the dust properties and the star formation rate (SFR) of its host-galaxy. We obtain the most accurate estimate so far of the temperature, mass and emissivity index of the dust, having $T_{\rm dust}=48.4\pm2.3$ K, $M_{\rm dust}=(2.29\pm0.83)\times 10^7$ M$_\odot$, $\beta=2.63\pm 0.23$. This allows us to measure the SFR with the smallest statistical error for this QSO, SFR$=265\pm 32\ \rm M_\odot yr^{-1}$. Our results enable us to evaluate the relative growth of the SMBH and host galaxy of J0100+2802, finding that the SMBH is dominating the process of BH-galaxy growth in this QSO at $z=6.327$, when the Universe was $865$ Myr old. Such unprecedented constraints on the host galaxy SFR and dust temperature can only be obtained through high frequency observations, and highlight the importance of ALMA Band 9 to obtain a robust overview of the build-up of the first quasars' host galaxies at $z>6$.Comment: 10 pages, 4 figures, 1 table. Accepted for publication in ApJ

PhotoAffinity bits : a photoaffinity-based fragment screening platform for efficient identification of protein ligands

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space, however, it remains challenging to develop techniques that are both sufficiently high-throughput and sensitive. We present a fragment screening platform, termed PhABits (PhotoAffinity Bits), which utilises a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. We envision that the PhABits will be widely applicable to novel protein targets, identifying starting points in the development of therapeutic

Reactive fragments targeting carboxylate residues employing direct to biology, high-throughput chemistry

The screening of covalent or ‘reactive’ fragment libraries against proteins is becoming an integral approach in hit identification, enabling the development of targeted covalent inhibitors and tools. To date, reactive fragment screening has been limited to targeting cysteine residues, thus restricting applicability across the proteome. Carboxylate residues present a unique opportunity to expand the accessible residues due to high proteome occurrence (∼12%). Herein, we present the development of a carboxylate-targeting reactive fragment screening platform utilising 2-aryl-5-carboxytetrazole (ACT) as the photoreactive functionality. The utility of ACT photoreactive fragments (ACT-PhABits) was evaluated by screening a 546-membered library with a small panel of purified proteins. Hits identified for BCL6 and KRASG12D were characterised by LC-MS/MS studies, revealing the selectivity of the ACT group. Finally, a photosensitised approach to ACT activation was developed, obviating the need for high energy UV-B light

Efficient ligand discovery using sulfur(VI) fluoride reactive fragments

Sulfur(VI) fluorides (SFs) have emerged as valuable electrophiles for the design of "beyond-cysteine" covalent inhibitors and offer potential for expansion of the liganded proteome. Since SFs target a broad range of nucleophilic amino acids, they deliver an approach for the covalent modification of proteins without requirement for a proximal cysteine residue. Further to this, libraries of reactive fragments present an innovative approach for the discovery of ligands and tools for proteins of interest by leveraging a breadth of mass spectrometry analytical approaches. Herein, we report a screening approach that exploits the unique properties of SFs for this purpose. Libraries of SF-containing reactive fragments were synthesized, and a direct-to-biology workflow was taken to efficiently identify hit compounds for CAII and BCL6. The most promising hits were further characterized to establish the site(s) of covalent modification, modification kinetics, and target engagement in cells. Crystallography was used to gain a detailed molecular understanding of how these reactive fragments bind to their target. It is anticipated that this screening protocol can be used for the accelerated discovery of "beyond-cysteine" covalent inhibitors

Complement membrane attack complex is an immunometabolic regulator of NLRP3 activation and IL-18 secretion in human macrophages

The complement system is an ancient and critical part of innate immunity. Recent studies have highlighted novel roles of complement beyond lysis of invading pathogens with implications in regulating the innate immune response, as well as contributing to metabolic reprogramming of T-cells, synoviocytes as well as cells in the CNS. These findings hint that complement can be an immunometabolic regulator, but whether this is also the case for the terminal step of the complement pathway, the membrane attack complex (MAC) is not clear. In this study we focused on determining whether MAC is an immunometabolic regulator of the innate immune response in human monocyte-derived macrophages. Here, we uncover previously uncharacterized metabolic changes and mitochondrial dysfunction occurring downstream of MAC deposition. These alterations in glycolytic flux and mitochondrial morphology and function mediate NLRP3 inflammasome activation, pro-inflammatory cytokine release and gasdermin D formation. Together, these data elucidate a novel signalling cascade, with metabolic alterations at its center, in MAC-stimulated human macrophages that drives an inflammatory consequence in an immunologically relevant cell type