On the origin of ACPA : exploring the role of P. gingivalis in the development of rheumatoid arthritis

Rheumatoid Arthritis (RA) is a systemic autoimmune disease characterized by chronic synovial inflammation, joint destruction, and the presence of anti-citrullinated protein autoantibodies (ACPA) in a majority of patients. Accumulating evidence suggests that ACPA play an important role in RA pathogenesis. ACPA are often detected years before the onset of clinical symptoms, with increasing levels and epitope-spreading preceding the diagnosis of RA. The presence of ACPA is associated with a more severe disease course and recent studies imply that ACPA may directly contribute to inflammation, mediate pain, osteoclast differentiation, and fibroblast migration, and ACPA have been shown to worsen experimental arthritis. Despite progress in revealing ACPA-mediated pathology, the origin of the ACPA response remains largely unknown. The best-known genetic risk factor for RA, HLA-DRB1 shared epitope (SE) alleles, and the most studied environmental risk factor, cigarette smoking, have been linked to ACPA-positive RA. In addition, chronic periodontitis (PD), an inflammatory disease of the tooth supporting tissue, has been epidemiologically linked to RA. Shared genetic and environmental risk factors, together with a unique ability of the periodontal pathogen Porphyromonas gingivalis to express an enzyme that can citrullinate proteins, led to the hypothesis that the initial brake of immune tolerance to citrullinated proteins may be triggered in the gum mucosa during chronic PD. Based on this hypothesis, the aim of my thesis was to investigate the role of P.gingivalis in the etiology of ACPA-positive RA. We have examined the anti-P.gingivalis antibody response in a PD/non-PD cohort and in population-based RA/pre-RA case-control cohorts, and found that anti-P.gingivalis antibody levels are not only significantly elevated in PD patients compared to periodontally-healthy individuals, but in RA patients (in particular ACPA-positive RA) compared to non-RA controls. We identified an association between anti-P.gingivalis antibodies and RA, that was even stronger than the well-known association between smoking and RA, and we could show elevated anti-P.gingivalis antibody levels more than 10 years before clinical onset of RA. Moreover, we have shown that not only RA patients, but a substantial proportion of the general population (likely individuals with PD), have a citrulline-specific antibody response against P.gingivalis. Furthermore, analysis of gingiva-derived monoclonal antibodies from patients with PD revealed the presence of citrulline-reactive B cells in inflamed gingival tissue, and B cells with cross-reactivity between a citrullinated P.gingivalis peptide and citrullinated human antigens were found in the gingival tissue, as well as in peripheral blood and bronchoalveolar lavage of ACPA-positive RA patients. One of the most intriguing findings was that two of these clones were positive in the gold standard clinical CCP2 test, and when one of the clones was converted back to the predicted germline sequence, autoreactivity was lost, while some reactivity against P.gingivalis remained. These data suggest that the initial antibody response was directed against P.gingivalis, and that autoimmunity developed as a result of somatic mutations during affinity maturation of the B cell response. In summary, this thesis supports the hypothesis that in a subset of RA patients, loss of tolerance to citrullinated self-proteins may be triggered in the gum mucosa during chronic PD caused by P.gingivalis. However, in order to establish a causative role for P.gingivalis in the development of ACPA-positive RA, further research is warranted

CHEK2 1100 delC mutation in Russian ovarian cancer patients

BRCA1 and BRCA2 germ-line mutations occur in a significant number of unselected ovarian cancer (OC) patients, thus making a noticeable contribution to OC morbidity. It is of interest whether CHEK2, which is frequently regarded as a third breast cancer specific gene, is also relevant to ovarian cancer pathogenesis. In this report we analyzed the presence of CHEK2 1100 delC founder mutation in 268 randomly recruited OC patients. The mutation was identified in 2 women with OC (0.8%) as compared to 1/448 (0.2%) healthy middle-aged and 0/373 elderly tumour-free women. Taken together this result and the negative findings of two other published reports on an association of CHEK2 with ovarian cancer indicate that there is no justification for intensive ovarian cancer screening in CHEK2 1100 delC carriers

Pengaruh Kualitas Produk, Harga, dan EWOM terhadap Kepuasan Konsumen dengan Keputusan Pembelian Online sebagai Variabel Mediasi pada UMKM “Dapoer Naycha”, Kabupaten Sidoarjo, Jawa Timur.

Jawa Timur merupakan salah satu provinsi di Indonesia yang memiliki wilayah laut serta pesisir yang tersebar potensi perikanannya yang dinilai sangat besar dimana jumlah produksi perikanan lut secara keseluruhan mencapai hingga 111,29 ribu ton. Adanya potensi perikanan tersebut dapat menjadi peluang usaha baik usaha kecil maupun besar. Tidak hanya itu, permintaan yang semakin meningkat ini juga didasari atas adanya kesadaran masyarakat untuk memulai hidup sehat dengan mengkonsumsi makanan yang memiliki kandungan nutrisi yang baik bagi tubuh. Adanya kesadaran dari masyarakat akan pentingnya mengkonsumsi makanan sehat seperti ikan menyebabkan semakin meningkatnya jumlah permintaan konsumen akan produk perikanan, sejalan dengan perkembangan dari bisnis kuliner maupun UMKM yang menjualkan produk perikanan tersebut. Salah satu UMKM yang ada di Jawa Timur yang menjualkan produk perikanan yakni UMKM Dapoer Naycha dengan produk keripik kulit ikan patin merek “Rechista”. UMKM Dapoer Naycha ini berdiri sejak akhir tahun 2019 dan mengalami banyak kemajuan. UMKM ini menjualkan produknya secara online dan ada pun konsumen yang memberikan ulasan terkait kualitas produk, serta harga dari produk UMKM Dapoer Naycha ini. Oleh karenanya, penting sekali bagi UMKM Dapoer Naycha untuk memperhatikan strategi pemasaran yang digunakan, dengan melihat pengaruh dari kualitas produk, harga, dan eWOM terhadap kepuasan konsumen dengan keputusan pembelian online sebagai variabel mediasi. Penelitian ini bertujuan untuk mengetahui pengaruh kualitas produk terhadap kepuasan konsumen, pengaruh harga terhadap kepuasan konsumen, pengaruh eWOM terhadap kepuasan konsumen, hubungan antara keputusan pembelian online dalam memediasi hubungan kualitas produk terhadap kepuasan konsumen, hubungan antara keputusan pembelian online dalam memediasi hubungan harga terhadap kepuasan konsumen, hubungan antara keputusan pembelian online dalam memediasi hubungan eWOM terhadap kepuasan konsumen, dan hubungan antara keputusan pembelian online terhadap kepuasan konsumen Penelitian ini dilaksanakan selama Februari – Maret 2024 di UMKM Dapoer Naycha dengan pendekatan deskriptif kuantitatif. Pada penelitian ini, adapun sampel yang digunakan berjumlah 140 responden yakni konsumen yang pernah membeli produk keripik kulit ikan patin merek “Rechista” dengan kriteria minimal 17 tahun. Adapun analisis data yang digunakan pada penelitian ini ialah dengan menggunakan warpPLS SEM Method serta analisis deskriptif.Adapun hasil penelitian yang diperoleh menunjukkan bahwa kualitas produk, harga, dan eWOM memiliki pengaruh terhadap keputusan pembelian online. Kualitas produk, harga, dan eWOM memiliki pengaruh terhadap kepuasan konsumen. Keputusan pembelian online sebagai variabel mediasi mampu memutuskan kualitas produk terhadap kepuasan konsumen, keputusan pembelian online sebagai variabel mediasi mampu memutuskan harga terhadap kepuasan konsumen, keputusan pembelian online sebagai variabel mediasi tidak mampu memutuskan eWOM terhadap kepuasan konsumen, serta keputusan pembelian online sebagai variabel mediasi memiliki pengaruh signifikan terhadap kepuasan konsumen. Saran yang diberikan yakni perusahaan harus mampu mempertahankan serta meningkatkan strategi pemasaran dengan pendekatan variabel kualitas produk, harga, dan eWOM agar UMKM ini lebih mampu memberikan kepuasan konsumen dan menciptakan adanya keputusan pembelian yang berulang dari konsumen yang puas terhadap produk dari UMKM ini. Adapun saran bagi peneliti selanjutnya yakni dengan menggunakan variabel yang berbeda dan memperluas variabel-variabel lainnya yang tidak terdapat dalam penelitian ini, serta diharapkan bagi peneliti selanjutnya yakni mengambil sampel yang lebih banyak sehingga data yang diperoleh pun lebih akurat

Perencanaan usaha pengolahan pangan Goguma Latte "Guma-guma" dengan kapasitas 1000 botol (@250ml) per hari

Goguma Latte merupakan minuman yang berasal dari negara Korea Selatan, biasanya terbuat dari beberapa bahan seperti ubi manis kukus atau bakar, susu, dan gula atau madu. Variasi pengolahan ubi jalar di Indonesia masih kurang, sehingga erlu pengembangan pengolahan ubi jalar menjadi produk pangan dengan variasi yang lebih beragam dengan harapan terjadi peningkatan konsumsi ubi jalar sekaligus meningkatkan nilai tambah. Goguma Latte merupakan salah satu produk minuman yang dapat dibuat dari ubi jalar terutama ubi jalar ungu. Usaha Goguma Latte “GumaGuma” direncanakan dengan kapasitas produksi sebesar 1.000 botol (@250 mL)/hari. Bahan yang digunakan dalam produksi Goguma Latte adalah ubi jalar ungu, susu low-fat, dan madu. Tahapan proses produksi Goguma Latte adalah penimbangan, pencucian, pengukusan, penghancuran, penyaringan, pengemasan, dan pendinginan. Produk Goguma Latte "Guma-Guma” dikemas dalam botol PET (Polyethylen Therepthalate) dengan tutup yang bersegel. Produk Goguma Latte “Guma-Guma” dijual dengan harga Rp 12.500,00 dan diperoleh keuntungan sebesar 36,64%. Lokasi usaha direncanakan didirikan di Jalan Doho No. 14, Surabaya, Jawa Timur. Usaha Goguma Latte “Guma-Guma” merupakan usaha kecil dengan jumlah pekerja sebanyak tiga orang dan jam kerja delapan jam/hari. Pemasaran produk dilakukan melalui media sosial dan penawaran langsung kepada konsumen. Usaha Goguma Latte ”Guma-Guma” memiliki total modal investasi sebesar Rp 183.815.590 dan total biaya produksi sebesar Rp 2.841.297.005 dengan laju pengembalian sebelum pajak sebesar 249,33% dan sesudah pajak sebesar 240,36%. Waktu pengembalian sebelum pajak adalah 4 bulan 78 hari sedangkan sesudah pajak adalah 4 bulan 96 hari. Usaha Goguma Latte “Guma-Guma” memiliki titik impas sebesar 59,45%

CHEK2 1100 delC mutation in Russian ovarian cancer patients

Abstract BRCA1 and BRCA2 germ-line mutations occur in a significant number of unselected ovarian cancer (OC) patients, thus making a noticeable contribution to OC morbidity. It is of interest whether CHEK2, which is frequently regarded as a third breast cancer specific gene, is also relevant to ovarian cancer pathogenesis. In this report we analyzed the presence of CHEK2 1100 delC founder mutation in 268 randomly recruited OC patients. The mutation was identified in 2 women with OC (0.8%) as compared to 1/448 (0.2%) healthy middle-aged and 0/373 elderly tumour-free women. Taken together this result and the negative findings of two other published reports on an association of CHEK2 with ovarian cancer indicate that there is no justification for intensive ovarian cancer screening in CHEK2 1100 delC carriers.</p

Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis

Background: The periodontal pathogen Porphyromonas gingivalis is hypothesized to be important in rheumatoid arthritis (RA) aetiology by inducing production of anti-citrullinated protein antibodies (ACPA). We have shown that ACPA precede RA onset by years, and that anti-P. gingivalis antibody levels are elevated in RA patients. The aim of this study was to investigate whether anti-P. gingivalis antibodies pre-date symptom onset and ACPA production. Methods: A case-control study (251 cases, 198 controls) was performed within the Biobank of Northern Sweden. Cases had donated blood samples (n = 422) before the onset of RA symptoms by 5.2 (6.2) years (median (interquartile range)). Blood was also collected from 192 RA patients following diagnosis. Antibodies against P. gingivalis virulence factor arginine gingipainB (RgpB), and a citrullinated peptide (CPP3) derived from the P. gingivalis peptidylarginine deiminase enzyme, were analysed by ELISA. Results: Anti-RgpB IgG levels were significantly increased in pre-symptomatic individuals (mean +/- SEM; 152.7 +/- 14.8 AU/ml) and in RA patients (114.4 +/- 16.9 AU/ml), compared with controls (p &lt; 0.001). Anti-CPP3 antibodies were detected in 5 % of pre-symptomatic individuals and in 8 % of RA patients, with elevated levels in both subsets (4.33 +/- 0.59 and 9.29 +/- 1.81 AU/ml, respectively) compared with controls (p &lt; 0.001). Anti-CPP3 antibodies followed the ACPA response, with increasing concentrations over time, whilst anti-RgpB antibodies were elevated and stable in the pre-symptomatic individuals with a trend towards lower levels after RA diagnosis. Conclusions: Anti-P. gingivalis antibody concentrations were significantly increased in RA patients compared with controls, and were detectable years before onset of symptoms of RA, supporting an aetiological role for P. gingivalis in the development of RA