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"Kanker paru-paru merupakan jenis kanker yang paling banyak diderita dan paling mematikan di dunia. Tipe kanker paru-paru paling banyak diderita merupakan kanker paru-paru non-sel-kecil (NSCLC). Senyawa flavonoid digunakan sebagai inhibitor protein reseptor faktor pertumbuhan epidermal (EGFR) dalam penelitian ini karena memiliki kemampuan bioaktivitas dan bioavailabilitas yang berpotensi sebagai obat antikanker. Penelitian ini menggunakan pendekatan in silico untuk menemukan senyawa flavonoid yang dapat menghambat protein reseptor EGFR secara efektif untuk dijadikan kandidat obat melalui desain obat berbasis fragmen. Beberapa metode komputasi yang digunakan adalah metode Protein-Ligand Interaction Fingerprint (PLIF), penentuan titik farmakofor, simulasi penambatan molekul, serta uji farmakologi dan toksisitas. Setelah dilakukan screening secara virtual melalui penambatan dengan protein EGFR (PDB. 1M17) menggunakan data flavonoid berasal dari basis data pubchem yang berjumlah 25.189 didapat dua fragmen terbaik yang memiliki tiga ikatan hidrogen untuk dilakukan fragment growing dan dari penambatan molekul senyawa hasil fragment growing yang berjumlah 25.600 diperoleh sepuluh senyawa terbaik, dengan parameter ΔGbinding lebih kecil dibanding standar erlotinib yaitu -8,8536 dan nilai RMSD lebih kecil dari 2,0 Å. Ligan tersebut diuji farmakologi dan prediksi toksisitas diperoleh dua senyawa sebagai kandidat inhibitor EGFR yaitu compound 980 dan compound 760 yang memiliki inhibisi CYP yang lebih sedikit dibanding standar dan tidak bersifat toksik untuk organ hati. Berdasarkan hasil tersebut maka compound 980 dan compound 760 dapat menjadi inhibitor EGFR yang potensial.

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Lung cancer is the most suffered and deadly type of cancer in the world. The most common type of lung cancer is non-small cell lung cancer (NSCLC). Flavonoid compounds are used as epidermal growth factor receptor (EGFR) protein inhibitors in this study because they have the potential for bioactivity and bioavailability as anticancer drugs. This study uses an in silico approach to find flavonoid compounds that can effectively inhibit EGFR receptor proteins to be drug candidates through fragment-based drug design. Some computational methods used are the Protein-Ligand Interaction Fingerprint (PLIF) method, pharmacophore point determination, molecular tethering simulation, and pharmacology and toxicity tests. After a virtual screening with EGFR protein (PDB. 1M17) used flavonoid data from the pubchem database with totat number 25,189 is obtained the two best fragments that have three hydrogen bonds to do fragment growing and from molecular docking simulation of compound molecules from fragment growing totaling 25,600 is obtained the ten best compounds, with the parameter ΔGbinding smaller than the erlotinib standard which is -8.8536 and an RMSD value smaller than 2.0 Å. The ligand was tested pharmacologically and the the toxicity was predicted is obtained two compounds as EGFR inhibitor candidates namely compound 980 and compound 760, which had less CYP inhibition than standard and were not toxic to liver. Based on these results, compound 980 and compound 760 can be potential EGFR inhibitors.

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"Kanker payudara merupakan salah satu penyebab utama kematian pada wanita di seluruh dunia. Protein HER2 tirosin kinase merupakan salah satu penyebab kanker payudara, yaitu sebesar 30% dari keseluruhan jumlah kasus kanker payudara. Protein HER2 tirosin kinase berperan penting dalam reaksi dimerisasi yang menyebabkan terjadinya autofosforilasi residu tirosin pada domain sitoplasma. Mekanisme ini dapat memicu pertumbuhan sel kanker. Penghambatan aktivitas protein HER2 dapat menjadi alternatif pengobatan kanker payudara. Dalam penelitian ini digunakan senyawa bahan alam flavonoid sebagai basis data dalam perancangan obat kanker payudara secara in silico. Pada perancangan obat secara in silico, dilakukan beberapa tahapan antara lain, preparasi protein, preparasi flavonoid, preparasi standar, simulasi penambatan molekul, pertumbuhan fragmen, serta studi farmakologi kandidat obat. Proses preparasi dan simulasi penambatan molekul dilakukan dengan menggunakan perangkat lunak MOE 2014.09. Tahapan pertumbuhan fragmen dilakukan dengan perangkat lunak Osiris DataWarrior. Studi farmakologi kandidat obat dilakukan dengan perangkat lunak pkCSM, SwissADME, dan AdmetSar. Penelitian ini diharapkan dapat menemukan kandidat ligan penghambat aktivitas protein HER2.

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Breast cancer is one of the main women death cause around the world. HER2 tyrosine kinase protein is one of the causes of breast cancer, which is 30% of the total number of breast cancer cases. The HER2 tyrosine kinase protein plays an important role in the dimerization reaction which causes the autophosphorylation of tyrosine residues in the cytoplasmic domain. This mechanism can trigger the growth of cancer cells. The inhibition of HER2 protein activity can be an alternative treatment for breast cancer. In this study, natural flavonoid compounds were used as a database in designing breast cancer drugs. In drug design using in silico method, several steps were carried out, such as protein preparation, flavonoid preparation, standard preparation, molecular docking simulation, fragment growing process, and pharmacological studies of drug candidates. The preparation and molecular docking simulation process were conducted using MOE 2014.09 software. Fragment growing process were conducted with Osiris DataWarrior software. Pharmacological studies of candidate drugs were carried out with pkCSM, SwissADME, and AdmetSar software. This study is expected to find inhibitor candidates to inhibit the HER2 protein activity."

"Kanker payudara adalah jenis kanker yang memiliki kasus baru terbanyak dan penyebab kematian tertinggi di kalangan wanita. Hal tersebut menjadikan pemahaman mengenai konsep pengobatan presisi (precision medicine) perlu dikembangkan, salah satunya dengan penggunaan kultur primer dari jaringan kanker pasien. Epidermal growth factor receptor (EGFR) telah dilaporkan umum digunakan sebagai marker prognostik kanker payudara melalui deteksi protein menggunakan metode immunohistokimia (IHK). Namun, metode tersebut memiliki kekurangan dalam menjadi acuan penentuan terapi adjuvant. Penggunaan kultur primer sebagai pengganti cell lines dalam penelitian kanker perlu terus dikembangkan karena lebih mewakili karakteristik fenotipe dan genotipe dari jaringan kanker in vivo. Oleh sebab itu, penelitian ini bertujuan untuk mengetahui tingkat ekspresi relatif gen EGFR pada sampel kultur primer dan jaringan asalnya serta mengetahui perbandingan ekspresi relatif gen EGFR pada sampel jaringan jinak dan jaringan ganas kanker payudara. Metode yang digunakan, yaitu melalui deteksi mRNA gen EGFR dengan semi kuantitatif RT-PCR pada dua pasien yang mewakili jaringan jinak dan ganas. Hasil penelitian menunjukkan tidak terdapat perbedaan signifikan antara ekspresi EGFR pada kultur primer dan jaringan asal, serta ekspresi EGFR pada jaringan ganas lebih tinggi dibandingkan dengan jaringan jinak. Berdasarkan hasil yang diperoleh, dapat disimpulkan bahwa kultur primer dapat dijadikan model alternatif dalam penelitian kanker, serta EGFR dapat dijadikan marker potensial dalam menentukan tingkat agresivitas kanker payudara.

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Breast cancer is a type of cancer that has a highest rate of incidence as well as mortality among women. This makes the understanding of the concept of precision medicine need to be continuously developed, in wich one of the methods is through using primary cultures from patient's tissue. It has been reported that epidermal growth factor receptor (EGFR) is commonly used as a prognostic marker of breast cancer through protein detection using the Immunohistochemical (IHC) method. However, this method has shortcomings in being a reference for determining adjuvant therapy. The use of primary culture as a subtitute cell lines in cancer research needs to be developed due to its more representative of the phenotype and genotype characteristics of cancer tissue in vivo. Therefore, this study aims to determine the relative expression level of the EGFR gene in primary culture sample and its tissue origin as well as comparing the relative expression of the EGFR gene in samples of benign tissue and malignant tissue of breast cancer. The method used is the detection of EGFR gene mRNA with semi-quantitative RT-PCR in two patients representing benign and malignant tissues. The results showed that there was no significant difference between EGFR expression in primary culture and tissue of origin, and EGFR expression in malignant tissue was higher than in benign tissue. Hence, it can be concluded that primary culture can be used as an alternative model in cancer research, and EGFR can be used as a potential marker in determining aggressiveness level of breast cancer."

"Demam berdarah dengue adalah penyakit yang disebabkan oleh virus dari keluarga Flaviviridae yang memiliki tingkat mutasi tinggi dan menyebabkan munculnya variasi serotipe Dengue, yang membuat penemuan obat menjadi sulit. Oleh karena itu, dalam penelitian ini, pencarian kandidat obat baru yang dapat menyembuhkan penyakit untuk semua serotipe dilakukan dengan menggunakan host protein sebagai target protein untuk perannya dalam proses pematangan amplop glikoprotein virus dengue dalam tubuh manusia. Dalam penelitian ini, struktur RE α-Glucosidase I akan diidentifikasi dan berinteraksi dengan kandidat obat dari senyawa bahan alam melalui molecular penambatan molekul dan desain berbasis fragmen. Struktur senyawa ini kemudian akan menjalani pengujian farmakologis untuk menentukan sifat ADME-Tox-nya. Senyawa yang diperoleh diharapkan memiliki interaksi yang baik dengan RE α-Glucosidase I dan memiliki hsil ADME-Tox yang cocok untuk digunakan sebagai kandidat antivirus yang spesifik dan efisien untuk demam berdarah dengue. Setelah melakukan molecular penambatan molekul terhadap lead compounds dan merging fragments, 3 senyawa terbaik diidentifikasi memiliki nilai ikatan hidrogen yang baik, stabilitas, dan sifat farmakologis berdasarkan RMSD, pengikatan dG, dan ADME-Tox. Ligand 34 (1) menunjukkan nilai terkecil ΔG dan RMSD antara lain dengan nilai -9.923 kkal/mol dan 0,8770 Å. Ligand 228 (6) dan Ligand 230 (6) juga menunjukkan nilai ΔG dan RMSD yang kecil yaitu -9.5856 kkal/mol dan -8.7359 kkal/mol dan juga 1.5790 Å dan 1.1164 Å. Ligan-ligan tersebut juga menunjukkan sifat farmakologis yang baik.

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Dengue hemorrhagic fever is a disease caused by the virus from the family Flaviviridae that have high levels of mutation and cause a variety of dengue serotype, which make drug discovery becomes difficult. Therefore, in this study, the search for new drug candidates that can cure disease for all serotypes was carried out using host proteins as protein target for its role in the maturation process of dengue virus glycoprotein envelopes in humans body. In this study, the structure of ER α-Glucosidase I would be identified as interacting with candidates for drugs based on natural compounds through molecular penambatan molekul and fragment-based design. The structure of this compound would then undergo pharmacological testing to determine its ADME-Tox properties. The compounds obtained were expected to have good interactions with RE α-Glucosidase I and ADME-Tox characters that were suitable to be used as a specific and efficient antiviral candidate for dengue hemorrhagic fever. After performing molecular penambatan molekul of lead compounds and merging fragments, 3 best compounds were identified for having good hydrogen bond value, stability, and pharmacological properties based on RMSD, dG binding, and ADME-Tox. Ligand 34 (1) shows the smallest value of ΔG and RMSD, among others with a value of -9.923 kcal/mol and 0.8770 Å. Ligand 228 (6) and Ligand 230 (6) also show small ΔG and RMSD values of -9.5856 kcal/mol and -8.7359 kcal/mol and also 1.5790 Å and 1.1164 Å. The ligands also exhibit good pharmacological properties."

"Penyakit kardiovaskular merupakan penyakit tidak menular penyebab kematian paling banyak setiap tahunnya. Salah satu gangguan kardiovaskular adalah sindrom koroner akut. Pasien dengan kondisi ini umumnya diberikan terapi antiplatelet. Bagian penting dalam proses aktivasi platelet adalah interaksi ADP dengan reseptor P2Y₁₂. Inhibitor P2Y₁₂ yang tersedia mempunyai efek samping yang tidak diharapkan, sehingga pengembangan obat dengan tujuan mendapatkan antiplatelet baru yang lebih optimal masih perlu dilakukan. Penemuan obat baru secara in silico berbasis fragmen memiliki banyak keuntungan dan cerita sukses. Pada penelitian ini, metode tersebut diterapkan dengan tujuan memperoleh struktur senyawa rancangan yang berpotensi sebagai inhibitor P2Y₁₂; memprediksi profil farmakokinetika, kemudahan sintesis, dan toksisitasnya; dan mengetahui interaksi yang terjadi antara senyawa rancangan dengan P2Y₁₂. Fragmen diperoleh dari basis data ZINC, ditapiskan terhadap parameter Rule of Three dan heavy atoms, dan ditambatkan terhadap P2Y₁₂. Penggabungan fragmen (metode linking) kemudian dilakukan setelah menganalisis interaksi fragmen dengan residu asam amino pada makromolekul. Senyawa rancangan hasil penggabungan fragmen diprediksi drug-likeness, aksesibilitas sintesis, ADME, dan toksisitasnya, serta dianalisis interaksinya dengan makromolekul. Penelitian ini menghasilkan 7 senyawa yang diprediksi memiliki nilai aksesibilitas sintesis berkisar antara 4,77 – 5,61, memiliki kriteria drug-likeness dan ADME yang baik, dan tidak bersifat toksik. Senyawa rancangan menunjukkan adanya interaksi dengan residu penting pada P2Y₁₂ yaitu residu Tyr105, Asn191, dan Lys280. Dari hasil penelitian ini, dapat disimpulkan bahwa metode in silico berbasis fragmen berhasil dilakukan untuk memperoleh kandidat inhibitor P2Y₁₂ baru.

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Cardiovascular disease is a non-infectious disease causing the highest deaths every year. One of the cardiovascular disorders is acute coronary syndrome. Patients with this condition are generally given antiplatelet therapy. An important part of the platelet activation process is the interaction of ADP with P2Y₁₂ receptors. The commercially available P2Y₁₂ inhibitors have unexpected side effects, so the development of drug with the aim of getting more optimal antiplatelet agents remains to be done. The discovery of new drugs using an in silico fragment-based drug design has many advantages and success stories. In this study the method was applied with the aims of obtaining the new design of compound's structure which has the potential as a P2Y₁₂ inhibitor; predicting their pharmacokinetic profile, synthetic accessibility, toxicity; and knowing the interactions between the compounds and P2Y₁₂. Fragments were obtained from the ZINC database, screened on the Rule of Three and heavy atoms parameters, and docked against P2Y₁₂. Fragment linking was then performed after analyzing the interaction of fragments with amino acid residues of the macromolecule. The newly design compounds were then analyzed for their drug-likeness, accessibility of synthesis, ADME, and toxicity, and their interactions with the macromolecule. This study produced seven newly designed compounds that are predicted to have synthetic accessibility scores ranging from 4.77 to 5.61, have good drug-likeness and ADME criteria, and not toxic. Each compound showed interactions with important residues in P2Y₁₂ which are the Tyr105, Asn191 and Lys280 residues. It can be concluded that the fragment-based drug design was successfully carried out to obtain new P2Y₁₂ inhibitor candidates.

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"Latar Belakang: Jumlah kasus KPKBSK diperkirakan 85% dari seluruh kasus kanker paru dan 40% diantaranya adalah jenis adenokarsinoma. Sebanyak 10%-30% pasien adenokarsinoma mengalami mutasi EGFR dan mendapatkan terapi EGFR-TKI. Mayoritas pasien KPKBSK memiliki respons dan toleransi baik terhadap terapi EGFR- TKI tetapi sebagian kecil pasien mengalami penyakit paru interstisial akibat EGFR- TKI. Penelitian ini bertujuan untuk mengetahui proporsi gambaran penyakit paru interstisial pada pasien KPKBSK dengan terapi EGFR-TKI di RSUP Persahabatan.Metode: Penelitian ini merupakan penelitian observasional analitik dengan pendeketan kohort retrospektif yang dilakukan bulan Januari 2021 hingga Juni 2022. Subjek penelitian adalah pasien KPKBSK yang mendapatkan terapi EGFR-TKI. Subjek penelitian dipilih sesuai kriteria inklusi dan eksklusi. Pengambilan data melalu data sekunder berupa rekam medis dan hasil CT scan toraks pasien yang kontrol di poliklinik onkologi RSUP Persahabatan.Hasil: Pada penelitian ini diperoleh 73 subjek penelitian, pasien KPKBSK dengan mutasi EGFR yang mendapatkan terapi EGFR-TKI di RSUP Persahabatan. Sebanyak 12 dari 73 subjek penelitian mengalami gambaran ILD yang dievaluasi berdasarkan CT scan toraks RECIST I dan II dengan karakteristik jenis kelamin laki-laki (22,2%), kelompok usia 40-59 tahun (19,4%), perokok (24,1%), indeks brinkman berat (42,9%) dan mendapatkan terapi afatinib (26,1%). Proporsi gambaran ILD pada pasien KBPKBSK dengan terapi EGFR-TKI adalah opasitas retikular (58,3%), parenchymal band (33,3%), ground-glass opacities (25%), traction bronchiectasis (25%) dan crazy paving pattern (8,3%). Hasil analisis bivariat dan multivariat menunjukkan tidak terdapat perbedaan antara faktor-faktor seperti jenis kelamin, usia, jenis EGFR-TKI, riwayat merokok, indeks brinkman, riwayat penyakit paru dan tampilan status terhadap gambaran ILD.Kesimpulan: Gambaran ILD pada pasien KPKBSK dengan terapi EGFR-TKI meliputi opasitas retikular, parenchymal band, ground-glass opacities, traction bronchiectasis dan crazy paving pattern. Tidak terdapat perbedaan bermakna secara statistik antara faktor-faktor yang memengaruhi terhadap gambaran ILD.

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Background: The number of cases of NSCLC is estimated around 85% of all lung cancer cases and 40% among them are adenocarcinoma. Approximately 10%-30% of adenocarcinoma patients have EGFR mutations and receive EGFR-TKI therapy. The majority of NSCLC patients have a good response and tolerance to EGFR-TKI therapy, but a small group of patients experience EGFR-TKI induced interstitial lung disease. This study aims to determine the proportion of features of interstitial lung disease ini NSCLC patients treated with EGFR-TKI at Persahabatan Hospital.

Methods: This study was an analytic observational with a retrospective cohort approach that was conducted from January 2021 until June 2022. The subject were NSCLC patients who received EGFR-TKI treatment. The inclusion and exclusion criteria were used to determine which subjects will be included in the study. Data collection through secondary data from medical record and chest CT scan results of patients controlled at oncology polyclinic at Persahabatan Hospital.

Result : In this study, there were 73 subjects of NSCLC with EGFR mutations and received EGFR-TKI therapy at Persahabatan Hospital. There were 12 out of 73 subjects had ILD features which were evaluated based on RECIST I and II chest CT scan with predominant of male (22.2%), age group 40-59 years old (19.4%), smokers (24.1%), severe Brinkman index (42.9%) and received afatinib (26.1%). The proportion of ILD features in NSCLC patients with EGFR-TKI therapy are reticular opacities (58.3%), parenchymal bands (33.3%), ground-glass opacities (25%), traction bronchiectasis (25%) and crazy paving pattern (8.3%). The results of bivariate and multivariate analyzes showed that there was no differences between factors such as sex, age, type of GEFR-TKI, smoking history, Brinkman index, history of lung disease and performance status with features of ILD.

Conclusion: Features of ILD in NSCLC patients with EGFR-TKI therapy include reticular opacities, parenchymal bands, ground-glass opacities, traction bronchiectasis and crazy paving pattern. There is no statistically significa"

"Pada akhir tahun 2019, telah muncul suatu tipe virus korona baru yaitu SARS-CoV-2 yang menyebabkan pandemik global dengan tingkat kematian yang relatif sangat tinggi. Dikarenakan oleh belum adanya obat maupun vaksin yang efektif untuk mengobati virus ini maka diperlukan suatu senyawa yang bisa menginhibisi protein yang berperan dalam infeksi virus SARS-CoV-2. Virus SARS-CoV-2 terdiri dari beberapa protein penyusun. Salah satu protein yang berperan penting adalah protein nukleokapsid (NP). Protein ini berperan dalam proses transkripsi maupun replikasi dari RNA virus SARS-CoV-2. Oleh karena itu, protein ini memiliki potensi untuk dijadikan target protein yang akan diinhibisi. Pada penelitian ini akan dilakukan pemanfaatan senyawa bahan alam yang dapat menginhibisi protein target tersebut sehingga dapat mengurangi dampak dari pandemik global ini. Struktur tiga dimensi (3D) dari NP dimodel melalui sekuen yang diunduh melalui basis data GenBank. Struktur protein kemudian dioptimisasi dan dikarakterisasi untuk mengetahui keakurasian struktur hasi homologi model. Kemudian, penapisan dilakukan terhadap basis data senyawa bahan alam yang berasal dari NPASS dengan menggunakan Astex’s Rule of Three (RO3) dan sifat toksisitas untuk mendapatkan senyawa fragmen. Kemudian dilakukan simulasi penambatan molekul senyawa-senyawa fragmen ini terhadap sisi ikat dari NP menggunakan perangkat lunak MOE 2014.09. Kemudian setelah didapatkan delapan ligan terbaik, ligan-ligan tersebut ditumbuhkan dengan menggunakan proses penumbuhan fragmen yang menghasilkan 14.332 senyawa yang nantinya akan dievaluasi melalui simulasi penambatan molekul sekali lagi. Simulasi ini menghasilkan 40 ligan terbaik dengan nilai energi bebas Gibbs terendah terhadap struktur ptorein. Ligan terpilih diprediksi sifat farmakologinya secara komputasi, dan menghasilkan 2 ligan (CFG-17 dan NFG-11) yang memiliki sifat farmakologis yang baik. Kedua ligan ini divalidasi interaksinya dengan menggunakan simulasi dinamika molekul dan menunjukkan stabilitas interaksi yang baik sebagai kandidat obat untuk terapi SARS-CoV-2.

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The outbreak of COVID-19 caused by the SARS-CoV-2 virus caused a global pandemic that affects the worldwide. Because of the lacking effective prescribed drugs or vaccines as a therapeutic strategy, there is a need to identify a novel inhibitor to inhibit a protein that plays a vital role in the infection of SARS-CoV-2. The Nucleocapsid protein (NP) of the SARS-CoV-2 is a protein that is necessary for viral RNA replication and transcription. Thus, in this study, a three-dimensional (3D) NP structure was modeled using the protein sequences of NP obtained from the GenBank database. After that, the modeled protein structure was characterized and optimized. The natural compound databases obtained from the NPASS database were screened based on Astex’s Rule of Three and toxicity filter to gain lead-like fragments. The filtered fragments were docked into the binding site of the NP utilizing MOE 2014.09 software. Then potential eight potential lead-like fragments were grown to generate 14,332 new ligands by utilizing DataWarrior software. Then molecular docking simulation was performed once again with the same protocol as the first molecular docking simulation. The simulation resulted in 40 best ligands with the lowest value of Gibbs free energy binding to NP. The selected ligands were subjected to the computational pharmacological properties prediction using several tools and resulted in two compounds candidate with favorable interaction and ADME-Tox properties. Then these two compounds were further analyzed with the molecular dynamic simulation."

"Latar Belakang: Beberapa bukti menunjukkan bahwa quiescent cancer stem cell (CSC) terlibat dalam resistans terhadap gefitinib pada adenokarsinoma paru sebagai mekanisme nonmutasi. Kami sebelumnya telah mempublikasikan bahwa gefitinib- resistant persister (GRP) mengekspresikan stemness factor dengan level yang tinggi dan memiliki ciri khas fenotip CSC. Studi terbaru menunjukkan bahwa FBXW7, merupakan jenis protein F-box, memainkan peran penting dalam pemeliharaan quiescent CSC dengan memediasi degradasi protein c-MYC melalui proses ubiquination. Tujuan dari penelitian ini adalah untuk mengetahui peran FBXW7 dalam resistans terhadap gefitinib pada adenokarsinoma paru dengan mutasi EGFR.Metode: Cell line dari sel adenokarsinoma paru, PC9, yang mengandung mutasi sensitif EGFR dipajankan pada gefitinib dengan konsentrasi tinggi untuk mengembangkan GRP. Kami mencoba melakukan abrogasi ekspresi gen FBXW7, dan mengevaluasi sensitivitasnya terhadap gefitinib dan populasi CD133-positive stem cell di GRP. Kami juga memasukkan plasmid FUCCI melalui proses infeksi lentiviral ke dalam sel dan kemudian menyelidiki siklus sel dan sel pada fase G0 dalam GRP. Selanjutnya, kami telah mengembangkan model gefitinib-resistant tumor (GRT) dengan menyuntikkan sel PC9 ke dalam mencit NOG diikuti dengan pemberian gefitinib setelah pertumbuhan tumor, dan mengevaluasi ekspresi mRNA dan ekspresi protein dari penanda terkait quiescence, FBXW7 in vivo.Hasil: GRP menunjukkan ekspresi yang tinggi dari penanda cancer stem cell, CD133 dan penanda terkait quiescence, FBXW7 dan ekspresi c-MYC yang rendah pada tingkat protein secara in vitro. Analisis siklus sel menunjukkan bahwa mayoritas GRP berada pada fase G0/G1. TIndakan abrogasi gen FBXW7 menurunkan populasi sel CD133-positive di GRPs. Abrogasi FBXW7 juga meningkatkan kerentanan sel terhadap gefitinib, membalikkan populasi sel fase G0/G1 menjadi sel S/G2/M, dan menurunkan jumlah sel GRP. Secara in vivo, pada GRT setelah pengobatan gefitinib menunjukkan ekspresi FBXW7 yang tinggi dan ekspresi c-MYC yang rendah. Kami juga menemukan bahwa ekspresi FBXW7 dalam sel CD133-positive meningkat dan ekspresi c-MYC menurun pada mencit dan pada 9 dari 14 spesimen tumor dari pasien adenokarsinoma paru dengan mutasi EGFR resistan terhadap gefitinib.Kesimpulan: Temuan ini menunjukkan bahwa FBXW7 dapat memainkan peran penting dalam pemeliharaan quiescence pada gefitinib-resistant lung CSC pada adenokarsinoma paru dengan mutasi positif EGFR

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Background: Accumulating evidence indicates that quiescent cancer stem cells (CSCs) are involved in the resistance to gefitinib in non-small cell lung cancer (NSCLC) as non-mutational mechanism. We have previously reported that gefitinib-resistant persisters (GRPs) highly expressed stemness factors and had characteristic features of the CSCs phenotype. Recent studies demonstrate that FBXW7, a type of F-box protein, plays an important role in the maintenance of quiescent CSC by mediating the degradation of c-MYC protein by ubiquination. The aim of this study is to figure out the role of FBXW7 in the resistance to gefitinib in lung adenocarcinoma with EGFR mutation.

Methods: lung adenocarcnoma cell lines, PC9, harboring sensitive-EGFR mutation were exposed to high concentration of gefitinib in order to develop GRPs. We tried to knockdown FBXW7 gene expression, and evaluated their sensitivity to gefitinib and CD133-positive stem cell population in GRPs. We also introduced FUCCI plasmid via lentiviral infection in the cells and then investigated the cell cycle and G0-phase cells in GRPs. Furthermore, we established gefitinib-resistant tumor (GRT) model by injecting PC9 cells into NOG-mice followed by gefitinib administration after tumor growth, and evaluated mRNA and protein expression of quiescence-related markers including FBXW7 in vivo.

Results: In vitro, GRPs showed high expression of stem cell marker CD133 and quiescence-related markers including FBXW7 and low expression of c-MYC at protein level. Cell cycle analysis revealed that majority of GRPs existed in G0/G1 phase. Silencing of FBXW7 gene reduced CD133-positive cell population in GRPs. Knockdown of FBXW7 also increased susceptibility of cells to gefitinib, reversed population of G0/G1 cells to G2/S/M cells, and decreased cell number of GRPs. In vivo, GRTs after gefitinib treatment revealed high expression of FBXW7 and low expression of c-MYC. We also found that FBXW7 expression in CD133-positive cells was increased and c-MYC expression was decreased in mice and in 9 out of

14 tumor specimens from EGFR-mutant lung adenocarcinoma patients with acquired resistance to gefitinib.

Conclusion: These findings suggest that FBXW7 plays a pivotal role in the maintenance of quiescence in gefitinib-resistant lung CSCs in EGFR mutation- positive lung adenocarcinoma."

"[ABSTRAKPendahuluan. Kanker paru jenis karsinoma bukan sel kecil (KPKBSK) terdiri dari nonskuamosa dan skuamosa. Kanker paru jenis karsinoma bukan sel kecil nonskuamosa adalah adenokarsinoma dan karsinoma sel besar. Saat ini terapi kanker paru sangat berkembang dari agen kemoterapi sampai terapi target terutama EGFR-TKI. Penelitian ini bertujuan untuk menilai angka tahan hidup pasien KPKSBK nonskuamosa yang mendapat kemoterapi lini pertama dibandingkan terapi EGFR-TKI di RSUP Persahabatan.Metode. Penelitian ini adalah penelitian retrospektif antara tahun 2010 sampai 2013 dari rekam medis pasien KPKBSK non skumosa yang mendapatkan kemoterapi lini pertama dan EGFR-TKI. Pasien dikemoterapi dengan platinum baseddan EGFR-TKI diterapi gefitinib 1x250 mg/hari atau erlotinib 1x150 mg/hari. Angka tahan hidup dinilai dari mulai tegak diagnosis sampai pasien meninggal atau saat penelitian dihentikan.Hasil. Dari 96 sampel KPKBSK non skuamosa terdiri dari 48 pasien yang mendapat kemoterapi lini pertama dan 48 pasien yang diterapi EGFR-TKI. Berdasarkan karakteristik pasien, usia terbanyak adalah 40-60 tahun (kemoterapi 32 (66,7%) dan EGFR-TKI 31 (64,6%) dengan jenis kelamin laki-laki yang mendominasi (kemoterapi 25(52,1%), EGFR-TKI 27 (56,2%). Pasien merokok yang mendapat kemoterapi lini pertama 41,7% dan EGFR-TKI 56,3% dengan IB terbanyak untuk kemoterapi (IB ringan 27,1%) dan untuk EGFR-TKI (IB sedang 22,9%). Jenis histologi adenokarsinoma 95,8% dengan dominasi stage IV 89,6% (kemoterapi 91,7% dan EGFR-TKI 87,5%) disertai tampilan status 2 59,4%. Angka tahan hidup pasien (ATH) 6 bulan 74%, ATH 1 tahun 22,90% dan ATH 2 tahun 6,20%. Masa tengah tahan hidup (MTTH) pasien yang mendapat EGFR-TKI lebih lama sedikit dibandingkan yang mendapat kemoterapi lini pertama (263 hari versus 260 hari.Kesimpulan. Masa tahan hidup 1 tahun pasien KPKBSK non skuamosa yang diterapi EGFR-TKI sedikit lebih lama dibandingkan kemoterapi lini pertama (263 hari vs 260 hari). Sedangkan ATH 1 tahun pasien kemoterapi lini pertama lebih besar dibandingkan EGFR-TKI (25% vs 20,8%). Faktor yang paling mempengaruhi angka tahan hidup adalah stage dengan nilai p<0,05.

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ABSTRACT Introduction. Lung cancer is the type of non-small cell carcinoma (NSCLC) consists of non-squamous and squamous. Non-small cell lung cancer of non squamous types consist of adenocarcinoma and large cell carcinoma. Currently, lung cancer therapy is highly developed of chemotherapeutic agents to targeted therapy especially EGFR-TKI. This study aims to assess the survival rate of NSCLC patients of non-squamous type who receive first line chemotherapy and those who recieve EGFR-TKI therapy at Persahabatan hospital.Methods. This study is a retrospective study between 2010 to 2013 from the medical records of NSCLC patients of non-squmous type who receive first-line chemotherapy and thise who recieve EGFR-TKI.Patients with platinum-based chemotherapy and EGFR-TKI with gefitinib therapy 1x250 mg/day or erlotinib 1x150mg/day. Survival rate assessed from start to erect the diagnosis until the patient dies or when the study is discontinued.Result. From 96 subject of NSCLC patients with non-squamous type consisted of 48 patients who receive first-line chemotherapy, and 48 patients are treate with EGFR-TKI. Based on the characteristics of the patients, most are 40-60 years old (chemotherapy 32 (66.7%) and EGFR-TKI 31 (64.6%) with the male gender that dominates (chemotherapy 25 (52.1%), EGFR-TKI 27 (56.2%). Smoking patients who received first-line chemotherapy are 41.7% and 56.3% of EGFR-TKIs with chemotherapy highest IB (mild IB 27.1%) and for EGFR-TKI (moderate IB are 22.9%). 95.8% of adenocarcinoma histology type with a predominance of stage IV 89.6% (91.7% for chemotherapy and EGFR-TKI 87.5%) with performance status 2 59.4% . Survival rate of patients are 74% for 6 months survival, 1 year survival rate is 22.90% and 2 years survival rate of 6.20%. Median period of survival rate in patients who receiving EGFR-TKI longer than they received first-line chemotherapy (263 days versus 260 days).Conclusion. Median survival rate of non-squamous NSCLC that treated by EGFR-TKI is longer than first-line chemotherapy (263 days vs 260 days). Although 1 year survival rate first-line chemotherapy in patients is greater than EGFR-TKI (25% vs 20.8%). The factors that most influence the survival rate is stages with p value<0.05.;Introduction. Lung cancer is the type of non-small cell carcinoma (NSCLC) consists of non-squamous and squamous. Non-small cell lung cancer of non squamous types consist of adenocarcinoma and large cell carcinoma. Currently, lung cancer therapy is highly developed of chemotherapeutic agents to targeted therapy especially EGFR-TKI. This study aims to assess the survival rate of NSCLC patients of non-squamous type who receive first line chemotherapy and those who recieve EGFR-TKI therapy at Persahabatan hospital.Methods. This study is a retrospective study between 2010 to 2013 from the medical records of NSCLC patients of non-squmous type who receive first-line chemotherapy and thise who recieve EGFR-TKI.Patients with platinum-based chemotherapy and EGFR-TKI with gefitinib therapy 1x250 mg/day or erlotinib 1x150mg/day. Survival rate assessed from start to erect the diagnosis until the patient dies or when the study is discontinued.Result. From 96 subject of NSCLC patients with non-squamous type consisted of 48 patients who receive first-line chemotherapy, and 48 patients are treate with EGFR-TKI. Based on the characteristics of the patients, most are 40-60 years old (chemotherapy 32 (66.7%) and EGFR-TKI 31 (64.6%) with the male gender that dominates (chemotherapy 25 (52.1%), EGFR-TKI 27 (56.2%). Smoking patients who received first-line chemotherapy are 41.7% and 56.3% of EGFR-TKIs with chemotherapy highest IB (mild IB 27.1%) and for EGFR-TKI (moderate IB are 22.9%). 95.8% of adenocarcinoma histology type with a predominance of stage IV 89.6% (91.7% for chemotherapy and EGFR-TKI 87.5%) with performance status 2 59.4% . Survival rate of patients are 74% for 6 months survival, 1 year survival rate is 22.90% and 2 years survival rate of 6.20%. Median period of survival rate in patients who receiving EGFR-TKI longer than they received first-line chemotherapy (263 days versus 260 days).Conclusion. Median survival rate of non-squamous NSCLC that treated by EGFR-TKI is longer than first-line chemotherapy (263 days vs 260 days). Although 1 year survival rate first-line chemotherapy in patients is greater than EGFR-TKI (25% vs 20.8%). The factors that most influence the survival rate is stages with p value<0.05.;Introduction. Lung cancer is the type of non-small cell carcinoma (NSCLC) consists of non-squamous and squamous. Non-small cell lung cancer of non squamous types consist of adenocarcinoma and large cell carcinoma. Currently, lung cancer therapy is highly developed of chemotherapeutic agents to targeted therapy especially EGFR-TKI. This study aims to assess the survival rate of NSCLC patients of non-squamous type who receive first line chemotherapy and those who recieve EGFR-TKI therapy at Persahabatan hospital.Methods. This study is a retrospective study between 2010 to 2013 from the medical records of NSCLC patients of non-squmous type who receive first-line chemotherapy and thise who recieve EGFR-TKI.Patients with platinum-based chemotherapy and EGFR-TKI with gefitinib therapy 1x250 mg/day or erlotinib 1x150mg/day. Survival rate assessed from start to erect the diagnosis until the patient dies or when the study is discontinued.Result. From 96 subject of NSCLC patients with non-squamous type consisted of 48 patients who receive first-line chemotherapy, and 48 patients are treate with EGFR-TKI. Based on the characteristics of the patients, most are 40-60 years old (chemotherapy 32 (66.7%) and EGFR-TKI 31 (64.6%) with the male gender that dominates (chemotherapy 25 (52.1%), EGFR-TKI 27 (56.2%). Smoking patients who received first-line chemotherapy are 41.7% and 56.3% of EGFR-TKIs with chemotherapy highest IB (mild IB 27.1%) and for EGFR-TKI (moderate IB are 22.9%). 95.8% of adenocarcinoma histology type with a predominance of stage IV 89.6% (91.7% for chemotherapy and EGFR-TKI 87.5%) with performance status 2 59.4% . Survival rate of patients are 74% for 6 months survival, 1 year survival rate is 22.90% and 2 years survival rate of 6.20%. Median period of survival rate in patients who receiving EGFR-TKI longer than they received first-line chemotherapy (263 days versus 260 days).Conclusion. Median survival rate of non-squamous NSCLC that treated by EGFR-TKI is longer than first-line chemotherapy (263 days vs 260 days). Although 1 year survival rate first-line chemotherapy in patients is greater than EGFR-TKI (25% vs 20.8%). The factors that most influence the survival rate is stages with p value<0.05.;Introduction. Lung cancer is the type of non-small cell carcinoma (NSCLC) consists of non-squamous and squamous. Non-small cell lung cancer of non squamous types consist of adenocarcinoma and large cell carcinoma. Currently, lung cancer therapy is highly developed of chemotherapeutic agents to targeted therapy especially EGFR-TKI. This study aims to assess the survival rate of NSCLC patients of non-squamous type who receive first line chemotherapy and those who recieve EGFR-TKI therapy at Persahabatan hospital.Methods. This study is a retrospective study between 2010 to 2013 from the medical records of NSCLC patients of non-squmous type who receive first-line chemotherapy and thise who recieve EGFR-TKI.Patients with platinum-based chemotherapy and EGFR-TKI with gefitinib therapy 1x250 mg/day or erlotinib 1x150mg/day. Survival rate assessed from start to erect the diagnosis until the patient dies or when the study is discontinued.Result. From 96 subject of NSCLC patients with non-squamous type consisted of 48 patients who receive first-line chemotherapy, and 48 patients are treate with EGFR-TKI. Based on the characteristics of the patients, most are 40-60 years old (chemotherapy 32 (66.7%) and EGFR-TKI 31 (64.6%) with the male gender that dominates (chemotherapy 25 (52.1%), EGFR-TKI 27 (56.2%). Smoking patients who received first-line chemotherapy are 41.7% and 56.3% of EGFR-TKIs with chemotherapy highest IB (mild IB 27.1%) and for EGFR-TKI (moderate IB are 22.9%). 95.8% of adenocarcinoma histology type with a predominance of stage IV 89.6% (91.7% for chemotherapy and EGFR-TKI 87.5%) with performance status 2 59.4% . Survival rate of patients are 74% for 6 months survival, 1 year survival rate is 22.90% and 2 years survival rate of 6.20%. Median period of survival rate in patients who receiving EGFR-TKI longer than they received first-line chemotherapy (263 days versus 260 days).Conclusion. Median survival rate of non-squamous NSCLC that treated by EGFR-TKI is longer than first-line chemotherapy (263 days vs 260 days). Although 1 year survival rate first-line chemotherapy in patients is greater than EGFR-TKI (25% vs 20.8%). The factors that most influence the survival rate is stages with p value<0.05., Introduction. Lung cancer is the type of non-small cell carcinoma (NSCLC) consists of non-squamous and squamous. Non-small cell lung cancer of non squamous types consist of adenocarcinoma and large cell carcinoma. Currently, lung cancer therapy is highly developed of chemotherapeutic agents to targeted therapy especially EGFR-TKI. This study aims to assess the survival rate of NSCLC patients of non-squamous type who receive first line chemotherapy and those who recieve EGFR-TKI therapy at Persahabatan hospital.Methods. This study is a retrospective study between 2010 to 2013 from the medical records of NSCLC patients of non-squmous type who receive first-line chemotherapy and thise who recieve EGFR-TKI.Patients with platinum-based chemotherapy and EGFR-TKI with gefitinib therapy 1x250 mg/day or erlotinib 1x150mg/day. Survival rate assessed from start to erect the diagnosis until the patient dies or when the study is discontinued.Result. From 96 subject of NSCLC patients with non-squamous type consisted of 48 patients who receive first-line chemotherapy, and 48 patients are treate with EGFR-TKI. Based on the characteristics of the patients, most are 40-60 years old (chemotherapy 32 (66.7%) and EGFR-TKI 31 (64.6%) with the male gender that dominates (chemotherapy 25 (52.1%), EGFR-TKI 27 (56.2%). Smoking patients who received first-line chemotherapy are 41.7% and 56.3% of EGFR-TKIs with chemotherapy highest IB (mild IB 27.1%) and for EGFR-TKI (moderate IB are 22.9%). 95.8% of adenocarcinoma histology type with a predominance of stage IV 89.6% (91.7% for chemotherapy and EGFR-TKI 87.5%) with performance status 2 59.4% . Survival rate of patients are 74% for 6 months survival, 1 year survival rate is 22.90% and 2 years survival rate of 6.20%. Median period of survival rate in patients who receiving EGFR-TKI longer than they received first-line chemotherapy (263 days versus 260 days).Conclusion. Median survival rate of non-squamous NSCLC that treated by EGFR-TKI is longer than first-line chemotherapy (263 days vs 260 days). Although 1 year survival rate first-line chemotherapy in patients is greater than EGFR-TKI (25% vs 20.8%). The factors that most influence the survival rate is stages with p value<0.05.]"

"Diabetes mellitus adalah penyakit tidak menular tetapi merupakan salah satu penyebab kematian tertinggi di dunia karena dapat menyebabkan kerusakan organ dan memicu berbagai jenis penyakit. Menurut Federasi Diabetes Internasional (IDF) pada tahun 2017, jumlah orang dengan diabetes di dunia telah meningkat menjadi 425 juta, dan diperkirakan jumlahnya akan terus meningkat menjadi 629 juta orang pada tahun 2045. Dengan diabetes mellitus tipe 2 mencapai 90-95% dari total populasi penderita diabetes yang umumnya orang dengan T2DM di atas 45 tahun, tetapi saat ini ada juga orang dengan T2DM di antara remaja dan anak-anak dan populasi meningkat. Oleh karena itu, dalam penelitian ini, senyawa yang merupakan kandidat potensial untuk DMT2 akan dicari. Penelitian terbaru menunjukkan bahwa dengan mencegah hidrolisis pati, melalui penghambatan enzim α-amilase dapat digunakan sebagai strategi untuk mengendalikan hiperglikemia. Jadi, dalam mendesain obat untuk terapi penyakit T2DM adalah mencari senyawa yang mampu menghambat enzim α-amilase, yang kemudian dapat mengurangi peningkatan kadar glukosa darah postprandial secara signifikan. Penelitian ini dilakukan secara silico oleh farmakofor, skrining virtual, docking molekul dan pertumbuhan fragmen dengan target protein α-amilase. Penentuan fitur farmakofor dan penambatan molekul didasarkan pada struktur 3D α-amilase yang diperoleh dari Data Bank Protein dengan kode (ID GDP: 1HNY) dengan ligan standar acarbose dan miglitol yang diperoleh dari basis data ChemSpider. Fragmen yang digunakan adalah senyawa mirip timbal yang berasal dari basis data MOE dengan total 653.214 senyawa dan dipilih 5 fragmen potensial yang kemudian menghasilkan sebanyak 64.000 senyawa baru menggunakan metode penanaman Fragmen (pertumbuhan fragmen). Selain itu, semua senyawa baru adalah simulasi tambatan molekul dengan kondisi enzim α-amilase yang kaku dan fleksibel. Berdasarkan hasil simulasi penambatan molekuler, enam senyawa baru diperoleh dengan interaksi molekuler yang berpotensi menghambat protein target. Kemudian dilanjutkan dengan tes farmakologis (ADME dan toksisitas) melalui beberapa perangkat lunak seperti Osiris DataWarrior, SwissADME, admetSAR, pkCSM, dan Toxtree. Berdasarkan interaksi molekuler dan uji farmakologis tiga senyawa baru ditemukan menjadi kandidat inhibitor terbaik, yaitu senyawa Kojai-1 Kojai-5 dan Fhama-3.

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Diabetes mellitus is a non-communicable disease but it is one of the highest causes of death in the world because it can cause organ damage and trigger various types of diseases. According to the International Diabetes Federation (IDF) in 2017, the number of people with diabetes in the world has increased to 425 million, and it is estimated that the number will continue to increase to 629 million by 2045. With type 2 diabetes mellitus reaching 90-95% of the total population Diabetics are generally people with T2DM over 45 years, but currently there are also people with T2DM among teenagers and children and the population is increasing. Therefore, in this study, compounds which are potential candidates for T2DM will be sought. Recent research shows that by preventing the hydrolysis of starch, through inhibition of the α-amylase enzyme can be used as a strategy to control hyperglycemia. So, in designing drugs for the treatment of T2DM disease is to look for compounds that are able to inhibit the α-amylase enzyme, which can then significantly reduce postprandial blood glucose levels. The research was carried out silicoally by pharmacophores, virtual screening, molecular docking and fragment growth with the target protein α-amylase. Determination of pharmacophoric features and molecular tethering is based on 3D α-amylase structure obtained from the Protein Bank Data coded (ID GDP: 1HNY) with standard ligand acarbose and miglitol obtained from the ChemSpider database. The fragments used were lead-like compounds derived from the MOE database with a total of 653,214 compounds and 5 potential fragments were selected which then produced as many as 64,000 new compounds using the Fragment planting method (fragment growth). In addition, all new compounds are molecular moorings simulations with rigid and flexible α-amylase enzymes. Based on the results of molecular docking simulations, six new compounds were obtained by molecular interactions that could potentially inhibit the target protein. Then proceed with pharmacological tests (ADME and toxicity) through several software such as Osiris DataWarrior, SwissADME, admetSAR, pkCSM, and Toxtree. Based on molecular interactions and pharmacological tests, three new compounds were found to be the best inhibitor candidates, namely Kojai-1 Kojai-5 and Fhama-3 compounds."