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Machine-assisted pathological recognition has been focused on supervised learning (SL) that suffers from a significant annotation bottleneck. We propose a semi-supervised learning (SSL) method based on the mean teacher architecture using 13,111 whole slide images of colorectal cancer from 8803 subjects from 13 independent centers. SSL (~3150 labeled, ~40,950 unlabeled; ~6300 labeled, ~37,800 unlabeled patches) performs significantly better than the SL. No significant difference is found between SSL (~6300 labeled, ~37,800 unlabeled) and SL (~44,100 labeled) at patch-level diagnoses (area under the curve (AUC): 0.980 ± 0.014 vs. 0.987 ± 0.008, P value = 0.134) and patient-level diagnoses (AUC: 0.974 ± 0.013 vs. 0.980 ± 0.010, P value = 0.117), which is close to human pathologists (average AUC: 0.969). The evaluation on 15,000 lung and 294,912 lymph node images also confirm SSL can achieve similar performance as that of SL with massive annotations. SSL dramatically reduces the annotations, which has great potential to effectively build expert-level pathological artificial intelligence platforms in practice. Machine-assisted recognition of colorectal cancer has been mainly focused on supervised deep learning that suffers from a significant bottleneck of requiring massive amounts of labeled data. Here, the authors propose a semi-supervised model based on the mean teacher architecture that provides pathological predictions at both patch- and patient-levels.

The M2 isoform of pyruvate kinase (PKM2), as a key glycolytic enzyme, plays important roles in tumorigenesis and chemotherapeutic drug resistance. However, the intricate mechanism of PKM2 as a protein kinase regulating breast cancer progression and tamoxifen resistance needs to be further clarified. Here, we reported that PKM2 controls the expression of survivin by phosphorylating c-Myc at Ser-62. Functionally, PKM2 knockdown suppressed breast cancer cell proliferation and migration, which could be rescued by overexpression of survivin. Interestingly, we found that the level of PKM2 expression was upregulated in the tamoxifen resistant breast cancer cells MCF-7/TAMR, and knockdown of PKM2 sensitized the cells to 4-hydroxytamoxifen (4OH-T). In addition, the elevated level of PKM2 correlates with poor relapse-free survival in breast cancer patients treated with tamoxifen. Overall, our findings demonstrated that PKM2–c-Myc–survivin cascade regulated the proliferation, migration and tamoxifen resistance of breast cancer cells, suggesting that PKM2 represents a novel prognostic marker and an attractive target for breast cancer therapeutics, and that PKM2 inhibitor combined with tamoxifen may be a promising strategy to reverse tamoxifen resistance in breast cancer patients.

Coral reefs are among the most biodiverse and economically important marine ecosystems worldwide. Recently, these ecosystems have faced threats and degradation from multiple factors. In particular, coral species living at the edges of subtropical zones are important “barometers” for indicating the global boundaries of coral communities. From 2023 to 2024, we investigated the coral species composition and coverage surrounding the Dapeng Peninsula, which is located at the northern edge of the subtropical zone, and explored the influence of environmental factors on the coral community structure. Fifty‐one species belonging to 20 genera and 13 families were identified in five habitats (conservation, wind‐wave, tourist, fishery, and pristine areas) across three seasons. Owing to rapid urbanization and global warming, the dominant coral species shifted from branching types, which are essential reef‐builders for creating structural substrates, to clumping types, which are more adaptable to environmental pressures. Notably, compared with the first report four decades ago, our current results demonstrated that coral coverage around the Dapeng Peninsula declined at an approximate rate of 0.54% per year from 1983 to 2023. Redundancy correspondence analysis revealed that substrate type, especially rock and dead coral skeletons, nitrogen and phosphorus levels, suspended particulate matter, chemical oxygen demand, and water transparency were key environmental factors that significantly (p < 0.05) influenced the distribution of coral species. The lowest diversity of coral communities was recorded in fishery and wind‐wave areas, where intense human disturbance and harsh natural environments limit the survival of sensitive coral species. In contrast, owing to stable hydrological conditions, shallow sunlit water, and diverse substrate types, coral biodiversity was the highest in the pristine habitat. Accordingly, the coral indicator species varied from Pavona decussata in the conservation area to Platygyra carnosus in the wind‐wave area, to Montipora peltiformis and Leptastrea purpurea in the tourist area, to Turbinaria peltata, Porites deformi, Goniopora columna, and Goniopora lobata in the pristine area, while no indicator species were found in the fishery area. The distribution and coverage of these indicator species can effectively reflect the extent of human disturbance to local habitats. In the future, it will be important to conduct real‐time monitoring of coral community characteristics around the Dapeng Peninsula to determine environmental changes in subtropical marine zones, providing insights into the response of global coral communities to anthropogenic disturbances and climate change. The dominant coral species in Dapeng Peninsula changed from branching types to clumping types. Fishing and tourism had significant negative impacts on coral reef development. Water quality and substrate types determined the distribution and structure of coral communities. Nine coral species across different habitat types were selected as indicators to reflect region‐specific environmental changes.

River ecosystems are facing significant degradation from human activities, which impact both biotic (e.g., fish and invertebrates) and abiotic components (e.g., water and habitat). A comprehensive comparison of energy flow patterns and system attributes among river food webs under different levels of human interference is highly important for developing management strategies to protect river ecosystems. Along the subtropical Pearl River, six spatial zones, including agricultural, industrial, island, urban, factory, and estuarine areas, were chosen to construct the Ecopath models. The output results revealed that the highest trophic level of the Pearl River was 3.8–4.2, which was occupied by softshell turtles and piscivorous/carnivorous fish. The most diverse functional groups were found in island and estuarine zones due to their heterogeneous habitats (e.g., high submerged vegetation coverage and the transition area between fresh and brackish water). In contrast, the food web structure in the industrial zone was destroyed due to water pollution (e.g., sewage discharge) and habitat degradation. The increase in exotic species and the decrease in native top predators were two factors that result in the low efficiency of energy transmission. A series of trophic (e.g., Lindeman transfer efficiency and mixed predator–prey impacts), structural (e.g., keystoneness, omnivory, and Finn's path length), and theoretical (e.g., connectance and ascendency) indices revealed that the health and maturity of the Pearl River sections can be ranked as island > estuarine > agricultural > urban > factory > industrial zones. The food chains led by softshell turtles (Pelodiscus sinensis), piscivores (e.g., Elopichthys bambusa), molluscivores (e.g., Mylopharyngodon piceus), and herbivores (e.g., Ctenopharyngodon idelus) could be used to indicate the health and functioning of river ecosystems. Our results suggest that the ecological management of river ecosystems should focus more efforts on protecting original habitats (e.g., the island zone with fish feeding/spawning grounds), monitoring bioindicators with keystone trophic impacts in the food web, and evaluating the food chains that play important roles in upward energy transmission. The undisturbed island zone, which provided essential feeding/spawning habitats, should be protected to maintain river health. The food web structure in the industrial zone was collapsed due to water pollution and habitat degradation. The appearance of softshell turtles and herbivorous/molluscivorous fish can be used to indicate the integrity of the food web structure.

Epidermal growth factor-like domain-containing protein 7 (EGFL7) is upregulated in human epithelial tumors and so is a potential biomarker for malignancy. Indeed, previous studies have shown that high EGFL7 expression promotes infiltration and metastasis of gastric carcinoma. The epithelial-mesenchymal transition (EMT) initiates the metastatic cascade and endows cancer cells with invasive and migratory capacity; however, it is not known if EGFL7 promotes metastasis by triggering EMT. We found that EGFL7 was overexpressed in multiple human gastric cancer (GC) cell lines and that overexpression promoted cell invasion and migration as revealed by scratch wound and transwell migration assays. Conversely, shRNA-mediated EGFL7 knockdown reduced invasion and migration. Furthermore, EGFL7-overexpressing cells grew into larger tumors and were more likely to metastasize to the liver compared to underexpressing CG cells following subcutaneous injection in mice. EGFL7 overexpression protected GC cell lines against anoikis, providing a plausible mechanism for this enhanced metastatic capacity. In excised human gastric tumors, expression of EGFL7 was positively correlated with expression levels of the mesenchymal marker vimentin and the EMT-associated transcription repressor Snail, and negatively correlated with expression of the epithelial cell marker E-cadherin. In GC cell lines, EGFL7 knockdown reversed morphological signs of EMT and decreased both vimentin and Snail expression. In addition, EGFL7 overexpression promoted EGF receptor (EGFR) and protein kinase B (AKT) phospho-activation, effects markedly suppressed by the EGFR tyrosine kinase inhibitor AG1478. Moreover, AG1478 also reduced the elevated invasive and migratory capacity of GC cell lines overexpressing EGFL7. Collectively, these results strongly suggest that EGFL7 promotes metastasis by activating EMT through an EGFR-AKT-Snail signaling pathway. Disruption of EGFL7-EGFR-AKT-Snail signaling may a promising therapeutic strategy for gastric cancer.

Autophagy can protect stressed cancer cell by degradation of damaged proteins and organelles. However, the regulatory mechanisms behind this cellular process remain incompletely understood. Here, we demonstrate that RSK2 (p90 ribosomal S6 kinase 2) plays a critical role in ER stress-induced autophagy in breast cancer cells. We demonstrated that the promotive effect of RSK2 on autophagy resulted from directly binding of AMPKα2 in nucleus and phosphorylating it at Thr172 residue. IRE1α, an ER membrane-associated protein mediating unfolded protein response (UPR), is required for transducing the signal for activation of ERK1/2-RSK2 under ER stress. Suppression of autophagy by knockdown of RSK2 enhanced the sensitivity of breast cancer cells to ER stress both in vitro and in vivo. Furthermore, we demonstrated that inhibition of RSK2-mediated autophagy rendered breast cancer cells more sensitive to paclitaxel, a chemotherapeutic agent that induces ER stress-mediated cell death. This study identifies RSK2 as a novel controller of autophagy in tumor cells and suggests that targeting RSK2 can be exploited as an approach to reinforce the efficacy of ER stress-inducing agents against cancer.

: To determine the role of UCH-L1 in regulating ERα expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with loss or reduction of ERα. : Expressions of UCH-L1 and ERα were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ERα, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases. The molecular pathways by which UCH-L1 regulates ERα were analyzed using immunoblotting, qRT-PCR, immunoprecipitation, ubiquitination, luciferase and ChIP assays. The effects of UCH-L1 inhibition on the efficacy of tamoxifen in ERα (-) breast cancer cells were tested both and . : UCH-L1 expression was conversely correlated with ERα status in breast cancer, and the negative regulatory effect of UCH-L1 on ERα was mediated by the deubiquitinase-mediated stability of EGFR, which suppresses ERα transcription. High expression of UCH-L1 was associated with poor therapeutic response and prognosis in patients with breast cancer. Up-regulation of ERα caused by UCH-L1 inhibition could significantly enhance the efficacy of tamoxifen and fulvestrant in ERα (-) breast cancer both and . : Our results reveal an important role of UCH-L1 in modulating ERα status and demonstrate the involvement of UCH-L1-EGFR signaling pathway, suggesting that UCH-L1 may serve as a novel adjuvant target for treatment of hormone therapy-insensitive breast cancers. Targeting UCH-L1 to sensitize ER negative breast cancer to anti-estrogen therapy might represent a new therapeutic strategy that warrants further exploration.

Cathepsin L (CTSL) is a lysosomal acid cysteine protease that has been implicated in tumorigenesis and malignant progression. In the present study, the role of CTSL in tumorigenesis and prognosis of breast cancer was evaluated. The prognostic value of CTSL was analyzed using immunohistochemistry in patients with breast cancer, as well as online microarray datasets. CTSL expression was knocked down in the breast cancer cell line T-47D using RNA interference. MTT and colony formation assays were performed to assess the role of CTSL in the proliferation of breast cancer cells. Cell cycle progression and apoptosis were measured using flow cytometry. A physical interaction of CTSL and cyclin dependent kinase 2 associated protein 1 (CDK2-AP1) was determined using a glutathione S-transferase pull-down assay. Endogenous CTSL expression was high in breast cancer cells and exhibited an inverse association with CDK2-AP1 expression; aberrant expression of CTSL in breast cancer tissues predicted an improved clinical outcome and prognosis. In addition, CTSL knockdown decelerated the progression of breast cancer cells by arresting cell cycle progression and increasing apoptosis. Thus, CTSL may be a potential therapeutic target for treating patients with breast cancer.

Background Vitex negundo L (Verbenaceae) is an aromatic shrub that is abundant in Asian countries. A series of compounds from Vitex negundo have been used in traditional Chinese medicine for the treatment of various diseases. Cutaneous melanoma is one of the most aggressive malignancies. A significant feature of melanoma is its resistance to traditional chemotherapy and radiotherapy; therefore, there is an urgent need to develop novel treatments for melanoma. Methods We first examined the effects of VB1 (vitexin compound 1) on cell viability by CCK-8 (cell counting kit) and Colony Formation Assay; And then, we analyzed the apoptosis and cell cycle by flow cytometry, verified apoptosis by Immunoblotting. The in vivo effect of VB1 was evaluated in xenograft mouse model. Potential mechanisms of VB1’s antitumor effects were explored by RNA sequencing and the key differential expression genes were validated by real-time quantitative PCR. Finally, the intracellular reactive oxygen species (ROS) level was detected by flow cytometry, and the DNA damage was revealed by Immunofluorescence and Immunoblotting. Results In this study, we show that VB1, which is a compound purified from the seed of the Chinese herb Vitex negundo , blocks melanoma cells growth in vitro and in vivo, arrests the cell cycle in G2/M phase and induces apoptosis in melanoma cell lines, whereas the effects are not significantly observed in normal cells. To study the details of VB1, we analyzed the alteration of gene expression profiles after treatment with VB1 in melanoma cells. The findings showed that VB1 can affect various pathways, including p53, apoptosis and the cell cycle pathway, in a variety of melanoma cell lines. Furthermore, we confirmed that VB1 restored the P53 pathway protein level, and then we demonstrated that VB1 significantly induced the accumulation of ROS, which resulted in DNA damage in melanoma cell lines. Interestingly, our results showed that VB1 also increased the ROS levels in BRAFi (BRAF inhibitor)-resistant melanoma cells, leading to DNA cytotoxicity, which caused G2/M phase arrest and apoptosis. Conclusions Taken together, our findings indicate that vitexin compound 1 might be a promising therapeutic Chinese medicine for melanoma treatment regardless of BRAFi resistance.

Stratifin plays an important role in cancer biology by interfering with intracellular signalling pathways and cell-cycle checkpoints. Decreased expression of stratifin gene has been reported to be a poor prognostic indicator in a variety of human malignant tumors. Aim To clarify the role and prognostic significance of stratifin in esophageal squamous cell carcinoma (ESCC). Methods The alteration of stratifin messenger RNA (mRNA) and protein was analyzed by reverse-transcription and quantitative real-time polymerase chain reaction (QRT-PCR) and Western blotting in 20 paired ESCC and nonneoplastic esophageal mucosa tissues, respectively. Then, immunohistochemistry (IHC) was used to evaluate expression of stratifin in tissues of 148 ESCC patients (including the former 20 pairs of tissues) and correlate it with clinicopathological parameters and prognosis of ESCC patients. Results The stratifin level of mRNA and protein was markedly downregulated in ESCC tissue compared with in corresponding nonneoplastic esophageal epithelium (P < 0.05). Similarly, the positive rate of stratifin protein expression was lower in the esophageal cancer than in paired nonneoplastic esophageal epithelium as detected by IHC (P = 0.007). Statistically, the downregulation of stratifin expression was correlated with tumor infiltration depth (P = 0.003), lymph node metastasis (P = 0.008), distant metastasis (P = 0.013), and lymphovascular invasion (P = 0.007) of ESCC. Furthermore, the reduced stratifin expression was associated with shorter 5-year survival rate of ESCC patients after curative surgery (P < 0.0001). On the basis of univariate and multivariate Cox regression analysis, we found that reduced stratifin expression, T4 stage, lymph node metastasis, and distant metastasis were independent risk factors for worse prognosis in ESCC patients. Conclusion The present report indicates that stratifin could be a useful indicator for prognosis of this disease, as well as a potential target for more effective therapy.