Diabetes Mellitus and Reprogrammed Glucose Metabolism in Pancreatic Cancer: Features for Clinical Translation

The reprogrammed metabolism of cancer cells underlies the shift of glucose energetics from the highly efficient oxidative phosphorylation to the less efficient aerobic glycolysis, the Warburg effect. This phenomenon, with the activation of the glutamine pathway, advantage survival and proliferation of pancreatic ductal adenocarcinoma (PDAC) cells, which live in an adverse hypoxic and nutrient restricted microenvironment. In PDAC, glucose metabolic alterations occur also at the whole organism, diabetes mellitus (DM) being diagnosed in approximately 60% to 80% of patients. The association beteen PDAC and DM is a dual face phenomenon, DM being both a risk factor for and a consequence of this tumor type. Data from epidemiology indicate that longstanding DM increases PDAC risk 1.5 to 2.0 fold, probably because of the pro-proliferative effects of hyperinsulinemia. By contrast early onset DM, i.e. diabetes diagnosed no more than two years prior to cancer diagnosis, is considered a consequence of PDAC. Secondary DM is due to complex interactions between tumor cells, tumor microenvironment and pancreatic endocrine cells. In this scenario the role of the inflammatory S100A8 calcium binding protein, matrix metalloproteinases, Vanin1 or amylin has been experimentally demonstrated. However, the efforts made to translate in the clinical practice any individual new poteantial biomarker failed, because none reached enough sensitivity and specificity to be considered a reliable biomarker to diagnose PDAC even in high risk subjects as those with new onset DM. Therefore the identification and clinical validation of new biomarkers remains a challenge for future studies

Pancreatic cancer-derived S-100A8 N-terminal peptide: a diabetes cause?

BACKGROUND: Our aim was to identify the pancreatic cancer diabetogenic peptide. METHODS: Pancreatic tumor samples from patients with (n=15) or without (n=7) diabetes were compared with 6 non-neoplastic pancreas samples using SDS-PAGE. RESULTS: A band measuring approximately 1500 Da was detected in tumors from diabetics, but not in neoplastic samples from non-diabetics or samples from non-neoplastic subjects. Sequence analysis revealed a 14 amino acid peptide (1589.88 Da), corresponding to the N-terminal of the S100A8. At 50 nmol/L and 2 mmol/L, this peptide significantly reduced glucose consumption and lactate production by cultured C(2)C(12) myoblasts. The 14 amino acid peptide caused a lack of myotubular differentiation, the presence of polynucleated cells and caspase-3 activation. CONCLUSIONS: The 14 amino acid peptide from S100A8 impairs the catabolism of glucose by myoblasts in vitro and may cause hyperglycemia in vivo. Its identification in biological fluids might be helpful in diagnosing pancreatic cancer in patients with recent onset diabetes mellitus

Pancreatic cancer-associated diabetes mellitus: an open field for proteomic applications.

Background: Diabetes mellitus is associated with pancreatic cancer in more than 80% of the cases. Clinical, epidemiological, and experimental data indicate that pancreatic cancer causes diabetes mellitus by releasing soluble mediators which interfere with both beta-cell function and liver and muscle glucose metabolism. Methods: We analysed, by matrix-assisted laser desorption ionization time of flight (MALDI-TOF), a series of pancreatic cancer cell lines conditioned media, pancreatic cancer patients' peripheral and portal sera, comparing them with controls and chronic pancreatitis patients' sera. Results: MALDI-TOF analysis of pancreatic cancer cells conditioned media and patients' sera indicated a low molecular weight peptide to be the putative pancreatic cancer-associated diabetogenic factor. The sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of tumor samples from diabetic and non-diabetic patients revealed the presence of a 1500 Da peptide only in diabetic patients. The amino acid sequence of this peptide corresponded to the N-terminal of an S-100 calcium binding protein, which was therefore suggested to be the pancreatic cancer-associated diabetogenic factor. Conclusions: We identified a tumor-derived peptide of 14 amino acids sharing a 100% homology with an S-100 calcium binding protein, which is probably the pancreatic cancer-associated diabetogenic facto

Polyclonal and monoclonal B lymphocytes response in HCV-infected patients treated with direct-acting antiviral agents

Hepatitis C virus (HCV) chronic infection can be associated with extrahepatic manifestations such as mixed cryoglobulinaemia and lymphoproliferative disorders that are endowed with increased rates of morbidity and all-cause mortality. In this study, we used flow cytometry to evaluate the effect of interferon-free antiviral treatment on peripheral blood lymphocytes in HCV-infected patients with or without associated lymphoproliferative disorders. Flow cytometry analysis of peripheral blood lymphocytes was performed at baseline and at the end of treatment. In HCV-infected patients with lymphoproliferative disorders, we evaluated immunoglobulin (Ig) light chain \u3ba/\u3bb ratio variations as a measure of monoclonal B-cell response to antiviral therapy. Healthy volunteers were enrolled as controls. A total of 29 patients were included, nine with and 20 without lymphoproliferative disorders. Sustained virological response was achieved in 29 of 29 patients. We observed a significant reduction in the B-cell compartment (39% global reduction) in eight of nine HCV-infected patients with lymphoproliferative disorders after viral clearance. We recognized the same trend, even if less pronounced, in HCV-infected patients without lymphoproliferative disorders (9% global reduction). Among HCV-infected patients with lymphoproliferative disorders, three showed an improvement/normalization of the immunoglobulin light chain ratio, whereas in the remaining six patients monoclonal B cells persisted to be clonally restricted even 1\ua0year after the end of treatment. Our data show that DAAs treatment can be effective in reducing the frequency of pathological B cells in the peripheral blood of HCV-infected patients affected by HCV-associated lymphoproliferative disorders; however, monoclonal populations can persist after viral eradication

Inflammation and pancreatic cancer: molecular and functional interactions between S100A8, S100A9, NT-S100A8 and TGFβ1

BACKGROUND: In order to gain further insight on the crosstalk between pancreatic cancer (PDAC) and stromal cells, we investigated interactions occurring between TGF\u3b21 and the inflammatory proteins S100A8, S100A9 and NT-S100A8, a PDAC-associated S100A8 derived peptide, in cell signaling, intracellular calcium (Cai2+) and epithelial to mesenchymal transition (EMT). NF-\u3baB, Akt and mTOR pathways, Cai2+ and EMT were studied in well (Capan1 and BxPC3) and poorly differentiated (Panc1 and MiaPaCa2) cell lines. RESULTS: NT-S100A8, one of the low molecular weight N-terminal peptides from S100A8 to be released by PDAC-derived proteases, shared many effects on NF-\u3baB, Akt and mTOR signaling with S100A8, but mainly with TGF\u3b21. The chief effects of S100A8, S100A9 and NT-S100A8 were to inhibit NF-\u3baB and stimulate mTOR; the molecules inhibited Akt in Smad4-expressing, while stimulated Akt in Smad4 negative cells. By restoring Smad4 expression in BxPC3 and silencing it in MiaPaCa2, S100A8 and NT-S100A8 were shown to inhibit NF-\u3baB and Akt in the presence of an intact TGF\u3b21 canonical signaling pathway. TGF\u3b21 counteracted S100A8, S100A9 and NT-S100A8 effects in Smad4 expressing, not in Smad4 negative cells, while it synergized with NT-S100A8 in altering Cai2+ and stimulating PDAC cell growth. The effects of TGF\u3b21 on both EMT (increased Twist and decreased N-Cadherin expression) and Cai2+ were antagonized by S100A9, which formed heterodimers with TGF\u3b21 (MALDI-TOF/MS and co-immuno-precipitation). CONCLUSIONS: The effects of S100A8 and S100A9 on PDAC cell signaling appear to be cell-type and context dependent. NT-S100A8 mimics the effects of TGF\u3b21 on cell signaling, and the formation of complexes between TGF\u3b21 with S100A9 appears to be the molecular mechanism underlying the reciprocal antagonism of these molecules on cell signaling, Cai2+ and EMT

TANGGUNG JAWAB HUKUM TERHADAP BARANG BAWAAN PENUMPANG YANG HILANG DALAM BAGASI BUS (Studi Kasus di PT. Abizar Wisata Tour & Travel Malang)

Tanggung jawab jasa perjalanan (travel agency) wisata sangat besar karena bertanggung jawab atas keselamatan keamanan penumpang dan barang yang diangkut. Pasal 188 Undang-Undang Nomor 22 Tahun 2009 tentang Lalu Lintas dan Angkutan Jalan menegaskan bahwa perusahaan jasa angkutan wajib memenuhi persyaratan teknis dan operasional untuk memastikan keselamatan dan keamanan selama perjalanan. Selain itu, perusahaan jasa perjalanan wisata juga bertanggung jawab atas kerugian pada barang yang mereka angkut dalam bagasi. Pasal 193 Undang-Undang Nomor 22 Tahun 2009 menyatakan bahwa perusahaan jasa angkutan dalam hal ini adalah perusahaan jasa perjalanan (travel agency) wisata, wajib memberikan ganti rugi atas kerugian yang timbul akibat kerusakan atau kehilangan barang yang mereka angkut.  Teknik pengumpulan data adalah teknik wawancara dan teknik studi dokumentasi. Analisis data hasil penelitian menggunakan cara deskriptif kualitatif yaitu, analisa data dengan cara mengelompokkan data dan informasi yang sama menurut suatu aspek dilanjutkan melakukan intrepetasi untuk memberikan makna terhadap sub aspek dan hubungannya satu sama lain, kemudian dilakukan analisis dan intrepetasi dari keseluruhan aspek untuk memahami makna antara satu aspek dengan aspek lainnya. Kesimpulan dari skripsi ini adalah: (1) Kerugian yang muncul bukan berasal dari kesalahan penyedia jasa, baik awak bus dan karyawan perusahaan. (2) Abdizar Tour & Travel Malang menggunakan mekanisme negosiasi dengan penumpang yang mengalami kehilangan, kerusakan, pertukaran barang. Hasil negosiasi observasi kasus selama 3x24 jam mendasari tindakan ganti kerugian yang dialami penumpang bus pariwisata PT. Abdizar Tour & Travel Malang. Kemudian, perusahaan dan penumpang melakukan negosiasi untuk mencapai kesepakatan yang saling menguntungkan. Kata Kunci:  Tanggung jawab, Barang bawaan, Hilang, Kerugian

TINJUAN YURIDIS TERHADAP PRINSIP KERAHASIAAN PERBANKAN DENGAN DIBERLAKUKANNYA PERATURAN PEMERINTAH PENGGANTI UNDANG-UNDANG NOMOR 1 TAHUN 2017 TENTANG AKSES INFORMASI KEUANGAN UNTUK KEPENTINGAN PERPAJAKAN

Abstrak Prinsip kerahasiaan perbankan yang diatur dalam Undang-Undang nomor 7 tahun 1992 tentang Perbankan sebagaimana diubah dengan Undang-Undang nomor 10 Tahun 1998 pada Pasal 40 yang memberikan pengertian bahwa bank dalam menjalankan usahanya wajib untuk merahasiakan segala sesuatu yang berhubungan dengan keterangan mengenai nasabah penyimpanan dan simpanannya, dalam Pasal 40 juga dijelaskan bahwa untuk kepentingan Negara, rahasia bank dapat dikesampingkan atau dibuka salah satunya untuk kepentingan perpajakan sebagaimana diatur dalam Pasal 41. Ketentuan dalam Pasal 40 dan Pasal 41 Undang-Undang Perbankan dicabut dengan adanya ketentuan PERPPU nomor 1 tahun 2017 tentang Akses Informasi Keuangan Untuk Kepentingan Perpajakan, yang mana isi dari PERPPU tersebut memberikan kewenangan penuh kepada Direktorat Jenderal Pajak (DJP) untuk dapat mengakses informasi keuangan untuk kepentingan perpajakan tanpa harus mengikuti prosedur dalam Undang-Undang Perbankan, sehingga menimbulkan konflik hukum bahwa pada Pasal 40 tersebut tidak hanya mengatur mengenai pengecualian terhadap kepentingan perpajakan saja, melainkan kepentingan lainnya yang tidak menuntut kemungkinan rahasia bank dapat sangat mudah dibuka untuk umum. Tujuan penelitian ini adalah untuk mengetahui dan memahami prinsip kerahasiaan perbankan setelah pemberlakuan PERPPU nomor 1 tahun 2017 beserta akibat hukumnya. Jenis penelitian yang digunakan adalah yuridis normatif dengan menggunakan pendekatan perundang-undangan dan pendekatan konsep. Hasil penelitian bahwa dengan adanya ketentuan PERPPU nomor 1 tahun 2017 tersebut Direktorat Jenderal Pajak tidak dapat serta merta membuka rekening wajib pajak yang menyimpan dananya di Bank, namun harus tetap melakukan pengajuan usulan pembukaan rekening kepada Menteri Keuangan yang kemudian dilanjutkan kepada Otoritas Jasa Keuangan dan dalam hal penerbitan surat perintah pelaksanaan tetap menggunakan prosedur dalam Undang-Undang Perbankan, serta menimbulkan akibat hukum bahwa semua pihak yang terlibat dalam pembukaan rekening nasabah bank tersebut memiliki kewajiban untuk merahasiakannya, apabila terdapat pihak yang melakukan pembocoran data nasabah maka akan dikenakan sanksi, dengan adanya sanksi tersebut jelas bahwa rahasia bank sangat penting untuk dilindungi. Kata Kunci : Rahasia Bank, PERPPU nomor 1 Tahun 2017, Perpajakan. Abstract The principle of banking secrecy stipulated in Law number 7 of 1992 concerning Banking as amended by Act number 10 of 1998 in Article 40 which gives the understanding that banks in carrying out their business are obliged to keep everything related to information regarding deposit and deposit customers confidential. , in Article 40 it is also explained that in the interest of the State, bank secrets can be excluded or opened for one of the purposes of taxation as stipulated in Article 41. Provisions in Article 40 and Article 41 of the Banking Law are revoked with the provisions of PERPPU number 1 of 2017 concerning Access Financial Information for Taxation Purposes, in which the contents of the PERPPU give full authority to the Directorate General of Taxes (DGT) to be able to access financial information for tax purposes without having to follow procedures in the Banking Law, thus giving rise to legal conflicts That Article 40 does not only regulate exceptions to the interests of taxation, but also other interests which do not require the possibility that bank secrets can be very easily opened to the public. The purpose of this study is to know and understand the principles of banking secrecy after the enactment of PERPPU number 1 of 2017 along with its legal consequences. The type of research used is normative juridical using a legal approach and conceptual approach. The results of the study show that the provisions of PERPPU number 1 in 2017 the Directorate General of Taxes cannot immediately open a taxpayer account that stores funds at the Bank, but must continue to submit a proposal for opening an account to the Minister of Finance and then proceed to the Financial Services Authority. issuance of executing orders still uses procedures in the Banking Law, and creates legal consequences that all parties involved in opening customer accounts of the bank have an obligation to keep it confidential, if there is a party who leaks customer data, sanctions will be imposed, with these sanctions it is clear that bank secrets are very important to protect. Keywords: Bank Secrets, PERPPU number 1 of 2017, Taxation

ANALISIS YURIDIS PERJANJIAN SEWA MENYEWA MOBIL ANTARA PIHAK PENYEWA DENGAN PT. KANIGARA JAYA RAYA TRANSPORT

Perkembangan bisnis penyewaan mobil saat ini semakin meningkat. Kebutuhan masyarakat yang semakin kompleks akan transportasi khususnya transportasi darat, sehingga memunculkan berbagai usaha transportasi. Salah satunya, PT. Kanigara Jaya Raya Transport yang bergerak dalam usaha penyewaan mobil. Perjanjian sewa menyewa mobil pada PT. Kanigara Jaya Raya Transport menggunakan perjanjian baku atau sepihak, karena isi dari perjanjian sewa menyewa mobil yang tercantum pada formulir pesanan tersebut hanya mencantumkan kewajiban-kewajiban dari pihak penyewa saja. Pihak penyewa hanya dapat memilih kontrak yang ditawarkan atau tidak sama sekali yang sudah diberikan oleh pihak PT. Kanigara Jaya Raya Transport. Penelitian ini mengkaji tentang tidak diberlakukannya asas kebebasan berkontrak kepada pihak penyewa pada isi dari perjanjian sewa menyewa mobil yang tercantum pada formulir pesanan yang dibuat oleh pihak PT. Kanigara Jaya Raya Transport dan upaya penyelesaian kedua belah pihak apabila terjadi wanprestasi. Tujuan penelitian ini adalah untuk mengetahui analisis isi perjanjian sewa menyewa mobil pada PT. Kanigara Jaya Raya Transport dilihat dari sudut pandang asas kebebasan berkontrak dalam Kitab Undang–Undang Hukum Perdata dan upaya penyelesaian antara pihak penyewa dengan PT. Kanigara Jaya Raya Transport jika terjadi wanprestasi dengan pihak penyewa. Jenis penelitian yang digunakan dalam penelitian ini adalah penelitian hukum normatif dengan pendekatan perundang-undangan dan pendekatan konsep. Jenis bahan hukum yang digunakan terdiri dari bahan hukum primer dan bahan hukum sekunder. Teknik pengumpulan bahan hukum teknik studi kepustakaan. Teknik analisis menggunakan metode preskriptif. Hasil penelitian menunjukkan bahwa perjanjian sewa menyewa mobil yang dibuat oleh pihak PT. Kanigara Jaya Raya Transport tidak seimbang dengan kedudukan pihak penyewa. Isi perjanjian sewa menyewa yang tercantum dalam formulir pesanan tersebut termasuk perjanjian baku, karena hanya dibuat oleh PT. Kanigara Jaya Raya Transport tanpa adanya keterlibatan pihak penyewa dalam pembuatan isi perjanjian sewa menyewa mobil tersebut. Pihak penyewa ketika diberikan formulir pesanan tidak mempunyai kesempatan untuk bernegosiasi dengan pihak PT. Kanigara Jaya Raya Transport dan berada pada posisi “take it or leave it”, hal ini tidak sesuai dengan asas kebebasan berkontrak. Berkaitan dengan wanprestasi saat berlangsungnya sewa menyewa mobil yang disebabkan oleh pihak penyewa maka diupayakan penyelesaian secara musyawarah dan kekeluargaan dengan mengedepankan rasa kekeluargaan dan rasa kebersamaan antara pihak penyewa dengan pihak PT. Kanigara Jaya Raya Transport. kata kunci: sewa menyewa, asas kebebasan berkontrak, wanpretasi