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The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies.

Breast cancer is a heterogeneous disease. To guide proper treatment decisions for each patient, robust prognostic biomarkers, which allow reliable prognosis prediction, are necessary. Gene feature selection based on microarray data is an approach to discover potential biomarkers systematically. However, standard pure-statistical feature selection approaches often fail to incorporate prior biological knowledge and select genes that lack biological insights. Besides, due to the high dimensionality and low sample size properties of microarray data, selecting robust gene features is an intrinsically challenging problem. We hence combined systems biology feature selection with ensemble learning in this study, aiming to select genes with biological insights and robust prognostic predictive power. Moreover, to capture breast cancer's complex molecular processes, we adopted a multi-gene approach to predict the prognosis status using deep learning classifiers. We found that all ensemble approaches could improve feature selection robustness, wherein the hybrid ensemble approach led to the most robust result. Among all prognosis prediction models, the bimodal deep neural network (DNN) achieved the highest test performance, further verified by survival analysis. In summary, this study demonstrated the potential of combining ensemble learning and bimodal DNN in guiding precision medicine.

Cancer is a major cause of death. The outcomes of current therapeutic strategies against cancer often ironically lead to even increased mortality due to the subsequent drug resistance and to metastatic recurrence. Alternative medicines are thus urgently needed. Cumulative evidence has pointed out that pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene, PS) has excellent pharmacological benefits for the prevention and treatment for various types of cancer in their different stages of progression by evoking apoptotic or nonapoptotic anti-cancer activities. In this review article, we first update current knowledge regarding tumor progression toward accomplishment of metastasis. Subsequently, we review current literature regarding the anti-cancer activities of PS. Finally, we provide future perspectives to clinically utilize PS as novel cancer therapeutic remedies. We, therefore, conclude and propose that PS is one ideal alternative medicine to be administered in the diet as a nutritional supplement.

Notch signaling is aberrantly activated in approximately 30% of hepatocellular carcinoma (HCC), significantly contributing to tumorigenesis and disease progression. Expression of the major Notch receptor, NOTCH1, is upregulated in HCC cells and correlates with advanced disease stages, although the molecular mechanisms underlying its overexpression remain unclear. Here, we report that expression of the intracellular domain of NOTCH1 (NICD1) is upregulated in HCC cells due to antagonism between the E3‐ubiquitin ligase F‐box/WD repeat‐containing protein 7 (FBXW7) and the large scaffold protein abnormal spindle‐like microcephaly‐associated protein (ASPM) isoform 1 (ASPM‐i1). Mechanistically, FBXW7‐mediated polyubiquitination and the subsequent proteasomal degradation of NICD1 are hampered by the interaction of NICD1 with ASPM‐i1, thereby stabilizing NICD1 and rendering HCC cells responsive to stimulation by Notch ligands. Consistently, downregulating ASPM‐i1 expression reduced the protein abundance of NICD1 but not its FBXW7‐binding‐deficient mutant. Reinforcing the oncogenic function of this regulatory module, the forced expression of NICD1 significantly restored the tumorigenic potential of ASPM‐i1‐deficient HCC cells. Echoing these findings, NICD1 was found to be strongly co‐expressed with ASPM‐i1 in cancer cells in human HCC tissues (P < 0.001). In conclusion, our study identifies a novel Notch signaling regulatory mechanism mediated by protein–protein interaction between NICD1, FBXW7, and ASPM‐i1 in HCC cells, representing a targetable vulnerability in human HCC. The upregulated expression of the oncogenic isoform 1 of ASPM (ASPM‐i1) in hepatocellular carcinoma (HCC) correlates with pathologic grade and poor patient survival. ASPM‐i1 hampers the FBXW7‐mediated polyubiquitination and degradation of NOTCH1 intracellular domain (NICD1), thereby rendering HCC cells responsive to stimulation by Notch ligands. The novel Notch‐activating mechanism represents a targetable vulnerability in human HCC.

The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergized with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers.

Elevated expression of prothymosin α (ProT) is frequently observed in cancers, but the underlying molecular mechanism remains poorly understood. Here, we report the clinical relevance of ProT expression and its correlation with lung cancer progression. We have shown that ProT was highly expressed in early‐stage lung cancer, exhibiting nuclear localization; on the contrary, a loss of nuclear ProT expression was detected in late‐stage tumor specimens. Furthermore, the expression of nuclear ProT impaired lung cancer cell migration, suppressed TGF‐β‐induced epithelial‐to‐mesenchymal transition (EMT)‐associated transcription factor expression, and inhibited in vivo tumor metastasis. The suppressive effect of ProT was further found to trigger Smad7 acetylation‐dependent deregulation of TGF‐β signaling. ProT enhanced Smad7 stability by promoting its lysine acetylation, thereby competing with the binding of Smad2 to the SNAI1, TWIST1, and ZEB1 promoters. Eventually, the binding of Smad7 in the presence of ProT resulted in reduced expression of the EMT transcription factors, leading to the inhibition of TGF‐β‐induced EMT and tumor metastasis. Collectively, this study unravels the role of ProT in lung cancer progression and highlights the potential of nuclear ProT as an indicator for monitoring tumor development. Nuclear prothymosin α inhibits epithelial‐mesenchymal transition (EMT) in lung cancer by increasing Smad7 acetylation and competing with Smad2 for binding to SNAI1, TWIST1, and ZEB1 promoters. In early‐stage cancer, ProT suppresses TGF‐β‐induced EMT, while its loss in the nucleus in late‐stage cancer leads to enhanced EMT and poor prognosis.

Background Polymeric fibronectin (polyFN) assembled on suspended breast cancer cells is required for metastasis. Conceivably, drugs that target such polyFN may fight against cancer metastasis. While stilbene analogs trigger pro-apoptotic effect on attached cancer cells, whether they prevent polyFN assembly and metastasis of suspended cancer cells via an apoptosis-independent manner remains unexplored. Methods We depleted suspended Lewis lung carcinoma (LLC) cells of polyFN by silencing the endogenous FN expression or pterostilbene (PS) to examine whether metastasis of lung cancer cells could thus be suppressed. We investigated whether PS regulates AKT-ERK signaling axis to suppress polyFN assembly in suspended LLC cells independently of apoptosis. We tested the therapeutic effects of orally administered PS against cancer metastasis. Results Both FN-silencing and PS among the three stilbenoids indeed significantly reduced polyFN assembly and lung metastasis of suspended LLC cells in an apoptosis-independent manner. Mechanistically, PS-induced AKT phosphorylation (pAKT) and suppressed ERK phosphorylation (pERK) in suspended LLC cells, whereas pretreatment with a PI3K inhibitor, LY294002, effectively reduced pAKT, rescued pERK, and consequently reversed the PS-suppressed polyFN assembly on LLC cells; these pretreatment effects were then overturned by the ERK inhibitor U0126. Indeed, PS-suppressed lung metastasis was counteracted by LY294002, which was further overruled with U0126. Finally, we found that PS, when orally administered in experimental metastasis assays, both significantly prevented lung colonization and metastasis of LLC cells and reduced the already established tumor growth in the mouse lungs. Conclusions PS suppressed AKT/ERK-regulated polyFN assembly on suspended LLC cells and pulmonary metastasis. PS possesses potency in both preventing and treating lung metastasis of lung cancer cells in apoptosis-independent and apoptosis-dependent manners, respectively.

Purpose: We aimed to design and evaluate a deep learning-based method to automatically predict the time-varying in-plane blood flow velocity within the cardiac cavities in long-axis cine MRI, validated against 4D flow. Methods: A convolutional neural network (CNN) was implemented, taking cine MRI as the input and the in-plane velocity derived from the 4D flow acquisition as the ground truth. The method was evaluated using velocity vector end-point error (EPE) and angle error. Additionally, the E/A ratio and diastolic function classification derived from the predicted velocities were compared to those derived from 4D flow. Results: For intra-cardiac pixels with a velocity > 5 cm/s, our method achieved an EPE of 8.65 cm/s and angle error of 41.27°. For pixels with a velocity > 25 cm/s, the angle error significantly degraded to 19.26°. Although the averaged blood flow velocity prediction was under-estimated by 26.69%, the high correlation (PCC = 0.95) of global time-varying velocity and the visual evaluation demonstrate a good agreement between our prediction and 4D flow data. The E/A ratio was derived with minimal bias, but with considerable mean absolute error of 0.39 and wide limits of agreement. The diastolic function classification showed a high accuracy of 86.9%. Conclusion: Using a deep learning-based algorithm, intra-cardiac blood flow velocities can be predicted from long-axis cine MRI with high correlation with 4D flow derived velocities. Visualization of the derived velocities provides adjunct functional information and may potentially be used to derive the E/A ratio from conventional CMR exams.

Background Alopecia is one of the most common adverse effects of chemotherapy. It reduces the patient’s self-esteem and quality of life and the effect of therapy. Scalp cooling is the only verified current method for prevention but success is not guaranteed, particularly after receiving anthracycline-based combinations. Low-level light therapy has been clinically proven to inhibit the progress of androgenic alopecia. A previous study using human subjects shows limited benefits for low-level light therapy for patients who suffer chemotherapy-induced alopecia but an increase in the number of probes and the optimization of light sources may improve the efficacy. This study determines the efficacy of low-level light therapy for the prevention of chemotherapy-induced hair loss for patients with breast cancer using a randomized controlled trial. Methods One hundred six eligible breast cancer patients were randomly distributed into a low-level light therapy group and a control group, after receiving chemotherapy. Subjects in the low-level light therapy group received 12 courses of intervention within 4 weeks. Subjects in the control group received no intervention but were closely monitored. The primary outcome is measured as the difference in the hair count in a target area between the baseline and at the end of week 4, as measured using a phototrichogram (Sentra scalp analyzer). The secondary outcomes include the change in hair count at the end of week 1, week 2, and week 3 and hair width at the end of week 1, week 2, week 3, and week 4, as measured using a phototrichogram, and the change in distress, the quality of life, and self-esteem due to chemotherapy-induced alopecia, at the end of week 4, as measured using a questionnaire. Discussion This study improves cancer patients’ quality of life and provides clinical evidence. Trial registration Registered at ClinicalTrials.gov— NCT05397457 on 1 June 2022.

Major cancer deaths can be ascribed to distant metastasis to which the assembly of pericellular fibronectin (periFN) on suspended tumor cells (STCs) in the bloodstream that facilitate endothelial attachment can lead. Even though mangosteen pericarps (MP) extracts and the major component α-mangostin (α-MG) exhibit potent cancer chemopreventive properties, whether they can prophylactically and therapeutically be used as dietary nutraceuticals to prevent distant metastasis by suppressing periFN assembly on STCs within the circulation remains obscure. Immunofluorescence staining, MTT assays, flow cytometric assays, immunoblotting, and experimental metastasis mouse models were used to detect the effects of MP extracts or α-MG on periFN on STCs, tumor cell proliferation and apoptosis, the AKT activity, and tumor lung metastasis. The periFN assembly on STCs was significantly diminished upon treatments of STCs with either α-MG or MP extracts in a dose-dependent manner without inhibiting cell proliferation and viability due to increased AKT activity. Pretreatment of STCs with α-MG appeared to suppress tumor lung metastasis and prolong mouse survival rates. Oral gavage with MP extracts could therapeutically, but not prophylactically, prevent lung metastasis of STCs. We concluded that MP extracts or the major component α-MG may therapeutically serve as a potent anti-metastatic nutraceutical.