Targeting EMSY-mediated methionine metabolism is a potential therapeutic strategy for triple-negative breast cancer.

Cancer stem cells (CSCs) are the most intractable subpopulation of triple-negative breast cancer (TNBC) cells, which have been associated with a high risk of relapse and poor prognosis. However, eradication of CSCs continues to be difficult. Here, we integrate the multiomics data of a TNBC cohort (n = 360) to identify vital markers of CSCs. We discover that EMSY, inducing a BRCAness phenotype, is preferentially expressed in breast CSCs, promotes ALDH+ cells enrichment, and is positively correlated with poor relapse-free survival. Mechanistically, EMSY competitively binds to the Jmjc domain, which is critical for KDM5B enzyme activity, to reshape methionine metabolism, and to promote CSC self-renewal and tumorigenesis in an H3K4 methylation-dependent manner. Moreover, EMSY accumulation in TNBC cells sensitizes them to PARP inhibitors against bulk cells and methionine deprivation against CSCs. These findings indicate that clinically relevant eradication of CSCs could be achieved with a strategy that targets CSC-specific vulnerabilities in amino acid metabolism.

Combined Single-Cell and Spatial Transcriptomics Reveal the Metabolic Evolvement of Breast Cancer during Early Dissemination.

Breast cancer is now the most frequently diagnosed malignancy, and metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the evolvement of dissemination. In this study, 65 968 cells from four patients with breast cancer and paired metastatic axillary lymph nodes are profiled using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. A disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS), including the upregulation of cytochrome C oxidase subunit 6C and dehydrogenase/reductase 2, is identified. The transition between glycolysis and OXPHOS when dissemination initiates is noticed. Furthermore, this distinct cell cluster is distributed along the tumor's leading edge. The findings here are verified in three different cohorts of breast cancer patients and an external scRNA-seq dataset, which includes eight patients with breast cancer and paired metastatic axillary lymph nodes. This work describes the dynamic metabolic evolvement of early disseminated breast cancer and reveals a switch between glycolysis and OXPHOS in breast cancer cells as the early event during lymph node metastasis.

Determining the Optimal (Neo)Adjuvant Regimen for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Regarding Survival Outcome: A Network Meta-Analysis.

Background: The optimal (neo)adjuvant regimen for human epidermal growth factor receptor-2 (HER2)-positive breast cancer regarding survival outcomes remains unclear. Methods: We searched Web of Science, PubMed, and the Cochrane Central Register of Controlled Trials systematically to find out randomized controlled studies, up to January 2022, that compared different anti-HER2 regimens in the (neo)adjuvant setting. The primary endpoint was disease-free survival (DFS). We used a Bayesian statistical model to combine direct and indirect comparisons and used odds ratios (ORs) to pool effect sizes and performed the surface under the cumulative ranking area (SUCRA) curves to estimate the ranking probabilities of various regimens. For survival outcomes, we performed two parallel analyses, one based on data from both neoadjuvant and adjuvant studies and the other specific to adjuvant studies. All statistics were two-sided. Results: Fifteen studies were finally enrolled. Regarding DFS, the overall analysis indicated that the top two regimens for HER2-positive breast cancer were chemotherapy plus trastuzumab with lapatinib, and chemotherapy plus trastuzumab with pertuzumab (SUCAR of 81% and 79%, respectively), with the OR of 0.99 [95% confidence interval (CI), 0.59 to 1.54]; the parallel analysis specific to adjuvant trials indicated that the top two regimens were chemotherapy plus trastuzumab with sequential neratinib, and chemotherapy plus trastuzumab with pertuzumab (SUCRA of 80% and 76%, respectively), with the OR of 1.04 (95% CI, 0.63 to 1.73). The dual-target therapy that combines trastuzumab and pertuzumab showed the highest risk of inducing cardiac events, with an SUCRA of 92%. Conclusions: Chemotherapy plus trastuzumab and pertuzumab might be the optimal regimen for HER2-positive breast cancer in improving the survival rate. However, the cardiotoxicity of this dual-target therapy should be taken care of.

De-escalation of five-year adjuvant endocrine therapy in patients with estrogen receptor-low positive (immunohistochemistry staining 1%-10%) breast cancer: Propensity-matched analysis from a prospectively maintained cohort.

BACKGROUND: The standard 5 years of endocrine therapy has demonstrated additional benefits compared with short-term (2-3 years) treatment in patients with estrogen receptor (ER)-positive breast cancer; however, data specific to ER-low positive breast cancer (1%-10% by immunohistochemistry) are limited, and it is unclear whether long-term treatment is still necessary for this subgroup. METHODS: The authors used the prospectively maintained Breast Surgery Database of Fudan University Shanghai Cancer Center for this propensity-matched analysis. The primary end point was disease-free survival. Multivariate Cox regression analysis and propensity score-matching methods were used to minimize bias. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. All statistics were 2-sided. RESULTS: From 2012 to 2017, 22,768 consecutive women had pathologically confirmed, early stage breast cancer, and 1013 (4.45%) were identified with ER-low positive disease. Among these, 634 patients met the inclusion criteria and were divided into 3 groups: those who received no endocrine therapy (n = 89), those who received 2 to 3 years of endocrine therapy (n = 185), and those who received approximately 5 years of endocrine therapy (n = 360). At a median follow-up of 65 months, there was no significant difference in disease-free survival between patients who received 2 to 3 years and 5 years of endocrine therapy (HR, 0.82; 95% CI, 0.51-1.33; P = .43). The findings were consistent after multivariate Cox analysis of the propensity score-matched samples (5 vs 2-3 years of treatment: HR, 0.74; 95% CI, 0.41-1.31; P = .30). CONCLUSIONS: Short-term endocrine therapy for 2 to 3 years might be an alternative for patients who have ER-low positive breast cancer instead of the standard 5 years of treatment.

Deep learning driven colorectal lesion detection in gastrointestinal endoscopic and pathological imaging.

Colorectal cancer has the second highest incidence of malignant tumors and is the fourth leading cause of cancer deaths in China. Early diagnosis and treatment of colorectal cancer will lead to an improvement in the 5-year survival rate, which will reduce medical costs. The current diagnostic methods for early colorectal cancer include excreta, blood, endoscopy, and computer-aided endoscopy. In this paper, research on image analysis and prediction of colorectal cancer lesions based on deep learning is reviewed with the goal of providing a reference for the early diagnosis of colorectal cancer lesions by combining computer technology, 3D modeling, 5G remote technology, endoscopic robot technology, and surgical navigation technology. The findings will supplement the research and provide insights to improve the cure rate and reduce the mortality of colorectal cancer.

Estrogen receptor-low breast cancer: Biology chaos and treatment paradox.

Hormone receptor testing mainly serves the purpose of guiding treatment choices for breast cancer patients. Patients with estrogen receptor (ER)-positive breast cancers show significant response to endocrine therapy. However, the methods to define ER status and eligibility for treatment remain controversial. Despite recent guidelines considering staining ≥1% of tumor nuclei by immunohistology as ER-positive, it has raised concerns on the benefit of endocrine therapy for tumors with ER 1%-10% expression, termed "ER-low positive". This subgroup accounts for 3% to 9% of all patients and is likely to have unique molecular features, and therefore distinct therapeutic response to endocrine therapy compared with ER-high positive tumors. The latest guidelines did not provide detailed descriptions for those patients, resulting in inconsistent treatment strategies. Consequently, we aimed to resolve this dilemma comprehensively. This review discusses molecular traits and recent ER-low positive breast cancer innovations, highlighting molecular-targeted treatment rather than traditional unified endocrine therapy for future basic and clinical research.

The efficacy and safety of SGLT2 inhibitors combined with ACEI/ARBs in the treatment of type 2 diabetes mellitus: A meta-analysis of randomized controlled studies.

BACKGROUND: The efficacy and safety of the combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARBs) in the treatment of type 2 diabetes mellitus (T2DM) was not clear yet. RESEARCH DESIGN AND METHODS: A meta-analysis of randomized controlled studies (RCTs) was performed by searching in CENTRAL, Web of Science, PubMed, and Embase. RESULTS: Eight RCTs involving 6,386 participants were finally enrolled in this meta-analysis. Compared with placebo plus ACEI/ARBs, combined therapy with SGLT2 inhibitors and ACEI/ARBs induced a significant reduction in glycated hemoglobin (HbA1c) level by 0.43% (95% confidence interval [CI]: -0.55, -0.31), fasting plasma glucose level by 16.51 mg/dL (95% CI: -21.94, -11.08); systolic/diastolic blood pressure (BP) by 5.34 mmHg (95% CI: -7.47, -3.21)/1.27 mmHg (95% CI: -1.95, -0.59), respectively; and body weight (BW) by 1.45 kg (95% CI: -2.24, -0.65). Combined therapy was also found to be associated with a lower risk of adverse events. However, a higher risk of genital infections was observed with combination therapy than with placebo. CONCLUSIONS: This combination therapy showed satisfactory effects on lowering glycemic, BW, and BP in the treatment of T2DM patients. The safety of this combination therapy was also acceptable.

The effects of "Fangcang, Huoshenshan, and Leishenshan" hospitals and environmental factors on the mortality of COVID-19.

BACKGROUND: In December 2019, a novel coronavirus disease (COVID-19) broke out in Wuhan, China; however, the factors affecting the mortality of COVID-19 remain unclear. METHODS: Thirty-two days of data (the growth rate/mortality of COVID-19 cases) that were shared by Chinese National Health Commission and Chinese Weather Net were collected by two authors independently. Student's t-test or Mann-Whitney U test was used to test the difference in the mortality of confirmed/severe cases before and after the use of "Fangcang, Huoshenshan, and Leishenshan" makeshift hospitals (MSHs). We also studied whether the above outcomes of COVID-19 cases were related to air temperature (AT), relative humidity (RH), or air quality index (AQI) by performing Pearson's analysis or Spearman's analysis. RESULTS: Eight days after the use of MSHs, the mortality of confirmed cases was significantly decreased both in Wuhan (t = 4.5, P < 0.001) and Hubei (U = 0, P < 0.001), (t and U are the test statistic used to test the significance of the difference). In contrast, the mortality of confirmed cases remained unchanged in non-Hubei regions (U = 76, P = 0.106). While on day 12 and day 16 after the use of MSHs, the reduce in mortality was still significant both in Wuhan and Hubei; but in non-Hubei regions, the reduce also became significant this time (U = 123, P = 0.036; U = 171, P = 0.015, respectively). Mortality of confirmed cases was found to be negatively correlated with AT both in Wuhan (r =  - 0.441, P = 0.012) and Hubei (r =  - 0.440, P = 0.012). Also, both the growth rate and the mortality of COVID-19 cases were found to be significantly correlated with AQI in Wuhan and Hubei. However, no significant correlation between RH and the growth rate/mortality of COVID-19 cases was found in our study. CONCLUSIONS: Our findings indicated that both the use of MSHs, the rise of AT, and the improvement of air quality were beneficial to the survival of COVID-19 patients.

Combination therapy with SGLT2 inhibitors for diabetic kidney disease.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral antihyperglycemic agents developed in recent years. They could block most glucose reabsorption in renal proximal tubules, thereby exerting glucose lowering effects through glycosuric ways. The renal and cardiovascular protection effects of SGLT2 inhibitors have also been demonstrated both in preclinical studies and clinical trials. However, SGLT2 inhibitors alone could induce an increase in endogenous/hepatic glucose production as well as in fasting plasma glucose levels; a sharp decrease of blood glucose concentration induced by SGLT2 inhibitors could also promote the secretion of counter-regulatory hormones such as glucagon, which has been reported to be associated with the occurrence of glycemic ketoacidosis. Therefore, coadministration of SGLT2 inhibitors and other antihyperglycemic agents should be considered when the therapeutic effect of SGLT2 inhibitors alone was unsatisfactory.

Potential of microRNA expression profile in predicting renal impairment risk in multiple myeloma patients.

BACKGROUND: This study aimed to investigate the correlation of microRNA (miRNA) expression profile with renal impairment (RI) risk in multiple myeloma (MM) patients. METHODS: Plasma cell samples were isolated from bone marrows of 20 RI-MM patients and 20 non-RI-MM patients, and then proposed to microarray assay. Then 5 candidate miRNAs were selected and further validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in plasma cell samples from bone marrows of 60 RI-MM patients and 60 non-RI-MM patients. RESULTS: Principal component analysis and heatmap analysis revealed that miRNA expression profile could clearly distinguish RI-MM patients from non-RI-MM patients, further Valcano plots identified 28 upregulated and 13 downregulated miRNAs in RI-MM patients compared to non-RI-MM patients, and enrichment analysis observed that these dysregulated miRNAs were enriched in renal/inflammatory/apoptosis pathways and renal/inflammatory diseases. Subsequent RT-qPCR validation discovered that miR-103a-3p, miR-449c-5p and let-7a-5p were greatly increased, while miR-877-5p and miR-455-3p were dramatically decreased in RI-MM patients compared to non-RI-MM patients, and all of them could predict RI risk in MM patients by receiver operating characteristic (ROC) curve analysis. Most importantly, the combination of these five miRNAs presented with a great predictive value for RI risk in MM patients with an area under the curve (AUC) of 0.934, 95% CI: 0.895-0.974. CONCLUSIONS: MiRNA expression profile is closely implicated in the RI development, and miR-103a-3p, miR-449c-5p, miR-877-5p, miR-455-3p and let-7a-5p may serve as novel biomarkers for RI risk in MM patients.

Efficacy of Chemotherapies and Stem Cell Transplantation for Systemic AL Amyloidosis: A Network Meta-Analysis.

BACKGROUND/AIMS: The present Bayesian network meta-analysis (NMA) was to compare the efficacy of different chemotherapies and autologous stem cell transplantation (ASCT) in immunoglobulin light-chain (AL) amyloidosis. METHODS: We systematically searched PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies compared the rates of hematological response (HR), complete response (CR), renal response, and cardiac response in AL amyloidosis patients. RESULTS: There were three randomized controlled trials (RCTs) and thirteen observational controlled trials (OCTs) comprising 3,402 participants enrolled for the comparisons of seven treatments: melphalan + dexamethasone (MDex), high-dose melphalan followed by ASCT, bortezomib + melphalan + dexamethasone (BMDex), thalidomide + cyclophosphamide + dexamethasone (CTD), bortezomib + dexamethasone (BDex), bortezomib + cyclophosphamide + dexamethasone (CyBorD), cyclophosphamide + lenalidomide + dexamethasone (CLD). BMDex was ranked first in the aspect of both HR and CR, CTD induced the highest rate of renal response, and BDex was possibly the best treatment for the cardiac response. CONCLUSION: Although more data about safety and cost are needed, BMDex was recommended as the most efficient treatment for AL amyloidosis patients for enhancing the response rate for HR and CR.