Polyamines, often elevated in cancer cells, have been shown to promote cell growth and proliferation. Whether polyamines regulate other cell functions remains unclear. Here, we explore whether and ...how polyamines affect genome integrity. When DNA double-strand break (DSB) is induced in hair follicles by ionizing radiation, reduction of cellular polyamines augments dystrophic changes with delayed regeneration. Mechanistically, polyamines facilitate homologous recombination-mediated DSB repair without affecting repair via non-homologous DNA end-joining and single-strand DNA annealing. Biochemical reconstitution and functional analyses demonstrate that polyamines enhance the DNA strand exchange activity of RAD51 recombinase. The effect of polyamines on RAD51 stems from their ability to enhance the capture of homologous duplex DNA and synaptic complex formation by the RAD51-ssDNA nucleoprotein filament. Our work demonstrates a novel function of polyamines in the maintenance of genome integrity via homology-directed DNA repair.
As iron‐bearing minerals—ferrimagnetic minerals in particular—are sensitive to stress, temperature, and presence of fluids in fault zones, their magnetic properties provide valuable insights into ...physical and chemical processes affecting fault rocks. Here, we review the advances made in magnetic studies of fault rocks in the past three decades. We provide a synthesis of the mechanisms that account for the magnetic changes in fault rocks and insights gained from magnetic research. We also integrate nonmagnetic approaches in the evaluation of the magnetic properties of fault rocks. Magnetic analysis unveils microscopic processes operating in the fault zones such as frictional heating, energy dissipation, and fluid percolation that are otherwise difficult to constrain. This makes magnetic properties suited as a “strain indicator,” a “geothermometer,” and a “fluid tracer” in fault zones. However, a full understanding of faulting‐induced magnetic changes has not been accomplished yet. Future research should focus on detailed magnetic property analysis of fault zones including magnetic microscanning and magnetic fabric analysis. To calibrate the observations on natural fault zones, laboratory experiments should be carried out that enable to extract the exact physicochemical conditions that led to a certain magnetic signature. Potential avenues could include (1) magnetic investigations on natural and synthetic fault rocks after friction experiments, (2) laboratory simulation of fault fluid percolation, (3) paleomagnetic analysis of postkinematic remanence components associated with faulting processes, and (4) synergy of interdisciplinary approaches in mineral‐magnetic studies. This would help to place our understanding of the microphysics of faulting on a much stronger footing.
Plain Language Summary
The Earth's surface is riddled with faults that largely contribute to landscape evolution and human activities. Some of these faults produce earthquakes of different magnitudes including some with catastrophic consequences. Understanding faulting mechanisms benefits society when predictions about rupture are made. Fault zones preserve an excellent record of chemical and physical processes involved in failure. Among other analytical methods, magnetic studies prove to be an emergent and untapped source of information on these processes. These methods, focused on prefaulting, synfaulting, and postfaulting mineral changes, have resulted in significant advances in our understanding of the conditions of faulting. In this review, we present an extensive account of the state of knowledge and highlight current challenges and future avenues of fault magnetism research.
Key Points
Iron‐bearing minerals and ferrimagnetic minerals in particular are sensitive to faulting‐associated physical and chemical processes
Laboratory faulting experiments and comparison with nonmagnetic approaches confirm results from magnetic studies on natural rocks
Rock magnetic methods offer novel tools to analyze strain, grain fining, temperature trends, and fluid‐rock interaction in fault zones
NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine ...(N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.
Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m
twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m
twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).
A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio HR, 0.76; 95% CI, 0.63 to 0.93; stratified log-rank
0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07;
2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8%
29.2%;
043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4;
1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74;
.0004). The most common all-grade adverse events were diarrhea (N+C 83%
L+C 66%) and nausea (53%
42%). Discontinuation rates and HRQoL were similar between groups.
N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.
Chemokines modulate angiogenesis and metastasis that dictate cancer development in tumor microenvironment. Osteosarcoma is the most frequent bone tumor and is characterized by a high metastatic ...potential. Chemokine CCL5 (previously called RANTES) has been reported to facilitate tumor progression and metastasis. However, the crosstalk between chemokine CCL5 and vascular endothelial growth factor (VEGF) as well as tumor angiogenesis in human osteosarcoma microenvironment has not been well explored. In this study, we found that CCL5 increased VEGF expression and production in human osteosarcoma cells. The conditioned medium (CM) from CCL5-treated osteosarcoma cells significantly induced tube formation and migration of human endothelial progenitor cells. Pretreatment of cells with CCR5 antibody or transfection with CCR5 specific siRNA blocked CCL5-induced VEGF expression and angiogenesis. CCL5/CCR5 axis demonstrably activated protein kinase Cδ (PKCδ), c-Src and hypoxia-inducible factor-1 alpha (HIF-1α) signaling cascades to induce VEGF-dependent angiogenesis. Furthermore, knockdown of CCL5 suppressed VEGF expression and attenuated osteosarcoma CM-induced angiogenesis in vitro and in vivo. CCL5 knockdown dramatically abolished tumor growth and angiogenesis in the osteosarcoma xenograft animal model. Importantly, we demonstrated that the expression of CCL5 and VEGF were correlated with tumor stage according the immunohistochemistry analysis of human osteosarcoma tissues. Taken together, our findings provide evidence that CCL5/CCR5 axis promotes VEGF-dependent tumor angiogenesis in human osteosarcoma microenvironment through PKCδ/c-Src/HIF-1α signaling pathway. CCL5 may represent a potential therapeutic target against human osteosarcoma.
Background and Aim
The serial serologic changes of hepatitis D virus (HDV) infection among chronic hepatitis B virus (HBV) infected patients who received oral nucleotide/nucleoside analogues are ...elusive.
Methods
Serum anti‐HDV and HDV RNA among chronic hepatitis B (CHB) patients were tested at the time of initiating anti‐HBV therapy and subsequently during the follow‐up period.
Results
The seropositive rate of anti‐HDV and HDV RNA among 2850 CHB patients, was 2.7% and 0.9%, respectively. Factors associated with anti‐HDV seropositivity were platelet counts (odds ratio OR/95% confidence intervals CI: 0.995/0.992–0.999; P = 0.006), HBV DNA levels (OR/CI: 0.81/0.70–0.94; P = 0.005), and hepatitis B e‐antigen (HBeAg) seropositivity (OR/CI: 0.22/0.05–0.95; P = 0.04). The only factor associated with HDV RNA positivity among anti‐HDV seropositive patients was age (OR/CI: 0.95/0.90–1.00; P = 0.03). The spontaneous clearance rate of serum anti‐HDV antibody was 3.0 per 100 person‐years with a median follow‐up period of 3.5 years (range 2–12 years), whereas the seroclearance rate of HDV RNA was 4.3 per 100 person‐years among anti‐HDV seropositive patients after a median follow‐up period of 6.0 years (range 2–11 years). A baseline anti‐HDV titer < 0.5 cut‐off index was the only factor predictive of anti‐HDV seroclearance (hazard ratio HR/CI: 30.11/3.73–242.85; P = 0.001).
Conclusions
HDV infection was not common among patients treated for HBV in Taiwan. Seroclearance of anti‐HDV and HDV RNA did occur over time, albeit the chance is rare.
Sprouty2 (SPRY2) is known to inhibit the RAS/MAPK/ERK pathway, and is a potential study target for cancer. The effect of SPRY2 in colorectal cancer (CRC) and whether it is influenced by KRAS mutation ...are not known. We manipulated SPRY2 gene expression and used an activating KRAS‐mutant plasmid to determine its effect on CRC cell function in vitro and/or in vivo. We performed SPRY2 immunohistochemical staining in 143 CRC specimens and analyzed the staining results with various clinicopathological characteristics in relation to KRAS mutation status. SPRY2 knockdown in Caco‐2 cells carrying the wild‐type (WT) KRAS gene upregulated phosphorylated ERK (p‐ERK) levels and increased cell proliferation in vitro, but inhibited cell invasion. However, SPRY2 knockdown in SW480 cells (activating KRAS mutant) or Caco‐2 cells transfected with KRAS‐mutant plasmid did not significantly alter p‐ERK levels, cell proliferation, or invasion. The xenografts of SPRY2‐knockdown Caco‐2 cells were larger with less deep muscle invasion than those of control cells. The clinical cohort study revealed a positive association of SPRY2 protein expression with pT status, lymphovascular invasion, and perineural invasion in KRAS‐WT CRCs. However, the associations were not observed in KRAS‐mutant CRCs. Interestingly, high SPRY2 expression was related to shorter cancer‐specific survival in both KRAS‐WT and KRAS‐mutant CRC patients. Our study demonstrated the dual role of SPRY2 as an inhibitor of RAS/ERK‐driven proliferation and as a promoter of cancer invasion in KRAS‐WT CRC. SPRY2 may promote the invasion and progression of KRAS‐WT CRC, and might also enhance KRAS‐mutant CRC progression through pathways other than invasion.
Colony-stimulating factor 1 receptor (CSF-1R) acts as the receptor for colony stimulating factor 1, a cytokine that controls the production, differentiation, and function of macrophages. Prior ...studies showed cancer patients harboring germline
c.1085A>G genetic variant had better survival. Here, primary tumor samples from a stage III colorectal cancer (CRC) cohort were analyzed by a targeted gene expression assay containing 395 immune-related genes to study the immune mechanism underlying the different outcomes. CRC patients with
c.1085 genotype A_G had a better disease-free and overall survival than those with
genotype A_A. Compared to the group of patients without
variant, higher
expression, a surface marker of T cells, was found in the tumor tissues of patients with
c.1085 variant. In parallel with the higher
gene expression, immunofluorescent staining also showed more CD3
CD40L
T cell infiltrates in tumors with
c.1085 genotype A_G. Moreover, higher IL-2 expression, known to be regulated by CD40 pathway, was also observed in tumors with
c.1085 genotype A_G than genotype A_A. Higher IL-2 expression generated by the interaction of CD40 ligand and CD40 between T cells and macrophages with
c.1085A>G variant is the potential mechanism explaining the different outcomes.
Cingulin (CGN) is a pivotal cytoskeletal adaptor protein located at tight junctions. This study investigates the link between CGN mutation and increased cancer susceptibility through genetic and ...mechanistic analyses and proposes a potential targeted therapeutic approach.
In a high-cancer-density family without known pathogenic variants, we performed tumor-targeted and germline whole-genome sequencing to identify novel cancer-associated variants. Subsequently, these variants were validated in a 222 cancer patient cohort, and CGN c.3560C > T was identified as a potential cancer-risk allele. Both wild-type (WT) (c.3560C > C) and variant (c.3560C > T) were transfected into cancer cell lines and incorporated into orthotopic xenograft mice model for evaluating their effects on cancer progression. Western blot, immunofluorescence analysis, migration and invasion assays, two-dimensional gel electrophoresis with mass spectrometry, immunoprecipitation assays, and siRNA applications were used to explore the biological consequence of CGN c.3560C > T.
In cancer cell lines and orthotopic animal models, CGN c.3560C > T enhanced tumor progression with reduced sensitivity to oxaliplatin compared to the CGN WT. The variant induced downregulation of epithelial marker, upregulation of mesenchymal marker and transcription factor, which converged to initiate epithelial-mesenchymal transition (EMT). Proteomic analysis was conducted to investigate the elements driving EMT in CGN c.3560C > T. This exploration unveiled overexpression of IQGAP1 induced by the variant, contrasting the levels observed in CGN WT. Immunoprecipitation assay confirmed a direct interaction between CGN and IQGAP1. IQGAP1 functions as a regulator of multiple GTPases, particularly the Rho family. This overexpressed IQGAP1 was consistently associated with the activation of Rac1, as evidenced by the analysis of the cancer cell line and clinical sample harboring CGN c.3560C > T. Notably, activated Rac1 was suppressed following the downregulation of IQGAP1 by siRNA. Treatment with NSC23766, a selective inhibitor for Rac1-GEF interaction, resulted in the inactivation of Rac1. This intervention mitigated the EMT program in cancer cells carrying CGN c.3560C > T. Consistently, xenograft tumors with WT CGN showed no sensitivity to NSC23766 treatment, but NSC23766 demonstrated the capacity to attenuate tumor growth harboring c.3560C > T.
CGN c.3560C > T leads to IQGAP1 overexpression, subsequently triggering Rac1-dependent EMT. Targeting activated Rac1 is a strategy to impede the advancement of cancers carrying this specific variant.
Tendons are hypocellular and hypovascular tissues, and thus, their natural healing capacity is low. In this study, we sought to evaluate the efficacy of platelet-rich fibrin (PRF) to serve as a ...bioactive scaffold in promoting the healing of rabbit Achilles tendon injury. For in vitro study, the essence portion of PRF was determined through bioluminescent assay. Furthermore, we analyzed the time-sequential cytokines-release kinetics of PRF and evaluated their effects on tenocytes proliferation and tenogenic gene expressions. In animal study, the rabbit Achilles tendon defect was left untreated or implanted with normal/heat-denatured PRF scaffolds. Six weeks postoperatively, the specimens were evaluated through sonographic imaging and histological analysis. The results revealed significantly more activated platelets on bottom half of the PRF scaffold. Cytokine concentrations released from PRF could be detected from the first hour to six days. For the in vitro study, PRF enhanced cell viability and collagen I, collagen III, tenomodulin, and tenascin gene expression compared to the standard culture medium. For in vivo study, sonographic images revealed significantly better tendon healing in the PRF group in terms of tissue echogenicity and homogeneity. The histological analysis showed that the healing tissues in the PRF group had more organized collagen fiber, less vascularity, and minimal cartilage formation. In conclusion, bioactive PRF promotes in vitro tenocytes viability and tenogenic phenotypic differentiation. Administration of a PRF scaffold at the tendon defect promotes tissue healing as evidenced by imaging and histological outcomes.
We present a magnetic fabric investigation of small oriented rock fragments from gouges and wall rocks from the Chelungpu fault (Taiwan), where the Chi‐Chi earthquake occurred (Mw 7.6, 1999). Samples ...are obtained from surface outcrops and at a depth of ~1 km, including the 3‐mm‐thick Chi‐Chi principal slip zone. Wall rocks at depth show magnetic foliation roughly parallel to bedding, whereas they are oblique at the surface. Within the gouges, the mean shape of magnetic ellipsoid is oblate, and the degree of anisotropy is up to 12%. The magnetic foliation diverges of ~40° from the fault plane, compatible with a simple shear westward. The magnetic lineation is oblique, resulting probably from coseismic and interseismic records. The reconstructed focal mechanism from the magnetic fabric closely matches the focal mechanism solutions for the Chi‐Chi earthquake. Our work demonstrates that magnetic fabric of gouge fragments can bring valuable kinematic information on modern earthquakes.
Plain Language Summary
Fault gouges often provide important and valuable information that can help to understand the fault mechanisms and to assess the seismic hazard, but to get access to the shape preferred orientation of micrometric minerals is generally a complex, time consuming and expensive procedure. In this study, we show that the anisotropy of magnetic susceptibility, which is a fast and nondestructive technique, can be a proxy of the structural fabric of historical gouges. This technique has already been previously applied to gouge zones, but this is the first time that it is used in the gouge from one of the best documented historical large seismic events: the 1999 Chi‐Chi earthquake (Mw 7.6) along the Chelungpu fault (Taiwan). Samples within and around this fault were obtained from fresh surface outcrop and 1‐km‐deep borehole (Hole B, Taiwan Chelungpu‐fault Drilling Project). The 1‐km‐deep gouge hosts the 3‐mm‐thick principal slip zone of the Chi‐Chi earthquake. The results show that the reconstructed focal mechanism based on the magnetic fabric geometry matches closely the focal mechanism solutions for the Chi‐Chi earthquake estimated by several previous studies.
Key Points
For the first time, the bulk fabric of small fragments of historical gouge, including the 1999 Chi‐Chi earthquake (Mw 7.6) slip zone, has been analyzed successfully
The bulk fabric of gouge is anisotropic, reflecting the grain orientation of billions of clays and magnetic particles
The magnetic fabric of gouge mimics the focal mechanism solutions of historical earthquake
We provide a new tool to elucidate earthquake properties from fault gouges
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