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"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."

"Faktor transkripsi Hoxa 10 dan gen targetnya integrin αvβ3, keduanya adalah marka penting yang meregulasi kondisi endometrium reseptif. Stimulasi ovarium telah dilaporkan dapat mengganggu reseptifitas endometrium yang berkaitan dengan kegagalan implantasi. Tujuan penelitian ini untuk menganalisis pengaruh stimulasi rFSH terhadap tingkat ekspresi Hoxa 10 dan integrin αvβ3 pada endometrium selama fase sekresi, serta menilai hubungan korelasi keduanya. Metode, dipilih 27 tikus betina dengan siklus estrus normal dibagi dalam kelompok siklus alamiah dan dua kelompok dengan siklus terstimulasi, dilakukan penyuntikan rFSH dosis 12,5 IU dan 25 IU dan 48 jam kemudian dilanjutkan penyuntikan hCG dosis 10 IU. Pengambilan sampel uterus dilakukan pada hari pertama, kedua dan ketiga setelah penyuntikan hCG. Ekspresi kedua marka dinilai menggunakan teknik imunohistokimia dan Western Immunoblotting. Hasil, Ekspresi Hoxa 10 di stroma tidak berbeda antara kelompok kontrol dan distimulasi dosis 12,5 UI (P > 0,05). Ekspresi integrin αvβ3 di epitel luminal tidak menurun secara bermakna akibat distimulasi dosis 25 UI (P > 0,05) dan perubahan ekspresi integrin αvβ3 di epitel kelenjar juga tidak berbeda bermakna setelah pemberian stimulasi (P > 0,05). Kedua marka berkorelasi positif pada hari kesatu (r = 0,607) dan hari ketiga ditemukan korelasi negatif (r = -0,616). Dari data tersebut disimpulkan bahwa stimulasi rFSH tidak menurunkan ekspresi Hoxa 10 dan integrin αvβ3 pada fase sekresi.The transcription factor Hoxa 10 and its target gene the αvβ3 integrin, are both essential molecules that regulate receptivite endometrial condition. Giving ovarian stimulation has been reported to impair endometrial receptivity in association with implantation failure. The aim of this study was to analyze the effect of rFSH administration on the expression level of Hoxa 10 and αvβ3 integrin in the endometrium during the secretory phase, as well as assess the correlation between the two. Methods, 27 Wistar female rats with normal estrus cycles were selected divided into natural cycle group and two groups were stimulated cycle of rFSH doses of 12.5 IU and 25 IU and 48 hours later followed by injection of hCG dose 10 IU. Uterine sampling was carried out on the first, second and third day after hCG injection. Hoxa 10 and αvβ3 integrin expression was assessed using immunohistochemistry and Western Immunobloting techniques. As a results, the expression of Hoxa 10 in the stromal cell did not differ between the control group and the group with stimulation dose 12,5 UI (P>0,05). The expression of αvβ3 integrin in the luminal epithelium did not decrease significantly due to stimulation dose 25 UI (P>0,05) and changes in αvβ3 integrin expression in the epithelial glands did not show a significant difference after stimulation (P>0,05). Both proved to be positively correlation on the first day (r = 0,607) and on the third day negatifly correlation (r = -0,616). From these data it was concluded that rFSH stimulation did not decrease Hoxa 10 and αvβ3 integrin expression in the secretory phase."

"Pendahuluan : Adenomiosis adalah sebuah kelainan jinak ginekologi dengan insidensi diperkirakan 20%, dimana kondisi ini berkaitan dengan nyeri pelvis kronis serta infertilitas. Saat ini pilihan terapi adenomiosis terbatas pada meringankan gejala menggunakan antinyeri, manipulasi hormon, dan pembedahan dengan efek samping yang signifikan dan dikontraindikasikan pada wanita yang ingin hamil. Salah satu pilihan terapi yang sedang dikembangkan saat ini adalah microRNA. Telah diketahui sebelumnya bahwa terdapat penurunan ekspresi E-Cadherin pada pasien adenomiosis, dimana salah satu yang meregulasi E-Cadherin adalah microRNA-10b. Selain itu diketahui microRNA-let-7a, yang mempengaruhi ekspresi gen KRAS, mengalami disregulasi pada berbagai kondisi dengan proliferasi abnormal, seperti pada kondisi keganasan.Tujuan : Tujuan penelitian ini adalah untuk mengetahui korelasi antara ekspresi microRNA let-7a terhadap KRAS dan microRNA-10b terhadap E-Cadherin pada jaringan endometrium adenomiosis dan jaringan endometrium non-adenomiosis.Desain : Studi potong lintang dengan analitik komparatif dan analitik korelasi.Material dan Metode : Sampel penelitian didapat dari total 31 wanita yang datang berobat ke poliklinik ginekologi atau klinik fertilitas RSUPN Dr. Cipto Mangunkusumo, dengan 17 subyek dimasukkan ke dalam kelompok adenomiosis, dan 15 subyek ke dalam kelompok non-adenomiosis. Sampel dari tiap subyek diambil melalui tindakan histeroskopi, laparoskopi, maupun laparotomi operatif, bergantung pada indikasi masing-masing subyek. Pada masing-masing sampel kemudian dilakukan pengukuran kadar ekspresi microRNA-10b, microRNA-let-7a, E-Cadherin, serta KRAS.Hasil : Terdapat perbedaan signifikan ekspresi E-Cadherin antara kelompok adenomiosis dan non-adenomiosis (P=0,001). Sementara itu tidak ditemukan perbedaan signifikan pada ekspresi microRNA-10b, microRNA-let-7a, dan KRAS antara kedua kelompok. Uji korelasi menunjukkan korelasi negatif lemah antara ekspresi microRNA-let-7a dengan KRAS pada kelompok non-adenomiosis (R=-0.287; P=0.3), namun tidak pada kelompok adenomiosis. Terdapat korelasi negatif lemah antara ekspresi microRNA-10b dengan E-Cadherin pada kedua kelompok sampel.Kesimpulan : Terdapat perbedaan signifikan pada ekspresi E-Cadherin antara kelompok adenomiosis dan non-adenomiosis. Terdapat korelasi negatif lemah antara ekspresi microRNA-let-7a dengan KRAS pada kelompok non-adenomiosis.

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Introduction : Adenomyosis is a benign gynecologic disorder with incidence estimation up to 20%. This condition is strongly associated with chronic pelvic pain and infertility. Until now, treatments of this disorder are limited to symptomatic relief using painkillers, hormonal therapy, and surgical procedure. But these treatments come with significant side effects and are contraindicated for women planning to conceive. One of the therapeutic options currently being developed is microRNA. It has been known previously that there is a decrease in the expression of E-Cadherin in adenomyosis patients. And one of the factors that regulates E-Cadherin is microRNA-10b. In addition, microRNA-let-7ahas been discovered to affect KRAS gene expression, and it is dysregulated in various conditions with abnormal proliferation, such as in conditions of malignancy.

Purpose : The purpose of this study is to observe the correlation between expression of microRNA-10b and E-Cadherin, microRNA-let-7a and KRAS, in endometrial tissue of adenomyosis and non-adenomyosis patients.

Design : Cross-sectional study using comparative and correlation analytic.

Materials and Methods : Samples were collected from 31 women at gynecology and fertility clinic in Dr. Cipto Mangunkusumo Hospital, Jakarta. Subjects are categorized into two groups, adenomyosis group with 17 subjects, and non-adenomyosis group with 15 subjects. Samples were taken through hysteroscopy, laparoscopy, or laparotomy, depending on the procedure indications for each subject. The expression of microRNA-10b, microRNA-let-7a, E-Cadherin, and KRAS then analyzed from each sample.

Result : A significant difference was found in E-Cadherin expression between adenomyosis and non-adenomyosis groups (P=0.001). No significant differences were found in the expression of microRNA-10b, microRNA-let-7a, and KRAS between the two groups. A weak negative correlation was found between the expression of microRNA-let-7a and KRAS in non-adenomyosis group (R=-0.287; P=0.3), but not in adenomyosis group. A weak negative correlation was found between the expression of microRNA-10b and E-Cadherin in both groups.

Conclusion : In this study we observed significant difference in E-Cadherin expression between adenomyosis and non-adenomyosis groups; a weak negative correlation between the expression of microRNA-let-7a and KRAS in the non-adenomyosis group."

"Latar Belakang:Prolaps Organ Panggul (POP) merupakan kondisi kompleks yang terjadi akibat defek pada struktur penyokong vagina. Kondisi ini dapat disebabkan oleh proses trauma pada otot penyokong levator ani yang menyebabkan melebarnya luas hiatus genital. Pelebaran hiatus genital ini disebut ballooning. Prevalensi POP berkisar antara 20-50%, dengan insidensi mencapai 1,5 – 1,8 per 1000 wanita per tahun dengan puncak usia 60 – 69 tahun. Kondisi POP memberi dampak terhadap kualitas hidup seorang wanita dan sering dikaitkan dengan gangguan berkemih, buang air besar hingga disfungsi seksual. Tatalaksana definitif dalam penanganan POP adalah tindakan pembedahan. Tindakan levatorplasty dapat dilakukan pada kasus penurunan kompartemen posterior, terutama pada pasien POP dengan hiatal ballooning. Tindakan ini bertujuan untuk mengurangi risiko prolaps berulang di masa mendatang. Pasien dengan rencana operasi POP di RS Cipto Mangunkusumo (RSCM) Jakarta yang disertai ballooning pada pemeriksaan USG pre-operatif dilakukan tambahan tindakan levatorplasty, namun belum ada penilaian pasca operasi mengenai perbaikan kondisi ballooning tersebut.Objektif:Penelitian ini bertujuan untuk mengetahui perbaikan ballooning sebelum dan setelah dilakukannya tindakan levatorplasty pada pasien dengan POP. Perbaikan yang dinilai berupa perbaikan luas dan panjang diameter anterioposterior hiatus levator, perbaikan panjang Gh + Pb, serta perubahan skor keluhan disfungsi dasar panggul sebelum dan sesudah tindakan. Penilaian dilakukan dengan menggunakan USG 3 dan 2 dimensi untuk hiatus levator, pemeriksaan klinis Pelvic Organ Prolapse Quantification System (POP-Q) untuk panjang Gh + Pb, serta kuisioner Pelvic Floor Distress Inventory-20 (PFDI-20) untuk penilaian keluhan klinis disfungsi dasar panggul.Metode:Studi analitik komparatif berpasangan dengan desain gabungan kohort retrospektif dan kohort prospektif yang dilakukan di Poliklinik Kebidanan dan Kandungan Divisi Uroginekologi dan Rekonstruksi Departemen Obstetri dan Ginekologi RSUPN dr. Cipto Mangunkusumo. Pengumpulan data retrospektif dilakukan dari Oktober 2021 hingga April 2022, dengan pengumpulan data prospektif untuk dilakukan tindakan levatorplasty dilakukan dari Oktober 2021 hingga Januari 2022. Sampel penelitian adalah wanita dengan POP dan ballooning yang dinilai dengan pemeriksaan USG Transperineal serta POP-Q, dan akan menjalani operasi levatorplasty.Hasil:Tingkat keberhasilan levatorplasty pada pasien POP dengan ballooning dilihat dari penurunan derajat ballooning berdasarkan kategori Lh max pada 28 pasien (87,5%), Ap hiatal pada 26 pasien (81,25%), dan panjang Gh + Pb pada 25 pasien (78,1%). Parameter PFDI yang diukur juga mengalami perbaikan dengan penurunan nilai median PFDI mencapai 31,2 (p = 0,009), serta penurunan pada nilai median sub-bagian POPDI-6 hingga 20,8 (p = 0,009), CRADI-6 hingga 6,2 (p = 0,096), dan UDI-6 hingga 10,4 (p = 0,360).Kesimpulan:Prosedur levatorplasty ditemukan dapat memperbaiki kondisi ballooning pada pasien POP yang dinilai dari perbaikan nilai luas dan panjang diameter anteroposterior hiatus levator, perbaikan klinis secara objektif (yang dinilai dengan pemeriksaan POP-Q) serta secara subjektif (yang dinilai dengan kuisioner PFDI-20). Hasil penelitian ini diharapkan mampu menjadi bukti untuk penerapan prosedur levatorplasty untuk dapat dilakukan pada pasien-pasien POP yang disertai dengan ballooning di tempat praktik klinis di semua penjuru Indonesia.

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Background:

Pelvic Organ Prolapse (POP) is a complex condition resulting from defects in the supporting structures of the vagina. This condition can be caused by a traumatic process to the supporting muscles of the levator ani which causes the widening of the genital hiatus. This widening process is called ballooning. The prevalence of POP ranges from 20-50%, with an incidence reaching 1.5-1.8 per 1000 women each year with a peak age of 60-69 years. POP conditions may have an impact on a woman's quality of life and are often associated with urinary and defecation disorders, and also sexual dysfunction. The definitive treatment for POP is surgery. Levatorplasty can be performed in cases of posterior compartment descent, especially in POP patients with Hiatal ballooning. This action aims to reduce the risk of recurrent prolapse in the future. At Dr. Cipto Mangunkusumo Hospital (RSCM) Jakarta, patients with POP who are found with Hiatal ballooning during pre-operative ultrasound examination will be planned for an additional levatorplasty procedure. But there was no postoperative assessment regarding the improvement of the ballooning condition.

Objective:

This study aims to determine the improvement of ballooning after the levatorplasty procedure in patients with POP. The improvements assessed were the area and length of the anteroposterior diameter of the levator hiatus, the length of Gh + Pb, and complaints improvement for pelvic floor dysfunction. The assessment was done using 3- and 2-dimensional ultrasound for levator hiatus, clinical examination of the Pelvic Organ Prolapse Quantification System (POP-Q) for length Gh + Pb, and the Pelvic Floor Distress Inventory-20 (PFDI-20) questionnaire to assess clinical complaints of pelvic floor dysfunction.

Methods:

A paired comparative analytic study with a combined retrospective and prospective cohort design was carried out at the Obstetrics and Gynecology Outpatient Unit, Division of Urogynecology and Reconstruction, Department of Obstetrics and Gynecology, dr. Cipto Mangunkusumo Central General Hospital Jakarta. Retrospective data was collected from October 2021 to April 2022, with prospective data for levatorplasty performed from October 2021 to January 2022. The study sample was women with POP and ballooning who were assessed by transperineal ultrasound examination and POP-Q examination and will undergo levatorplasty procedure.

Result:

The success rate of levatorplasty in POP patients with ballooning was seen from the decrease in the degree of ballooning by the measurement of Lh max in 28 patients (87.5%), Ap hiatal in 26 patients (81.25%), and the length of Gh + Pb in 25 patients (78, 1%). The measured PFDI parameters also improved with a decrease in the median value of PFDI reaching 31.2 (p = 0.009), as well as a decrease in the median value of the POPDI-6 subsection to 20.8 (p = 0.009), CRADI-6 to 6.2 (p = 0.096), and UDI-6 to 10.4 (p = 0.360).

Conclusion:

The levatorplasty procedure is proven to repair the ballooning conditions in POP patients as assessed by improvements in the area and length of the anteroposterior diameter of the levator hiatus, clinical improvement objectively (as assessed by the POP-Q examination), and subjectively (as assessed by the PFDI-20 questionnaire). The results of this study are expected to be evidence for the application of the levatorplasty procedure to be performed on POP patients accompanied by ballooning in many clinical practices throughout Indonesia.

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"A practical guide for the diagnostic surgical pathologist, this new edition of Biopsy Interpretation of the Breast presents the diverse spectrum of pathologic alterations that occur in the breast in a manner analogous to that in which they are encountered in daily practice. Lesions are grouped together according to their histologic patterns rather than by the traditional benign-malignant categorization in order to simulate the way pathologists face these lesions as they examine microscopic slides on a daily basis. The role of adjunctive studies in solving diagnostic problems in breast pathology is emphasized where appropriate.In addition, the clinical significance and impact on patient management of the various diagnoses are discussed and key clinical and management points highlighted."

"This manual for diagnostic cytologists offers detailed guidance on diagnostic problems likely to be encountered in everyday practice. It encompasses exfoliative and aspiration cytology of all major nongynecologic body sites. Each chapter opens with an algorithm that presents the reader with the relevant microscopic findings, the most important additional findings, and the differential diagnostic possibilities and problems in a clear and easily remembered form. Another important feature is the wealth of high-quality color photomicrographs, which clearly document the visual appearances of the most important lesions and highlight the differential diagnostic difficulties. The accompanying text contains helpful general remarks and presents further relevant information on diagnostics, differential diagnostic procedures, and auxiliary methods. Besides established cytologists and pathologists, cytopathologists in training and cytotechnologists will find this book to be a valuable aid."

"This new volume fills the gap in the literature as it will guide urologists and pathologists in the proper utilization of a variety of laboratory methods that are currently available to determine the presence, persistence or progression of tumors of the lower urinary tract. The volume emphasizes cytology of the urinary tract which is preferred over other methods (i.e. biochemical, immunological and cytogenetic) for its accuracy, especially for the important high grade tumors. This volume will appeal to urologists as well as pathologists, cytopathologists and related professions. The illustrations, nearly all in color, stress the key points of the text and enhance basic understanding of urothelial and other tumors of the urinary tract."