Genomic alteration discordance in the paired primary-recurrent ovarian cancers: based on the comprehensive genomic profiling (CGP) analysis.

PURPOSE: Ovarian cancer (OC) is characterized by a high recurrence rate, and homologous recombination deficiency (HRD) is an important biomarker in the clinical management of OC. We investigated the differences in clinical genomic profiles between the primary and platinum-sensitive recurrent OC (PSROC), focusing on HRD status. MATERIALS AND METHODS: A total of 40 formalin-fixed paraffin-embedded (FFPE) tissues of primary tumors and their first platinum-sensitive recurrence from 20 OC patients were collected, and comprehensive genomic profiling (CGP) analysis of FoundationOne®CDx (F1CDx) was applied to explore the genetic (dis)similarities of the primary and recurrent tumors. RESULTS: By comparing between paired samples, we found that genomic loss of heterozygosity (gLOH) score had a high intra-patient correlation (r2 = 0.79) and that short variants (including TP53, BRCA1/2 and NOTCH1 mutations), tumor mutational burden (TMB) and microsatellite stability status remained stable. The frequency of (likely) pathological BRCA1/2 mutations was 30% (12/40) in all samples positively correlated with gLOH scores, but the proportion of gLOH-high status (score > 16%) was 50% (10/20) and 55% (11/20) in the primary and recurrent samples, respectively. An additional 20% (4/20) of patients needed attention, a quarter of which carried the pathological BRCA1 mutation but had a gLOH-low status (gLOH < 16%), and three-quarters had different gLOH status in primary-recurrent pairs. Furthermore, we observed the PSROC samples had higher gLOH scores (16.1 ± 9.24 vs. 19.4 ± 11.1, p = 0.007), more CNVs (36.1% vs. 15.1% of discordant genomic alternations), and significant enrichment of altered genes in TGF-beta signaling and Hippo signaling pathways (p < 0.05 for all) than their paired primaries. Lastly, mutational signature and oncodrive gene analyses showed that the computed mutational signature similarity in the primary and recurrent tumors were best matched the COSMI 3 signature (Aetiology of HRD) and had consistent candidate cancer driver genes of MSH2, NOTCH1 and MSH6. CONCLUSION: The high genetic concordance of the short variants remains stable along OC recurrence. However, the results reveal significantly higher gLOH scores in the recurrent setting than in paired primaries, supporting further clinically instantaneity HRD assay strategy.

Electromagnetohydrodynamic (EMHD) flow of Jeffrey fluid through a rough circular microchannel with surface charge-dependent slip.

This research examines the electromagnetohydrodynamic (EMHD) flow of Jeffrey fluid in a rough circular microchannel while considering the effect of surface charge on slip. The channel wall corrugations are described as periodic sinusoidal waves with small amplitudes. The perturbation method is employed to derive solutions for velocity and volumetric flow rate, and a combination of three-dimensional (3D) and two-dimensional (2D) graphical representations is utilized to effectively illustrate the impacts of relevant parameters on them. The significance of the Reynolds number R e $Re$ in investigations of EMHD flow is particularly emphasized. Furthermore, the effect of wall roughness ε $\varepsilon $ and wave number k $k$ on velocity and the influence of wall roughness ε $\varepsilon $ and surface charge density σ s ${\sigma }_s$ on volumetric flow rate are primarily focused on, respectively, at various Reynolds numbers. The results suggest that increasing the wall roughness leads to a reduction in velocity at low Reynolds numbers ( R e = 1 $Re = 1$ ) and an increment at high Reynolds numbers ( R e = 10 $Re = 10$ ). For any Reynolds number, a roughness with an odd multiple of wave number ( k = 6 , 10 $k = 6,10$ ) will result in a more stable velocity profile compared to one with an even multiple of wave number ( k = 4 , 8 $k = 4,8$ ). Decreasing the relaxation time λ ¯ 1 ${\bar{\lambda }}_1$ while increasing the retardation time λ ¯ 2 ${\bar{\lambda }}_2$ and Hartmann number H a $Ha$ can diminish the impact of wall roughness ε $\varepsilon $ and surface charge density σ s ${\sigma }_s$ on volumetric flow rate, independent of the Reynolds number. Interestingly, in the existence of wall roughness, further consideration of the effect of surface charge on slip leads to a 15% drop in volumetric flow rate at R e = 1 $Re = 1$ and a 32% slippage at R e = 10 $Re = 10$ . However, in the condition where the effect of surface charge on slip is considered, further examination of the presence of wall roughness only results in a 1.4% decline in volumetric flow rate at R e = 1 $Re = 1$ and a 1.6% rise at R e = 10 $Re = 10$ . These findings are crucial for optimizing the EMHD flow models in microchannels.

Platinum Resistance After PARPi Resistance in a gBRCAmt Recurrent Ovarian Cancer Patient: a Case Report.

As the most lethal gynecological malignant tumor, ovarian cancer is prone to recurrence and drug resistance. Poly(ADP-ribose) polymerase inhibitors are known to be effective in ovarian cancer patients as maintenance treatment, especially in patients with BRCA mutation. The current controversy is whether the use of poly(ADP-ribose) polymerase inhibitors may affect subsequent platinum sensitivity. A Chinese female patient diagnosed with high-grade serous ovarian cancer experienced five platinum-sensitive relapses. After obtaining informed consent from the patient, we performed next-generation gene sequencing and detected a germline BRCA1 pathologic mutation. When the patient achieved partial response with platinum after the fifth platinum-sensitive relapse, exploratory posterior-line maintenance therapy was performed due to her genotype. But the patient rapidly progressed to platinum resistance after poly(ADP-ribose) polymerase inhibitor resistance. In a gBRCAmt patient with platinum-sensitive recurrent ovarian cancer, olaparib as exploratory posterior-line maintenance treatment is barely effective and may affect the response to subsequent platinum therapy.

Live cell measurements of interaction forces and binding kinetics between Discoidin Domain Receptor 1 (DDR1) and collagen I with atomic force microscopy.

BACKGROUND: Discoidin Domain Receptors (DDRs) are membrane-tethered proteins of the receptor tyrosine kinase family, which signal in response to collagen. DDR expression is associated with human diseases, including fibrosis and cancer. The role of DDRs in human pathogenesis is mediated by dysregulated receptor function in response to the collagenous milieu. Thus, understanding DDR-collagen interactions is important for developing novel therapeutic strategies against DDRs. METHODS: We developed a biophysical method to isolate and measure specific interactions between DDR1 and collagen in live cells at the single molecule level using atomic force microscopy. This new method is capable of providing density and kinetics of membrane receptors in live cells. RESULTS: We isolated DDR1-collagen interactions and quantified the association and dissociation rates of the DDR1-collagen I complex. We estimated separate binding probabilities of collagen I to DDR and integrin, and by combining kinetic and binding probability data, we were able to estimate the density of receptors in two cancer cell types. We also tested the viability of a DDR1 blocking antibody and determined its efficacy in suppressing DDR1-collagen binding. CONCLUSIONS: The new method shows promise in quantifying receptor-ligand kinetics and receptor density on live cells. GENERAL SIGNIFICANCE: The new approach is applicable to other receptor-ligand systems and allows the determination of critical parameters at the single cell/single molecule level - in particular, the direct determination of kinetic and density differences of receptors in different cell types. This capability should prove to be useful in cancer research and drug design.