The effects of knee meniscectomy on the development of osteoarthritis in the patellofemoral joint 40 years following meniscectomy

Abstract: Most knee osteoarthritis and meniscectomy studies focus on osteoarthritis in the tibiofemoral joint and ignore the patellofemoral joint. This study aims to assess the long-term effects of total meniscectomy on the patellofemoral joint. To our knowledge, this is the only study of osteoarthritis in the patellofemoral joint following meniscectomy that extends to a 40-year follow-up period. Twenty-two patients with osteoarthritis were evaluated at a mean of 40 years post-meniscectomy using standardised weight-bearing radiographs of the operated and non-operated knees. Patellofemoral joint osteoarthritis was diagnosed by the presence of osteophytes and joint space narrowing to less than 5 mm. Kellgren and Lawrence scores were calculated from the radiographs. Patellofemoral joint osteoarthritis and tibiofemoral joint osteoarthritis were correlated with International Knee Documentation Committee scores and range of movement measurements. A significant difference was observed between the operated and non-operated knees in terms of patellofemoral joint osteophyte formation. There was a significant difference in tibiofemoral joint Kellgren and Lawrence scores, International Knee Documentation Committee scores and range of movement measurements between knees with lateral facet patellofemoral joint space of 5 mm. This study shows an association between open total meniscectomy and patellofemoral joint osteoarthritis at 40 years following surgery. There was also an association between patellofemoral joint space narrowing in the lateral facet and tibiofemoral joint osteoarthritis. Possible causes include altered biomechanical loading patterns following meniscectomy as well as global processes within the knee

A Modified Method for Whole Exome Resequencing from Minimal Amounts of Starting DNA

Next generation DNA sequencing (NGS) technologies have revolutionized the pace at which whole genome and exome sequences can be generated. However, despite these advances, many of the methods for targeted resequencing, such as the generation of high-depth exome sequences, are somewhat limited by the relatively large amounts of starting DNA that are normally required. In the case of tumour analysis this is particularly pertinent as many tumour biopsies often return submicrogram quantities of DNA, especially when tumours are microdissected prior to analysis. Here, we present a method for exome capture and resequencing using as little as 50 ng of starting DNA. The sequencing libraries generated by this minimal starting amount (MSA-Cap) method generate datasets that are comparable to standard amount (SA) whole exome libraries that use three micrograms of starting DNA. This method, which can be performed in most laboratories using commonly available reagents, has the potential to enhance large scale profiling efforts such as the resequencing of tumour exomes

Hubungan Asupan Protein, Seng, Zat Besi, Dan Riwayat Penyakit Infeksi Dengan Z-score Tb/u Pada Balita

Latar Belakang : Masalah gizi yang paling banyak ditemukan pada anak di Indonesia adalah stunting, Indikator untuk menilai stunting berdasarkan pada Indeks Tinggi Badan menurut Umur (TB/U) dengan ambang batas (Z-score) <-2 Standart Deviasi (SD). Several micronutrients are required for adequate growth among children. However, it has been unclear as to which nutrient deficiencies contribute most often to growth faltering in populations at risk for poor nutrition and poor growth. Inadequate intakes of dietary energy and protein and frequent infections are well-known causes of growth retardation (3–5). However, the role of specific micronutrient deficiencies in the etiology of growth retardation has gained attention more recently (6–8). Tujuan : Mengetahui hubungan antara asupan protein, seng, zat besi, dan penyakit infeksi terhadap indeks z-score TB/U pada Balita usia 24-59 bulan.Metode : Penelitian observasional dengan pendekatan cross sectional di Kelurahan Jangli Semarang, jumlah sampel 61 Balita usia 24-59 bulan, dipilih dengan simple random sampling. Data yang dikumpulkan meliputi: identitas sampel, berat badan, tinggi badan, riwayat asupan makan, dan riwayat penyakit infeksi. Berat badan diukur menggunakan timbangan digital dan tinggi badan diukur menggunakan microtoise. Asupan protein, seng, zat besi, dan riwayat penyakit infeksi diperoleh dari food frequency questionairre semi-kuantitatif. Data dianalisis dengan uji analisis depskripsi, analisis bivariate menggunakan uji Chi Square, Pearson, dan Spearman.Hasil : Sebanyak 36,1 subjek mengalami stunting. Rerata z-score TB/U -1,25 ± 1,2. Rerata asupan protein, seng, dan zat besi subjek berturut-turut 34.8 ± 13 g, 5.2 ± 2.5 mg, 8.2 ± 6.5 mg dengan sebagian besar tingkat kecukupan protein, seng, dan zat besi subjek adalah cukup. Sebanyak 29.1% subjek memiliki riwayat infeksi. Terdapat hubungan antara protein dan penyakit infeksi dengan z-score TB/U pada Balita. Tidak terdapat hubungan antara asupan seng, dan zat besi dengan z-score TB/U pada Balita. Simpulan : Terdapat hubungan antara asupan protein dan riwayat penyakit infeksi terhadap indeks z-score TB/U pada Balita

High-throughput RNA interference screening using pooled shRNA libraries and next generation sequencing

RNA interference (RNAi) screening is a state-of-the-art technology that enables the dissection of biological processes and disease-related phenotypes. The commercial availability of genome-wide, short hairpin RNA (shRNA) libraries has fueled interest in this area but the generation and analysis of these complex data remain a challenge. Here, we describe complete experimental protocols and novel open source computational methodologies, shALIGN and shRNAseq, that allow RNAi screens to be rapidly deconvoluted using next generation sequencing. Our computational pipeline offers efficient screen analysis and the flexibility and scalability to quickly incorporate future developments in shRNA library technology

Comprehensive Genomic Analysis of a BRCA2 Deficient Human Pancreatic Cancer

Capan-1 is a well-characterised BRCA2-deficient human cell line isolated from a liver metastasis of a pancreatic adenocarcinoma. Here we report a genome-wide assessment of structural variations and high-depth exome characterization of single nucleotide variants and small insertion/deletions in Capan-1. To identify potential somatic and tumour-associated variations in the absence of a matched-normal cell line, we devised a novel method based on the analysis of HapMap samples. We demonstrate that Capan-1 has one of the most rearranged genomes sequenced to date. Furthermore, small insertions and deletions are detected more frequently in the context of short sequence repeats than in other genomes. We also identify a number of novel mutations that may represent genetic changes that have contributed to tumour progression. These data provide insight into the genomic effects of loss of BRCA2 function

Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.

Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer

Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor

Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.We acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre. Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA 148537 for Elucidating Loci Involved in Prostate cancer Susceptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I). Additional analytical support was provided by NIH NCI U01 CA188392. The PRACTICAL consortium was supported by Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692 and C16913/A6135; the European Commission’s Seventh Framework Programme grant agreement 223175 (HEALTH-F2-2009-223175) (D.F.E., R.E. and Z.K.-J.); and the NIH Cancer Post-Cancer GWAS initiative grant 1 U19 CA 148537-01 (the GAME-ON initiative). We thank the following for funding support: the Institute of Cancer Research and the Everyman Campaign, the Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), the Orchid Cancer Appeal, the National Cancer Research Network UK and the National Cancer Research Institute (NCRI) UK. We are grateful for NIHR funding to the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust. We acknowledge funding from the Swedish Cancer Society (CAN2011/484 and CAN2012/823), the Norwegian Cancer Society (grants 418975-71081-PR-2006-0387 and PK01-2007- 0375) and the Nordic Cancer Union (grant S-12/07). This study was supported by the Movember Foundation and the Institute of Cancer Research. K.L. is supported by a PhD fellowship from Cancer Research UK. R.S.H. and P.B. are supported by Cancer Research UK (C1298/A8362 Bobby Moore Fund for Cancer Research UK)

The effects of knee meniscectomy on the development of osteoarthritis in the patellofemoral joint 40 years following meniscectomy

Abstract: Most knee osteoarthritis and meniscectomy studies focus on osteoarthritis in the tibiofemoral joint and ignore the patellofemoral joint. This study aims to assess the long-term effects of total meniscectomy on the patellofemoral joint. To our knowledge, this is the only study of osteoarthritis in the patellofemoral joint following meniscectomy that extends to a 40-year follow-up period. Twenty-two patients with osteoarthritis were evaluated at a mean of 40 years post-meniscectomy using standardised weight-bearing radiographs of the operated and non-operated knees. Patellofemoral joint osteoarthritis was diagnosed by the presence of osteophytes and joint space narrowing to less than 5 mm. Kellgren and Lawrence scores were calculated from the radiographs. Patellofemoral joint osteoarthritis and tibiofemoral joint osteoarthritis were correlated with International Knee Documentation Committee scores and range of movement measurements. A significant difference was observed between the operated and non-operated knees in terms of patellofemoral joint osteophyte formation. There was a significant difference in tibiofemoral joint Kellgren and Lawrence scores, International Knee Documentation Committee scores and range of movement measurements between knees with lateral facet patellofemoral joint space of 5 mm. This study shows an association between open total meniscectomy and patellofemoral joint osteoarthritis at 40 years following surgery. There was also an association between patellofemoral joint space narrowing in the lateral facet and tibiofemoral joint osteoarthritis. Possible causes include altered biomechanical loading patterns following meniscectomy as well as global processes within the knee