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Fulltext Accuracy of Femoral Tunnel Placement between Anteromedial and Anterolateral Visualisation Portals in Anterior Cruciate Ligament Reconstruction - Outcomes of a CT based Cross-Sectional Study

Balaji G, Yadav G, Patel SA, Ramesh A, Nema S, Ramalingam T

Malays Orthop J, 2023 Jul;17(2):7-12.
PMID: 37583529 DOI: 10.5704/MOJ.2307.002

INTRODUCTION: Anatomical femoral tunnel placement is critical for anterior cruciate ligament reconstruction (ACLR). Tunnel placement may vary with different surgical techniques. The aim of this study was to compare the accuracy of femoral tunnel placement between the Anteromedial (AM) and Anterolateral (AL) visualisation portals on post-operative CT scans among a cohort of ACLR patients.
MATERIALS AND METHODS: This cross-sectional study was conducted from January 2018 to March 2020 after obtaining ethics clearance. Patients who went for arthroscopic ACLR in our institute were divided into an AM (group 1) and an AL (group 2) based on the visualisation portal for creating the femoral tunnel and a 3D CT scan was done. The femoral tunnel position was calculated in deep to shallow and high to low direction using the Bernard Hertel grid. Femoral tunnel angle was measured in the 2D coronal image. Statistical analysis was done with the data collected.
RESULTS: Fifty patients with an average age of 26.36 (18-55) years ±7.216 SD were enrolled in the study. In this study, the AM technique was significantly more accurate (p<0.01) than the AL technique in terms of femoral tunnel angle. Furthermore, the deep to the shallow position was significantly (p= 0.018) closer to normative values, as determined by the chi-square test. The chances of error in tunnel angle in femoral condyle are 2.6 times greater in the AL technique (minimal clinical difference).
CONCLUSION: To conclude, in ACLR the anteromedial visualisation portal can facilitate accurate femoral tunnel placement compared to the anterolateral visualisation portal.
Fulltext Endogenous HIF2A reporter systems for high-throughput functional screening

Zaini MN, Patel SA, Syafruddin SE, Rodrigues P, Vanharanta S

Sci Rep, 2018 08 13;8(1):12063.
PMID: 30104738 DOI: 10.1038/s41598-018-30499-2

Tissue-specific transcriptional programs control most biological phenotypes, including disease states such as cancer. However, the molecular details underlying transcriptional specificity is largely unknown, hindering the development of therapeutic approaches. Here, we describe novel experimental reporter systems that allow interrogation of the endogenous expression of HIF2A, a critical driver of renal oncogenesis. Using a focused CRISPR-Cas9 library targeting chromatin regulators, we provide evidence that these reporter systems are compatible with high-throughput screening. Our data also suggests redundancy in the control of cancer type-specific transcriptional traits. Reporter systems such as those described here could facilitate large-scale mechanistic dissection of transcriptional programmes underlying cancer phenotypes, thus paving the way for novel therapeutic approaches.
Fulltext A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma

Syafruddin SE, Rodrigues P, Vojtasova E, Patel SA, Zaini MN, Burge J, et al.

Nat Commun, 2019 03 11;10(1):1152.
PMID: 30858363 DOI: 10.1038/s41467-019-09116-x

Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.
Fulltext NF-κB-Dependent Lymphoid Enhancer Co-option Promotes Renal Carcinoma Metastasis

Rodrigues P, Patel SA, Harewood L, Olan I, Vojtasova E, Syafruddin SE, et al.

Cancer Discov, 2018 Jul;8(7):850-865.
PMID: 29875134 DOI: 10.1158/2159-8290.CD-17-1211

Metastases, the spread of cancer cells to distant organs, cause the majority of cancer-related deaths. Few metastasis-specific driver mutations have been identified, suggesting aberrant gene regulation as a source of metastatic traits. However, how metastatic gene expression programs arise is poorly understood. Here, using human-derived metastasis models of renal cancer, we identify transcriptional enhancers that promote metastatic carcinoma progression. Specific enhancers and enhancer clusters are activated in metastatic cancer cell populations, and the associated gene expression patterns are predictive of poor patient outcome in clinical samples. We find that the renal cancer metastasis-associated enhancer complement consists of multiple coactivated tissue-specific enhancer modules. Specifically, we identify and functionally characterize a coregulatory enhancer cluster, activated by the renal cancer driver HIF2A and an NF-κB-driven lymphoid element, as a mediator of metastasis in vivo We conclude that oncogenic pathways can acquire metastatic phenotypes through cross-lineage co-option of physiologic epigenetic enhancer states.Significance: Renal cancer is associated with significant mortality due to metastasis. We show that in metastatic renal cancer, functionally important metastasis genes are activated via co-option of gene regulatory enhancer modules from distant developmental lineages, thus providing clues to the origins of metastatic cancer. Cancer Discov; 8(7); 850-65. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.