The nephrotoxicity of sofosbuvir (SOF) on human immunodeficiency virus and hepatitis C virus (HIV/HCV)‐coinfected patients receiving antiretroviral therapy (ART) remains controversial. We ...prospectively compared the estimated glomerular filtration rate (eGFR) changes in 167 patients receiving SOF‐based direct‐acting antivirals (DAAs) who also received tenofovir disoproxil fumarate (TFV)‐based (n = 116) and TFV‐free ART (n = 51). The eGFR was assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation, and the eGFR changes between ART regimens were compared by the generalized estimated equation. During DAA treatment, participants on TFV‐based ART had a higher eGFR decline than those on TFV‐free ART (slope coefficient difference: −0.82 ml/min/1.73 m2/month 95% CI: −1.21 to −0.43; p < 0.001), whereas the eGFR changes did not differ between groups (slope coefficient difference: 0.13 ml/min/1.73 m2/month 95% CI: −0.32 to 0.58; p = 0.42) after discontinuing DAAs. Participants on TFV TDF‐based ART had a higher eGFR decline than those on TFV alafenamide fumarate (TAF)‐based ART (slope coefficient difference: −0.31 ml/min/1.73 m2/month 95% CI: −0.50 to −0.12; p = 0.01). After discontinuing DAAs, the eGFR changes did not differ between groups (slope coefficient difference: 0.06 ml/min/1.73 m2/month 95% CI: −0.98 to 1.10; p = 0.91). In conclusion, HIV/HCV‐coinfected patients on TFV‐based ART had a slight eGFR decline compared to those on TFV‐free ART during SOF‐based DAA therapy. A similar trend between TDF‐based and TAF‐based ART was also observed. Because the differences of eGFR changes are limited, the physicians should not discourage the use of SOF‐based DAAs in HIV‐positive patients on TFV‐based ART.
Cdk1 (cyclin-dependent kinase 1) is critical regulator of the G2-M checkpoint. Cyclin-dependent kinase pathways are considered possible targets for cancer treatment; however, the prognostic role of ...Cdk1 in colorectal cancer is still controversial. Therefore, we attempted to determine the impact of Cdk1 on the clinical outcome of colorectal cancer patients to further identify its role in colorectal cancer.
Cdk1 immunoreactivity was analyzed by immunohistochemistry (IHC) in 164 cancer specimens from primary colorectal cancer patients. The medium follow-up time after surgery was 3.7 years (range: 0.01 to 13.10 years). The prognostic value of Cdk1 on overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models.
All samples displayed detectable Cdk1 expression with predominant location in the cytoplasm and nucleus. A high Cdk1 nuclear/cytoplasmic (N/C) expression ratio was correlated with poor overall survival (5-year survival rate: 26.3% vs 46.9%, N/C ratio ≥1.5 vs N/C ratio <1.5, log-rank p = 0.027). Accordingly, a Cdk1 N/C expression ratio ≥1.5 was identified as an independent risk factor by multivariate analysis (hazard ratio = 1.712, P = 0.039).
We suggest that Cdk1 N/C expression ratio determined by IHC staining could be an independent prognostic marker for colorectal cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Oral squamous cell carcinoma (OSCC), an epithelial malignancy affecting a variety of subsites in the oral cavity, is prevalent in Asia. The survival rate of OSCC patients has not improved over the ...past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. Improvement in therapeutic strategies and tailored treatment options is an unmet need. To unveil the mutational spectrum, whole-exome sequencing of 120 OSCC from male individuals in Taiwan was conducted. Analyzing the contributions of the five mutational signatures extracted from the dataset of somatic variations identified four groups of tumors that were significantly associated with demographic and clinical features. In addition, known (
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) genes that were significantly and frequently mutated in OSCC were discovered. Further analyses of gene alteration status with clinical parameters revealed that the tumors of the tongue were enriched with copy-number alterations in several gene clusters containing
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. Through defining the catalog of targetable genomic alterations, 58% of the tumors were found to carry at least one aberrant event potentially targeted by US Food and Drug Administration (FDA)-approved agents. Strikingly, if targeting the p53-cell cycle pathway (
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) by the drugs studied in phase I-III clinical trials, those possibly actionable tumors are predominantly located in the tongue, suggesting a better prediction of sensitivity to current targeted therapies. Our work revealed molecular OSCC subgroups that reflect etiological and prognostic correlation as well as defined the landscape of major altered events in the coding regions of OSCC genomes. These findings provide clues for the design of clinical trials for targeted therapies and stratification of OSCC patients with differential therapeutic efficacy.
Our previous study demonstrated that lysine demethylase 2A (KDM2A) enhances stemness in breast cancer cells. This demethylase is also highly expressed in cancer-associated fibroblasts (CAFs). ...However, its clinical significance is unclear.
The expression of KDM2A in CAFs was studied using immunohistochemical staining and its association with clinicopathological features and patient's survival was tested. Overexpression and knockdown strategies were used to investigate KDM2A-regulated genes in fibroblasts. Senescent cells were detected by using β-galactosidase staining. The in vivo tumour-promoting activity of stromal KDM2A was confirmed by animal study.
Increase of stromal KDM2A is associated with advanced tumour stage and poor clinical outcome in breast cancer patients. Cancer-derived cytokines stimulated KDM2A expression in normal fibroblasts and transformed them into CAFs. Upregulation of KDM2A induced p53-dependent senescence in fibroblasts and enhanced the release of cytokines, which reciprocally promoted cancer cell proliferation. Additionally, KDM2A upregulated programmed death-ligand 1 (PD-L1) expression via transcriptional activation in fibroblasts. Knockdown of KDM2A completely abolished the tumour-promoting activity of CAFs on breast tumour growth in vivo and diminished PD-L1 expression in the stroma of tumour tissues.
Stromal KDM2A plays an oncogenic role in breast cancer and inhibition of KDM2A reduces fibroblast senescence and suppresses tumour growth.
Hepatitis B and C (HBV/HCV) coinfected patients have a potential risk of hepatitis B reactivation (HBVr) after direct-acting antivirals (DAAs) treatment. The study intends to investigate the ...predictive role of HBV biomarkers in HBVr. Forty-six HBV/HCV coinfected patients receiving DAAs were enrolled. All patients completed treatment and follow-up to the 12th-week post-DAA treatment (P12). Blood samples were measured for HBV biomarkers, including hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), and HBV pregenomic RNA (HBV pgRNA). The predictive factors for HBVr after DAA treatment were analyzed. Among 31 patients without nucleot(s)ide analogue (NA) treatment, seven (22.5%, 7/31) developed HBVr without hepatitis flare-up. Patients with HBVr had higher HBsAg titers than those without HBVr from baseline to P12 (p = 0.008, 0.009, 0.004, and 0.006 at baseline, week 4, end of treatment, and P12, respectively). The baseline HBsAg level was the only predictive factor associated with HBVr (HR, 2.303; 95% CI, 1.086−4.882; p = 0.030). In predicting HBVr, a baseline HBsAg titer > 20 IU/mL had a sensitivity, specificity, positive predictive value, and negative predictive value of 85.7%, 75.0%, 50%, and 94.7%, respectively. No patient had HBVr if the baseline HBsAg titer was <8 IU/mL. Serum HBcrAg and HBV pgRNA levels had no role in predicting HBVr. In conclusion, HBV/HCV coinfected patients are at risk of HBVr after DAA treatment. The baseline HBsAg level was the predictive factor associated with HBVr. Patients with a baseline HBsAg titer < 8 IU/mL can be considered as not having HBVr.
Breast cancer-derived vascular endothelial growth factor-C (VEGF-C) has been shown to enhance lymphangiogenesis in lymph nodes to accelerate cancer metastasis. However, the remodeling of lymph node ...microenvironments by VEGF-C remains elusive. By in vivo selection, we established a subline (named as "LC") with strong lymphatic tropism and high VEGF-C expression from the human MDA-MB-231 breast cancer cell line. Co-culture with LC cells or treatment with LC-conditioned medium upregulated the expression of CXC chemokines in lymphatic endothelial cells (LECs), which could be inhibited by pre-incubation with VEGF-C-neutralizing antibodies and VEGFR3 inhibitors. The chemokines produced by LECs enhanced recruitment of myeloid-derived suppressor cells (MDSCs) to tumor-draining and distant lymph nodes in tumor-bearing mice. Treatment with a CXCR2 inhibitor after tumor cell inoculation dramatically decreased the number of MDSCs in lymph nodes, suggesting the importance of the chemokine/CXCR2 signaling axis in MDSC recruitment. In addition, LEC-released chemokines also stimulated the expression of serum amyloid A1 (SAA1) in cancer cells, enhancing their lymphatic invasion by increasing VE-cadherin phosphorylation, junction disruption, and vascular permeability of LECs. Clinical sample validation confirmed that SAA1 expression was associated with increased lymph node metastasis. Collectively, we reveal a novel mechanism by which cancer cell-derived VEGF-C remodels lymphovascular microenvironments by regulating chemokine production in LECs to promote cancer invasion and MDSC recruitment. Our results also suggest that inhibition of CXCR2 is effective in treating lymphatic metastasis.
Hypoxia-inducible factor 1α (HIF-1α) plays a pivotal role in the survival, metastasis, and response to treatment of solid tumors. Autophagy serves as a mechanism for tumor cells to eliminate ...misfolded proteins and damaged organelles, thus promoting invasiveness, metastasis, and resistance to treatment under hypoxic conditions. MicroRNA (miRNA) research underscores the significance of these non-coding molecules in regulating cancer-related protein synthesis across diverse contexts. However, there is limited reporting on miRNA-mediated gene expression studies, especially with respect to epithelial-mesenchymal transition (EMT) and autophagy in the context of hypoxic breast cancer. Our study reveals decreased levels of miRNA-622 (miR-622) and miRNA-30a (miR-30a) in invasive breast cancer cells compared to their non-invasive counterparts. Inducing miR-622 suppresses HIF-1α protein expression, subsequently activating miR-30a transcription. This cascade results in reduced invasiveness and migration of breast cancer cells by inhibiting EMT markers, such as Snail, Slug, and vimentin. Furthermore, miR-30a negatively regulates beclin 1, ATG5, and LC3-II and inhibits Akt protein phosphorylation. Consequently, this improves the sensitivity of invasive MDA-MB-231 cells to docetaxel treatment. In conclusion, our study highlights the therapeutic potential of inducing miR-622 to promote miR-30a expression and thus disrupt HIF-1α-associated EMT and autophagy pathways. This innovative strategy presents a promising approach to the treatment of aggressive breast cancer.
Ovarian clear cell carcinoma (OCCC) is a distinct histotype of ovarian cancer, which usually presages a worse prognosis upon recurrence. Identifying patients at risk for relapse is an unmet need to ...improve outcomes. A retrospective cohort analysis of 195 early‐stage OCCC patients diagnosed between January 2011 and December 2019 at National Taiwan University Hospital was conducted to identify prognostic factors for recurrence, progression‐free survival (PFS) and overall survival (OS). Molecular profiling of tumors was performed in a case‐controlled cohort matched for adjuvant therapy for biomarker discovery. Multivariate Cox proportional hazard model revealed that paclitaxel‐based chemotherapy was associated with better PFS than nonpaclitaxel chemotherapy (HR = 0.19, P = .006). The addition of bevacizumab was associated with better PFS, compared to no bevacizumab (HR = 0.09, P = .02). Neither showed significant improvement in OS. Recurrence is associated with an Immune‐Hot tumor feature (P = .03), the CTLA‐4‐high subtype (P = .01) and increased infiltration of immune cells in general. The Immune‐Hot feature (HR = 3.39, P = .005) and the CTLA‐4‐high subtype (HR = 2.13, P = .059) were associated with worse PFS. Immune‐Hot tumor features could prognosticate recurrence in early‐stage OCCC.
What's new?
While adjuvant irradiation can improve progression‐free survival (PFS) in ovarian clear cell carcinoma (OCCC), control of metastatic disease remains a challenge. Especially problematic is the lack of optimal treatment for recurrent OCCC. In the present retrospective analysis, the addition of bevacizumab to paclitaxel‐based chemotherapy was associated with improved PFS in early‐stage OCCC patients. Moreover, molecular profiling revealed correlations between OCCC recurrence and immune‐hot tumor feature, CTLA‐4‐high subtype and increased immune cell infiltration. The findings suggest that immune profiling can help identify OCCC patients who are at risk for relapse and who may benefit from combined paclitaxel‐based chemotherapy and bevacizumab therapy.
Triple negative breast cancer (TNBC) displays higher risk of recurrence and distant metastasis. Due to absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor ...receptor 2 (HER2), TNBC lacks clinically established targeted therapies. Therefore, understanding of the mechanism underlying the aggressive behaviors of TNBC is required for the design of individualized strategies and the elongation of overall survival duration. Here, we supported a positive correlation between β1 integrin and malignant behaviors such as cell migration, invasion, and drug resistance. We found that silencing of β1 integrin inhibited cell migration, invasion, and increased the sensitivity to anti-cancer drug. In contrast, activation of β1 integrin increased cell migration, invasion, and decreased the sensitivity to anti-cancer drug. Furthermore, we found that silencing of β1 integrin abolished Focal adhesion kinese (FAK) mediated cell survival. Overexpression of FAK could restore cisplatin-induced apoptosis in β1 integrin-depleted cells. Consistent to in vitro data, β1 integrin expression was also positively correlated with FAK (p = 0.031) in clinical tissue. More importantly, β1 integrin expression was significantly correlated with patient outcome. In summary, our study indicated that β1 integrin could regulate TNBC cells migration, invasion, drug sensitivity, and be a potential prognostic biomarker in TNBC patient survival.
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