STAT3 can serve as a hit in the process of malignant transformation of primary cells

The transcription factor signal transducer and activator of transcription 3 (STAT3) acts downstream of many pro-oncogenic signals, including cytokines, growth factors and oncogenes, and is accordingly constitutively active in a wide variety of tumors that often become addicted to it. Moreover, STAT3 is a key player in mediating inflammation-driven tumorigenesis, where its aberrant continuous activation is typically triggered by local or systemic production of the pro-inflammatory cytokine IL-6. We recently showed that mouse embryonic fibroblasts (MEFs) derived from STAT3C k/in mice, which express physiological levels of the constitutively active mutant STAT3C, display features of transformed cells such as increased proliferation, resistance to apoptosis and senescence, and aerobic glycolysis. Here, we show that pre-existing constitutively active STAT3 is sufficient to prime primary MEFs for malignant transformation upon spontaneous immortalization. Transformation is strictly STAT3-dependent and correlates with high resistance to apoptosis and enhanced expression of anti-apoptotic/pro-survival genes. Additionally, hypoxia inducible factor (HIF)-1α level is elevated by twofold and contributes to STAT3 oncogenic activity by supporting high rates of aerobic glycolysis. Thus, constitutively active STAT3, an accepted essential factor for tumor growth/progression, can also act as a first hit in multistep carcinogenesis; this ability to predispose cells to malignant transformation may be particularly relevant in the pro-oncogenic niche represented by chronically inflamed tissues

Amyloid detection and typing yield of skin biopsy in systemic amyloidosis and polyneuropathy.

OBJECTIVE Disease-modifying therapies are available for amyloidosis but are ineffective if end-organ damage is severe. As small fiber neuropathy is an early and common feature of amyloidosis, we assessed detection and typing yield of skin biopsy for amyloid in patients with confirmed systemic amyloidosis and neuropathic symptoms. METHODS In this case-control study, patients with transthyretin and light chain amyloidosis (ATTRv, ATTRwt, and AL) were consecutively recruited. They were sex and age-matched to three control groups (1) non-neuropathic controls (NNC), (2) monoclonal gammopathy of undetermined significance (MGUS), and (3) other neuropathic disease controls (ONC). Patients underwent a double 3 mm skin biopsy in proximal and distal leg. Amyloid index and burden, protein typing by immuno-electron microscopy, intraepidermal nerve fiber density, electroneuromyography, and clinical characteristics were analyzed. RESULTS We studied 15 subjects with confirmed systemic amyloidosis, 20 NNC, 18 MGUS, and 20 ONC. Amyloid was detected in 100% of patients with amyloidosis (87% in ankle and 73% in thigh). It was not detected in any of the control groups. A small fiber neuropathy was encountered in 100% of amyloidosis patients, in 80% of MGUS, and in 78% of ONC. Amyloid burden was higher in ATTRv, followed by AL and ATTRwt. The ultrastructural examination allowed the identification of the precursor protein by immunotyping in most of the cases. INTERPRETATION Skin biopsy is a minimally invasive test with optimal sensitivity for amyloid. It allows amyloid typing by electron microscope to identify the precursor protein. The diagnostic work up of systemic amyloidosis should include a skin biopsy

T-Cell Leukemia/Lymphoma 1 (TCL1): An Oncogene Regulating Multiple Signaling Pathways

Almost 30 years ago, Carlo Croce's group discovered the T-Cell Leukemia/Lymphoma 1A oncogene (TCL1A or TCL1). TCL1 protein is normally expressed in fetal tissues and early developmental stage lymphocytes. Its expression is deregulated in chronic lymphocytic leukemia (B-CLL) and most lymphomas. TCL1 plays a central role in lymphomagenesis as a co-activator of AKT kinases and other recently elucidated interacting protein partners. These include ATM, HSP70 and TP63, which were all confirmed as binding partners of TCL1 from co-immunoprecipitation experiments utilizing endogenously expressed proteins. The nature of these interactions highlighted the role of TCL1 in enhancing multiple signaling pathways, including PI3K and NF-κB. Based on its role in the aforementioned pathways and, despite the lack of a well-defined enzymatic activity, TCL1 is considered a potential therapeutic target for TCL1-positive hematological malignancies. This perspective will provide an overview of TCL1A and its interacting partners

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer

FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model

Background: Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet. Methods: Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)-a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo. Results: We show that FTY720 significantly suppressed MM cell viability and anchorage-independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity. Conclusions: Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment

Malignant pleural mesothelioma incidence and survival in the Republic of Ireland 1994-2009.

OBJECTIVE: Malignant pleural mesothelioma (MPM) is a rare malignancy associated with exposure to asbestos. The protracted latent period of MPM means that its incidence has continued to rise across Europe after the introduction of restrictions on asbestos use. In order to obtain a clearer indication of trends in the Republic of Ireland (ROI), incidence and survival were assessed based on all MPM cases reported since the establishment of the National Cancer Registry of Ireland (NCR). METHODS: NCR recorded 337 MPM diagnoses in the ROI during 1994-2009. Survival was assessed for all cases diagnosed with adequate follow-up (n=330). Crude and European age-standardized incidence rates were calculated for all cases and for 4-year periods. A Cox model of observed (all-cause) survival was used to generate hazard ratios for the effect of: gender; age at diagnosis; diagnosis cohort; region of residence; histological type; and tumour stage. Single P-values for the variables indicated were calculated using either a stratified log-rank test or stratified trend test. RESULTS: Over the study period the age-standardized MPM incidence in the ROI rose from 4.98cases per million (cpm) to 7.24cpm. The 1-year survival rate for all MPM cases was 29.6% (CI 24.7-34.6%). Excess mortality risk was associated with age at diagnosis (75-89 yrs vs. 55-64 yrs, HR 1.88, 95% CI 1.35-2.63, P CONCLUSION: MPM incidence and mortality continued to rise in the ROI after the restrictions on asbestos use and the predictors of survival detected in this study are broadly consistent with those identified for other countries

Studi Potensi Jumlah Penumpang Bus Pemadu Moda Rute Malang – Bandar Udara Juanda Pp

Bandar Udara Malang yang belum melayani banyak tujuan penerbangan membuat pengguna moda pesawat memilih Bandar Udara Juanda. Disisi lain angkutan yang melayani rute Malang-Juanda PP hanya angkutan travel. Untuk itu dibutuhkan moda lain yang lebih ekonomis dan memiliki kapasitas lebih banyak dibandingkan angkutan travel. Bus pemadu moda adalah moda alternatif yang dapat memenuhi kebutuhan tersebut.Pengumpulan data dilakukan dengan penyebaran kuisioner karakteristik sosial-ekonomi, karakteristik perjalanan serta kuisioner dengan teknik penyusunan stated preference. Stated preference memiliki atribut biaya perjalanan, waktu tempuh dan frekuensi keberangkatan. Sedangkan untuk prediksi tarif bus pemadu moda yang direncanakan diperoleh dari perhitungan BOK. Tarif yang telah diperoleh dari perhitungan BOK dibandingkan dengan nilai ATP dan WTP yang diperoleh dari kuisioner yang telah disebarkan. Sehingga didapatkan tarif ideal yang akan diberlakukan apabila bus pemadu moda tersebut direalisasikan.Setelah melakukan perhitungan tarif berdasarkan BOK diperoleh tarif sebesar Rp 23.374,- serta berdasarkan ATP dan WTP diperoleh tarif sebesar Rp 43.675,-. Dengan demikian perkiraan awal tarif bus pemadu moda sebesar Rp 40.000,- dapat diberlakukan. Hasil dari pemodelan pemilihan moda dengan metode stated preference untuk selisih biaya perjalanan Malang-Juanda: dan Juanda-Malang : , untuk selisih waktu tempuh perjalanan () rute Malang-Juanda : dan rute Juanda-Malang : , sedangkan untuk selisih Frekuensi Keberangkatan () rute Malang-Juanda : dan rute Juanda-Malang : .Potensi perpindahan pengguna travel ke bus pemadu moda rute Malang-Juanda sebanyak 705 orang per hari (83,97%). Sedangkan untuk rute Juanda-Malang sebanyak 1516 orang per hari (90,24%)

Increase of Parkin and ATG5 plasmatic levels following perinatal hypoxic‐ischemic encephalopathy

Brain injury at birth is an important cause of neurological and behavioral disorders. Hypoxic‐ischemic encephalopathy (HIE) is a critical cerebral event occurring acutely or chronically at birth with high mortality and morbidity in newborns. Therapeutic strategies for the prevention of brain damage are still unknown, and the only medical intervention for newborns with moderate‐to‐severe HIE is therapeutic hypothermia (TH). Although the neurological outcome depends on the severity of the initial insult, emerging evidence suggests that infants with mild HIE who are not treated with TH have an increased risk for neurodevelopmental impairment; in the current clinical setting, there are no specific or validated biomarkers that can be used to both correlate the severity of the hypoxic insult at birth and monitor the trend in the insult over time. The aim of this work was to examine the presence of autophagic and mitophagic proteins in bodily fluids, to increase knowledge of what, early at birth, can inform therapeutic strategies in the first hours of life. This is a prospective multicentric study carried out from April 2019 to April 2020 in eight third‐level neonatal intensive care units. All participants have been subjected to the plasma levels quantification of both Parkin (a protein involved in mitophagy) and ATG5 (involved in autophagy). These findings show that Parkin and ATG5 levels are related to hypoxic‐ischemic insult and are reliable also at birth. These observations suggest a great potential diagnostic value for Parkin evaluation in the first 6 h of life

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients