Analyzing Parental Age to Determine Types of Cleft in Hayandra Peduli Foundation Patient, Indonesia

Cleft lip and palate are complex and known to have multifactorial risk factors with a prevalence of 0.2% in Indonesia. Also, there is no specific data about parental age-related to types of a cleft in Indonesia. This study aims to analyze parental age-related to types of cleft in patients treated by Hayandra Peduli Foundation, Indonesia. The data was collected from 2014 to 2018 from social service held by Hayandra Peduli Foundation. The data collected primarily, and 604 subjects were obtained. The results showed that 81.5% of patients were 0-5 of age, with patients' distribution were 356 male patients and 248 female patients. There was no significant correlation between maternal age and each type of cleft. Furthermore, there was no correlation between paternal age and types of cleft based on maternal group age. For young and ideal maternal group age, their p-value showed no significant correlation (p-value 0.393 for young maternal age and 0.941 for ideal maternal age). Surprisingly, the old maternal group age shows significant results, with a p-value of 0.045. In conclusion, we found that cleft palate will occur in infants born from an aging mother (>35 years old).

Novel cell based in vitro models to study nanoparticle interaction with the inflamed intestinal mucosa

Along with increasing research in the field of drug delivery and nanotechnology there is an urgent need to improve test tools for efficacy and safety of nanomedicines. In this thesis an in vitro model of the inflamed intestinal mucosa was developed which combined with a novel silicon nitride based cell culture support advances drug and formulation testing in the context of inflammatory bowel disease. The in vitro model consists of an epithelial cell line combined with primary macrophages and dendritic cells and stimulated via pro-inflammatory factors such as interleukin-1β (IL-1ß). The model reflects pathophysiological changes observed in vivo e.g. decreased epithelial barrier function, increased production of pro-inflammatory cytokines, and increased mucus production. The potential as a testing system for (nano)-formulations was demonstrated comparing anti-inflammatory activity of liposomal budesonide and polymeric nanospheres. Increased activity of budesonide nanoparticles which accumulate in the tight junctional region was observed. In addition, hindered diffusion of particles and macromolecules that caused underestimation of transport across standard, polyester based cell culture supports was addressed. The silicon nitride based microporous membranes of only 500 nm thickness proposed in this thesis provided excellent growth properties while reducing the membrane influence, thus allowing the first study on nanoparticle translocation across the intestine in vitro.Um die Effizienz und Sicherheit von Nanomedikamenten zu bestimmen müssen in vitro Testsysteme angepasst und optimiert werden. In dieser Arbeit wurde ein in vitro Modell der entzündeten Darmmukosa und einem neuartigen Silikonnitrid basiertem Zellkultursystem entwickelt, mit dem die Testung von Arzneistoffen und Formulierungen zur Therapie chronisch entzündlicher Darmerkrankungen erlaubt. In einer Ko-Kultur von intestinalen Epithelzellen mit primären Makrophagen und dendritischen Zellen, wird über die Zugabe von IL-1ß eine Entzündung ausgelöst. Im Modell zeigen sich daraufhin pathophysiologische Veränderungen wie eine Verminderung der Barriereeigenschaften und eine verstärkte Produktion von Mukus und Zytokinen. Der Einsatz als Testsystem für verschiedene pharmazeutische (Nano)-Formulierungen wurde am Beispiel des Budesonid überprüft und wurden miteinander verglichen. Nur die Nanopartikel reicherten sich zwischen den Epithelzellen an und hatten die höchste antientzündliche Potenz. Ein zusätzliches Problem in der in vitro Testung von Nanopartikeln stellen die herkömmlichen Zellkultursubstrate auf Basis von Polyestermembranen dar. Auf Grund des kleinen Porenradius und der relativen Membrandicke wird die freie Diffusion größerer Teilchen über den Filter eingeschränkt. Der Einsatz einer Silikonnitridmembran mit einer Dicke von nur 500 nm beschleunigte den Transport der Partikel und erlaubte erstmals die Bestimmung relevanter Translokationsdaten über funktionelle Caco-2 Monolayer

Faktor-Faktor yang Berhubungan dengan Keberhasilan Terapi GERD

AbstrakIntroduksi: Penyakit Refluks Gastro Esofagus (PRGE) atau yang lebih dikenal dengan nama Gastro Esophageal Reflux Disease (GERD), merupakan kondisi yang terjadi bila aliran balik isi lambung ke esofagus memberikan keluhan dan mengganggu kualitas hidup seseorang.Tujuan:  Penelitian  ini  bertujuan  untuk  menganalisis  faktor-faktor  yang  berhubungan  dengan keberhasilan terapi GERD, serta menguji keefektifan dalam mendiagnosis GERD dengan menggunakan kuesioner GERD Q.Metode: Enam puluh subjek yang memiliki gejala heartburn dan atau regurgitasi didata selama periode Maret-Mei 2015, dengan menggunakan disain analitik kuantitatif observasional. Kuesioner GERD Q terdiri atas enam pertanyaan sederhana meliputi gejala refluks, dispepsia, dan konsumsi obat, skor ≥8 yang mendukung diagnosis GERD. Pasien GERD diterapi selama dua minggu dan diberikan obat sesuai dengan resep dokter dan kontrol kembali.Hasil: Berdasarkan hasil univariat, didapatkan 56,7% (34 subjek) adalah perempuan, gejala klinis heartburn atau regurgitasi saja ditemukan 63.3% (38 subjek), usia < 40 sebanyak 55% (33 subjek), nilai IMT ≥25 ditemukan 66.7% (40 subjek), pemberian terapi PPI dan prokinetik ditemukan 50% (30 subjek), gaya  hidup  sehat  sebanyak  81.7%  (49  subjek),  dan  GERD  Q  post-test yang  membaik sebanyak  66.7%  (40  orang).  Pada  hasil  bivariat  didapatkan  hubungan  yang  bermakna  antarakeberhasilan terapi dengan usia (p 0.028 ,OR 3.667), jenis kelamin (p 0.002; OR 7.667), gejala klinis (p 0.037; OR 3.222), IMT (p 0.033; OR 4.188), dan terapi (p 0.001; OR 7.429).Kesimpulan: Pasien GERD di RSUD Koja yang berusia ≥ 40 tahun, laki-laki, nilai IMT ≥ 25 kg/m2, dan  memiliki  gejala  heartburn  atau  regurgitasi  saja, setelah  diterapi  dengan  PPI dan  prokinetik memiliki keberhasilan terapi yang lebih baik. Tetapi keberhasilan terapi GERD tidak dipengaruhi gaya hidup.Kata kunci: GERD Q, heartburn, regurgitasi, terapi AbstractIntroductions: Gastro Esophageal Reflux Disease (PRGE) or better known as Gastro Esophageal Reflux Disease (GERD) is a condition that occurs when the backflow of gastric contents into the esophagus giving complaints and interfere with quality of life.Objective: This study aimed to analyze the factors associated with the therapeutic efficacy on GERD as well as to test the effectiveness of using questionnaire that are to diagnose, GERD Q.Methods: Sixty subjects with symptoms of heartburn and regurgitation recorded during the period from  March  until  May  2015  using  a  quantitative analytical  observational  design.  Q  GERD questionnaire  consist  of  six  simple questions  include  symptoms  of  reflux, dyspepsia  and  drug consumption, the score ≥8 that support the diagnosis of GERD. GERD patients treated for 2 weeks and was given medication as prescribed and control back.Results: Based on univariate results, 56.7% (34 subjects) were women, the clinical symptoms of heartburn or regurgitation alone found in 63.3% (38 subjects), age <40 were 55% (33 subjects), the value  of  BMI ≥25  was  found  66.7% (40  subjects),  PPI  and  prokinetic therapy  found  50% (30 subjects), a healthy lifestyle as much as 81.7% (49 subjects) and GERD Q post-test were improved as much  as  66.7%  (40 people).  In  the  bivariate  results  of  a significant  association  between  the therapeutic efficacy with age (p 0.028, OR 3667), gender (p 0.002; OR 7,667), clinical symptoms (p 0.037; OR 3.222), BMI (p 0.033; OR 4188), and therapy (p 0.001; OR 7429).Conclusion: Patients GERD in Koja Hospital ≥ 40 years old, male, BMI values ≥ 25 kg / m2, and have symptoms of heartburn or regurgitation alone, after therapy with PPI and prokinetic have a better therapeutic success. But the success of GERD therapy is not influenced by lifestyle. Keywords: Q GERD, heartburn, regurgitation, therapy

Magnetically Bioprinted Human Myometrial 3D Cell Rings as A Model for Uterine Contractility

Deregulation in uterine contractility can cause common pathological disorders of the female reproductive system, including preterm labor, infertility, inappropriate implantation, and irregular menstrual cycle. A better understanding of human myometrium contractility is essential to designing and testing interventions for these important clinical problems. Robust studies on the physiology of human uterine contractions require in vitro models, utilizing a human source. Importantly, uterine contractility is a three-dimensionally (3D)-coordinated phenomenon and should be studied in a 3D environment. Here, we propose and assess for the first time a 3D in vitro model for the evaluation of human uterine contractility. Magnetic 3D bioprinting is applied to pattern human myometrium cells into rings, which are then monitored for contractility over time and as a function of various clinically relevant agents. Commercially available and patient-derived myometrium cells were magnetically bioprinted into rings in 384-well formats for throughput uterine contractility analysis. The bioprinted uterine rings from various cell origins and patients show different patterns of contractility and respond differently to clinically relevant uterine contractility inhibitors, indomethacin and nifedipine. We believe that the novel system will serve as a useful tool to evaluate the physiology of human parturition while enabling high-throughput testing of multiple agents and conditions

Macrophage Polarization Contributes to the Anti-Tumoral Efficacy of Mesoporous Nanovectors Loaded with Albumin-Bound Paclitaxel

Therapies targeted to the immune system, such as immunotherapy, are currently shaping a new, rapidly developing branch of promising cancer treatments, offering the potential to change the prognosis of previously non-responding patients. Macrophages comprise the most abundant population of immune cells in the tumor microenvironment (TME) and can undergo differentiation into functional phenotypes depending on the local tissue environment. Based on these functional phenotypes, tumor-associated macrophages (TAMs) can either aid tumor progression (M2 phenotype) or inhibit it (M1 phenotype). Presence of M2 macrophages and a high ratio of M2/M1 macrophages in the TME are clinically associated with poor prognosis in many types of cancers. Herein, we evaluate the effect of macrophage phenotype on the transport and anti-cancer efficacy of albumin-bound paclitaxel (nAb-PTX) loaded into porous silicon multistage nanovectors (MSV). Studies in a coculture of breast cancer cells (3D-spheroid) with macrophages and in vivo models were conducted to evaluate the therapeutic efficacy of MSV-nAb-PTX as a function of macrophage phenotype. Association with MSV increased drug accumulation within the macrophages and the tumor spheroids, shifting the inflammation state of the TME toward the pro-inflammatory, anti-tumorigenic milieu. Additionally, the treatment increased macrophage motility toward cancer cells, promoting the active transport of therapeutic nanovectors into the tumor lesion. Consequently, apoptosis of cancer cells was increased and proliferation decreased in the MSV-nAb-PTX-treated group as compared to controls. The results also confirmed that the tested system shifts the macrophage differentiation toward an M1 phenotype, possessing an anti-proliferative effect toward the breast cancer cells. These factors were further incorporated into a mathematical model to help analyze the synergistic effect of the macrophage polarization state on the efficacy of MSV-nAb-PTX in alleviating hypovascularized tumor lesions. In conclusion, the ability of MSV-nAb-PTX to polarize TAM to the M1 phenotype, causing (1) enhanced penetration of the drug-carrying macrophages to the center of the tumor lesion and (2) increased toxicity to tumor cells may explain the increased anti-cancer efficacy of the system in comparison to nAb-PTX and other controls

Insights into Nanomedicine for Immunotherapeutics in Squamous Cell Carcinoma of the head and neck

Xu Q, Fang M, Zhu J, et al. Insights into Nanomedicine for Immunotherapeutics in Squamous Cell Carcinoma of the head and neck. International Journal of Biological Sciences. 2020;16(14):2506-2517

Systemic Gene Silencing in Primary T Lymphocytes Using Targeted Lipid Nanoparticles

Modulating T cell function by down-regulating specific genes using RNA interference (RNAi) holds tremendous potential in advancing targeted therapies in many immune-related disorders including cancer, inflammation, autoimmunity, and viral infections. Hematopoietic cells, in general, and primary T lymphocytes, in particular, are notoriously hard to transfect with small interfering RNAs (siRNAs). Herein, we describe a novel strategy to specifically deliver siRNAs to murine CD4⁺ T cells using targeted lipid nanoparticles (tLNPs). To increase the efficacy of siRNA delivery, these tLNPs have been formulated with several lipids designed to improve the stability and efficacy of siRNA delivery. The tLNPs were surface-functionalized with anti-CD4 monoclonal antibody to permit delivery of the siRNAs specifically to CD4⁺ T lymphocytes. <i>Ex vivo</i>, tLNPs demonstrated specificity by targeting only primary CD4⁺ T lymphocytes and no other cell types. Systemic intravenous administration of these particles led to efficient binding and uptake into CD4⁺ T lymphocytes in several anatomical sites including the spleen, inguinal lymph nodes, blood, and the bone marrow. Silencing by tLNPs occurs in a subset of circulating and resting CD4⁺ T lymphocytes. Interestingly, we show that tLNP internalization and not endosome escape is a fundamental event that takes place as early as 1 h after systemic administration and determines tLNPs’ efficacy. Taken together, these results suggest that tLNPs may open new avenues for the manipulation of T cell functionality and may help to establish RNAi as a therapeutic modality in leukocyte-associated diseases

Systemic Gene Silencing in Primary T Lymphocytes Using Targeted Lipid Nanoparticles

Modulating T cell function by down-regulating specific genes using RNA interference (RNAi) holds tremendous potential in advancing targeted therapies in many immune-related disorders including cancer, inflammation, autoimmunity, and viral infections. Hematopoietic cells, in general, and primary T lymphocytes, in particular, are notoriously hard to transfect with small interfering RNAs (siRNAs). Herein, we describe a novel strategy to specifically deliver siRNAs to murine CD4⁺ T cells using targeted lipid nanoparticles (tLNPs). To increase the efficacy of siRNA delivery, these tLNPs have been formulated with several lipids designed to improve the stability and efficacy of siRNA delivery. The tLNPs were surface-functionalized with anti-CD4 monoclonal antibody to permit delivery of the siRNAs specifically to CD4⁺ T lymphocytes. <i>Ex vivo</i>, tLNPs demonstrated specificity by targeting only primary CD4⁺ T lymphocytes and no other cell types. Systemic intravenous administration of these particles led to efficient binding and uptake into CD4⁺ T lymphocytes in several anatomical sites including the spleen, inguinal lymph nodes, blood, and the bone marrow. Silencing by tLNPs occurs in a subset of circulating and resting CD4⁺ T lymphocytes. Interestingly, we show that tLNP internalization and not endosome escape is a fundamental event that takes place as early as 1 h after systemic administration and determines tLNPs’ efficacy. Taken together, these results suggest that tLNPs may open new avenues for the manipulation of T cell functionality and may help to establish RNAi as a therapeutic modality in leukocyte-associated diseases