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E2F family participates in most human malignancies by activating the transcription of the cell cycle-related genes. Whereas, as a specifical atypical member of this family, E2F7 was described as a repressor against its downstream genes and exerted oscillatory and controversial functions in cancers. Our previous study identified a molecular interaction promoting hepatocellular carcinoma (HCC) growth induced by SOX4 and Anillin. Meanwhile, we preliminarily identified SP1 as the upstream activator of SOX4. Intriguingly, we observed that the repressive E2F7 presents a remarkable high expression in HCC, and is positively correlated and involved in the same pathway with the potentially SP1/SOX4/Anillin axis. However, their exact interaction or mechanism controlling tumor progress between these genes has not been illustrated. Thus, we focused on this point in this study and attempted to improve the potential regulating axis in HCC cell proliferation and tumor growth for promoting tumor prevention and control. The expression profile of E2F7 in HCC tissues and tumor cells was detected along with the related candidate genes, through real-time quantitative polymerase chain reaction assay, the Western blot analysis, and the immunohistochemistry assay, combined with bioinformatics analysis of the HCC information from the the Cancer Genome Altas and Gene Expression Omnibus data sets. The correlation between E2F7 and HCC patients' clinicopathologic features was explored. Gain-of and loss-of-function assays were conducted both in vitro and in vivo along with the rescue experiment, for revealing the relative genes' functions in HCC progress. The ChIP and the dual-luciferase reporter assays were performed to verify the transcriptional regulating profile between E2F7 and SP1/SOX4/Anillin axis. E2F7 was upregulated in HCC and significantly correlated with SP1/SOX4/Anillin axis. High E2F7 expression is associated with dismal clinicopathologic features and poor survival of the patients. E2F7 depletion potently impaired SP1/SOX4/Anillin expression and significantly inhibited HCC growth. Furthermore, intensive exploration demonstrated that E2F7 preserves high SP1 levels by abrogating miR-383-5p in a transcriptional way. Atypical E2F7 is an important repressive transcription factor commonly upregulated in the HCC environment. E2F7 facilitates HCC growth by repressing miR-383-5p transcription and sequentially promoting SP1/SOX4/Anillin axis. Our findings provide us with probable targets for HCC prevention and therapeutic treatment.

Yujie Lu,1,&ast; Yiwei Tong,1,&ast; Jiahui Huang,1 Lin Lin,2 Jiayi Wu,1 Xiaochun Fei,3 Xiaosong Chen,1 Kunwei Shen1 1Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 2Department of Clinical Laboratory, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, People’s Republic of China; 3Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaosong Chen; Kunwei ShenDepartment of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of ChinaEmail chenxiaosong0156@hotmail.com; kwshen@medmail.com.cnBackground: It remains uncertain whether the 21-gene recurrence score (RS) of a primary tumor has selective prognostic value for locoregional recurrence (LRR) or distant metastasis (DM). The current study aimed to compare the distribution and single-gene expression on the RS panel in breast cancer patients with LRR versus DM.Methods: Consecutive early breast cancer patients who had been operated on at the Comprehensive Breast Health Center, Ruijin Hospital from January 2009 to December 2016 were retrospectively reviewed. Patients were divided into LRR, DM, and no-recurrence groups according to the first reported recurrent event. Comparison and subgroup analysis of 21-gene RS, RS category, and single-gene expression on the RS panel were conducted among patients with different recurrence status.Results: A total of 1,287 patients were included, with median follow-up of 61.5 months, and 27, 47, and 1,213 patients were classified as LRR, DM, and no recurrence groups, respectively. RS was significantly diversely distributed among the three groups (P< 0.001). No-recurrence patients (median 22) presented much lower RS than LRR (median 39, P< 0.001) and DM (median 30, P< 0.001) patients. LRR patients had lower PR (P< 0.001), BCL2 (P=0.010), and CEGP1 (P< 0.001) expression, and DM patients had higher STMY3 (P=0.019) expression than no-recurrence patients. Moreover, CEGP1 expression was significantly lower in the LRR group than the DM one (P=0.028).Conclusion: RS was differently distributed between recurrent and nonrecurrent patients. PR, BCL2, CEGP1, and STMY 3 expression was associated with LRR and DM, while CEGP1 was lower in the LRR group than DM patients, warranting further clinical evaluation.Keywords: breast cancer, 21-gene recurrence assay, gene expression, locoregional recurrence, distant metastasis

AimsCytokeratin 5 (CK5) is a surrogate maker of progenitor cells and early glandular and myoepithelial cells (MECs) in the breast, and CK5 expression in breast MECs varies from ducts to lobules, and from normal to diseased tissue. However, the mechanisms underlying immunophenotypic alterations of CK5 expression in MECs remain unclear.MethodsCK5 expression in MECs of 20 normal breast samples, 58 ductal carcinoma in situ (DCIS; including 21 DCIS with extensive lobular involvement), 11 atypical ductal hyperplasia (ADH), 18 non-invasive lobular neoplasia consisting of 11 atypical lobular hyperplasia (ALH) and 7 lobular carcinoma in situ (LCIS), 20 cystic lobules and 10 usual ductal hyperplasia (UDH) involving lobules were observed to evaluate the effects of contact with benign hyperplastic or cancerous luminal cells and pressure of dilated glands on CK5 expression.ResultsCK5 expression in normal ductal MECs was exclusively positive, whereas most normal lobular MECs were negative. In DCIS, cancerous ducts were primarily surrounded by CK5-positive MECs (91.0%), as were lobular acini involved by DCIS (89.2%), while the remaining normal acini maintained CK5-negative. CK5-positive MECs were found in 57.5% of acini in ALH and were more prevalent in LCIS (70.7%). CK5 expression was occasionally positive in both cystic lobules (16.7%) and lobules involved by UDH (14.3%), while an increase of CK5-positive MECs was found in ADH (38.2%).ConclusionsThese results suggest that CK5 expression in lobular MECs may be altered by contact with cancerous luminal cells rather than benign hyperplastic luminal cells or pressure from dilated glands.

Background: It is unknown whether molecular subtype is associated with axillary lymph node (ALN) status (ypN) after neoadjuvant therapy (NAT) in breast cancer patients who achieved breast pathological complete remission (pCR), especially for patients with different clinical stage. Our study aimed to investigate the association of clinical stage and molecular subtype with ALN status (ypN) after NAT in breast cancer patients. Patients and methods: Breast cancer patients receiving ≥ 4 cycles of NAT with complete clinicopathological data were retrospectively included between January 2009 to January 2020. Status of ypN according to breast pCR status was compared in cT1-2N0, cT1-2N1, and local advanced breast cancer (LABC) patients with different molecular subtype. Univariate and multivariate analyses were conducted to identify potential predictive factors for ypN status. Results: A total of 1999 patients were included. cT1-2N0, cT1-2N1, and LABC disease were found in 457 (22.86%), 884 (44.22%) and 658 (32.92%) patients, whose ypN+ rate was 24.5%, 60.3%, and 66.4%, respectively (P < 0.001). Compared with cT1-2N0 patients, ypN+ rate was significantly higher in cT1-2N1 (OR = 5.48, 95%CI = 3.77-7.97, P < 0.001) and LABC (OR = 10.90, 95%CI = 7.12-16.70, P < 0.001). Moreover, ypN+ rate varied across different molecular subtypes, which was 60.0% in Luminal A subtype, 61.4% in Luminal B (HER2-) subtype, 47.6% in Luminal B (HER2+) subtype, 42.2% in HER2-amplified subtype and 52.5% in TNBC (P < 0.001). Patients achieving breast pCR also had a significantly lower ypN+ rate than those without breast pCR (23.9% vs 62.5%, univariate P < 0.001; OR =0.14, 95%CI = 0.09-0.21, P < 0.001). Furthermore, in breast pCR patients, multivariate analyses showed that clinical stage and molecular subtype were substantially related to ypN+ rate: the ypN+ rate was significantly higher in cT1-2N1 (OR = 5.64, 95%CI = 2.31-13.76, P < 0.001) and LABC (OR = 9.80, 95%CI = 3.88-24.77, P < 0.001), compared with cT1-2N0 patients; while it was significantly lower in Luminal B HER2+ (OR =0.20, 95%CI = 0.05-0.82, P = 0.025) and HER2-amplified (OR = 0.19, 95%CI = 0.05-0.83, P = 0.026) subtype, compared with Luminal A subtype. In the cT1-2N0 subgroup, all patients with breast pCR with Luminal B HER2+ or HER2-amplified subtype achieved ALN pCR. Conclusion: Clinical stage and molecular subtype were significantly associated with ypN status in breast pCR patients after NAT. Patients with cT1-2N0 and HER2-positive patients who achieved breast pCR had low ypN+ rate, which possibly guides further clinical ALN management after NAT. Key words: Breast pathological complete remission; Neoadjuvant therapy; Molecular subtype; Clinical stage; Nodal residual burden. Table. Pathological node status stratified by clinical stage between patients with breast pCR and non-pCR.Response in breastpCRnon-pCRypN0 (N, %)ypN+ (N, %)ypN0 (N, %)ypN+ (N, %)Whole population331(76.1)104(23.9)586(37.5)978(62.5)cT1-2N088(93.6)6(6.4)257(70.8)106(29.2)cT1-2N1159(74.3)55(25.7)192(28.7)478(71.3)LABC84(66.1)43(33.9)137(25.8)394(74.2)Luminal A like9(69.2)4(30.8)37(36.3)65(63.7)cT1-2N06(85.7)1(14.3)19(73.1)7(26.9)cT1-2N13(50.0)3(50.0)12(27.9)31(72.1)LABC0(0.0)0(0.0)6(18.2)27(81.8)Luminal B like (HER2-)112(70.4)47(29.6)220(31.4)480(68.6)cT1-2N033(89.2)4(10.8)85(59.0)59(41.0)cT1-2N159(71.1)24(28.9)75(23.8)240(76.2)LABC20(51.3)19(48.7)60(24.9)181(75.1)Luminal B like (HER2+)89(83.2)18(16.8)140(42.4)190(57.6)cT1-2N019(100.0)0(0.0)70(83.3)14(16.7)cT1-2N146(83.6)9(16.4)43(30.5)98(69.5)LABC24(72.7)9(27.3)27(25.7)78(74.3)HER2 amplified66(82.5)14(17.5)97(48.0)105(52.0)cT1-2N014(100.0)0(0.0)42(82.4)9(17.6)cT1-2N125(78.1)7(21.9)32(42.1)44(57.9)LABC27(79.4)7(20.6)23(30.7)52(69.3)TNBC55(72.4)21(27.6)92(40.0)138(60.0)cT1-2N016(94.1)1(5.9)41(70.7)17(29.3)cT1-2N126(68.4)12(31.6)30(31.6)65(68.4)LABC13(61.9)8(38.1)21(27.3)56(72.7)Abbreviations: LABC, locally advanced breast cancer; HER2, human epidermal growth factor receptor 2; TNBC, triple negative breast cancer; pCR, breast pathological complete response. Citation Format: Jin Hong, Yiwei Tong, Ou Huang, Jiayi Wu, Li Zhu, Jianrong He, Weiguo Chen, Yafen Li, Xiaochun Fei, Xiaosong Chen, Kunwei Shen. Molecular subtype and clinical stage influenced axillary lymph node response in breast cancer patients with breast pathological complete remission after neoadjuvant therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-33.

PurposeThis retrospective study aimed to evaluate the distribution pattern and prognostic value of 21-gene recurrence score (RS) in Chinese patients with mucinous breast cancer (MC) and compared with infiltrating ductal carcinoma (IDC).Materials and MethodsPatients diagnosed with MC or IDC from January 2010 to January 2017 were retrospectively recruited. Reverse transcriptase–polymerase chain reaction assay of 21 genes was conducted to calculate the RS. Univariate and multivariate analyses were performed to assess the association between RS and clinicopathological factors. Survival outcomes including disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared by log-rank test.ResultsThe MC cohort included 128 patients and the IDC cohort included 707 patients. The proportions of patients with a low (RS < 18), intermediate (18-30), or high risk (RS > 30) were 32.0%, 48.4%, and 19.5% in MC cohort, and 26.9%, 46.8% and 26.3% in IDC cohort. The distribution of RS varied significantly according to different Ki-67 index and molecular subtype in both cohorts. Moreover, the receipt of chemotherapy was associated with RS in both cohorts. Among patients with MC, tumor stage was related to the DFS (p=0.040). No significant differences in DFS and OS were found among MC patients in different RS risk groups (OS, p=0.695; DFS, p=0.926).ConclusionRS was significantly related to Ki-67 index and molecular subtypes in MC patients, which is similar in IDC patients. However, RS was not able to predict DFS and OS in patients with MC.

Background: Clinical-pathological factors and 21-gene recurrence score (RS) influence adjuvant chemotherapy (ACT) decision for early breast cancer patients. We investigated the decision-making of ACT in patients with discordant risk classifications of clinical-pathological factors and RS. Methods: Patients with hormonal receptor (HR)+/ human epidermal growth factor receptor 2 (HER2)-, early breast cancer, who underwent 21-gene RS testing were identified from Ruijin Hospital (RJBC) and the Surveillance, Epidemiology, and End Results (SEER) database. According to Adjuvant! Online and RS (≤25 or >25), discordant risk classifications were defined as: clinical low-risk/ RS high-risk (C-low/ RS-high) and clinical high-risk/ RS low-risk (C-high/RS-low). McNemar's test was used to assess the changes between pre- and post-RS recommendations. Breast cancer-specific survival (BCSS) was estimated using the Kaplan-Meier methods. Results: Among 727 RJBC patients, the C-low/RS-high group and the C-high/RS-low group represented 19.7% and 21.3% of the cohort. After receiving 21-gene RS results, treatment recommendations were changed for 22.1% patients with discordant risk classifications: ACT rate increased from 41.9% to 75.5% in the C-low/RS-high group and decreased from 63.9% to 60.0% in the C-high/RS-low group. Among 2958 patients from the SEER cohort, 18.4% of the C-high/RS-low group and 59.2% of the C-low/RS-high group received ACT. There was no significant difference in the estimated 3-year BCSS between ACT or not among the C-low/RS-high group (p=0.708) and the C-high/RS-low groups (p=0.391). Conclusion: For patients with discordant risk classifications, physicians were apt to adopt the 21-gene RS rather than routine clinical-pathological factors to guide ACT selection.

Background: HER2-Low status is found in approximately half of breast cancer patients and shows potential benefits from novel antibody–drug conjugates (ADCs). Data on the accuracy of HER2-Low status between core needle biopsy (CNB) and surgical excision specimen (SES) samples are lacking. We aimed to investigate the accuracy of HER2-Low status diagnosis between CNB and SES samples. Methods: Consecutive early-stage breast cancer patients who underwent surgery from January 2009 to March 2022 with paired CNB and SES samples were retrospectively reviewed. HER2-Low was defined as IHC 1+ or IHC2+ and FISH-negative. Concordance rates were analyzed by the Kappa test. Further clinicopathological characteristics were compared among different HER2 status and their changes. Results: A total of 5610 patients were included, of whom 3209 (57.2%) and 3320 (59.2%) had HER2-Low status in CNB and SES samples, respectively. The concordance rate of HER2 status in the whole population was 82.37% (Kappa = 0.684, p < 0.001), and was 76.87% in the HER2-Negative patients (Kappa = 0.372, p < 0.001). Among 1066 HER2-0 cases by CNB, 530 patients were classified as HER2-Low tumors. On the contrary, in 3209 patients with HER2-Low tumor by CNB, 387 were scored as HER2-0 on the SES samples. ER-negative or Ki67 high expression tumor by CNB had a high concordance rate of HER2-Low status. Conclusions: A relatively low concordance rate was found when evaluating HER2-Low status between CNB and SES samples in HER2-Negative breast cancer patients, indicating the necessity of retesting HER2 low status at surgery, which may guide further therapy in the era of anti-HER2 ADCs.

Purpose To evaluate the predictive and prognostic value of tumor‐infiltrating lymphocytes (TILs) before and after neoadjuvant chemotherapy (NAC) in patients with breast cancer. Patients and methods Consecutive breast cancer patients treated with NAC between August 2008 and November 2019 were retrospectively analyzed. TIL levels were evaluated of invasive tumor samples, and high expression was defined as TILs >10%. Total pathological complete response (pCR) was defined as no invasive tumor in the breast or lymph nodes. Univariate and multivariate analyses were used to assess factors associated with pCR rate, disease‐free survival (DFS), and overall survival. Results A total of 461 patients were included. The mean pre‐NAC TIL level was higher among patients with pCR than among patients without pCR (24.28% ± 2.34% vs. 11.34% ± 0.60%, respectively, p

BackgroundPrimary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease of the exocrine glands characterized by specific pathological features. Previous studies have pointed out that salivary glands from pSS patients express a unique profile of cytokines, adhesion molecules, and chemokines compared to those from healthy controls. However, there is limited evidence supporting the utility of individual markers for different stages of pSS. This study aimed to explore potential biomarkers associated with pSS disease progression and analyze the associations between key genes and immune cells.MethodsWe combined our own RNA sequencing data with pSS datasets from the NCBI Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs)viabioinformatics analysis. Salivary gland biopsies were collected from 14 pSS patients, 6 non-pSS patients, and 6 controls. Histochemical staining and transmission electron micrographs (TEM) were performed to macroscopically and microscopically characterize morphological features of labial salivary glands in different disease stages. Then, we performed quantitative PCR to validate hub genes. Finally, we analyzed correlations between selected hub genes and immune cells using the CIBERSORT algorithm.ResultsWe identified twenty-eight DEGs that were upregulated in pSS patients compared to healthy controls. These were mainly involved in immune-related pathways and infection-related pathways. According to the morphological features of minor salivary glands, severe interlobular and periductal lymphocytic infiltrates, acinar atrophy and collagen in the interstitium, nuclear shrinkage, and microscopic organelle swelling were observed with pSS disease progression. Hub genes based on above twenty-eight DEGs, including MS4A1, CD19, TCL1A, CCL19, CXCL9, CD3G, and CD3D, were selected as potential biomarkers and verified by RT-PCR. Expression of these genes was correlated with T follicular helper cells, memory B cells and M1 macrophages.ConclusionUsing transcriptome sequencing and bioinformatics analysis combined with our clinical data, we identified seven key genes that have potential value for evaluating pSS severity.

Purpose The purpose of this study was to investigate the changes of tumor infiltrating lymphocytes (TILs) between core needle biopsy (CNB) and surgery removed sample (SRS) in early stage breast cancer patients and to identify the correlating factors and prognostic significance of TILs changes. Materials and Methods A retrospective study was carried out on 255 patients who received CNB and underwent surgical resection for invasive breast cancer. Stromal TILs levels of CNB and SRS were evaluated respectively. Tumors with ≥50% stromal TILs were defined as lymphocyte-predominant breast cancer (LPBC). Clinicopathological variables were analyzed to determine whether there were factors associated with TILs changes. Log-rank tests and Cox proportional hazards models were used to analyze the influences of TILs and TILs changes on survival. Results SRS-TILs (median, 10.0%) were significant higher than CNB-TILs (median, 5.0%; p

Background: Immune responses play an important role in the development of breast cancer. Trastuzumab can activate antibody-dependent cellular cytotoxicity (ADCC) in human epidermal growth factor receptor-2 (HER-2)-positive breast cancer. Many studies have demonstrated that inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC), are associated with prognosis in breast cancer. The aim of this study was to explore whether preoperative NLR, ALC or the absolute neutrophil count (ANC) is associated with prognosis in HER-2-positive breast cancer patients who received adjuvant trastuzumab. Patients and methods: Three hundred sixty-seven female patients with HER-2-positive invasive breast cancer who were treated with one-year adjuvant trastuzumab were analysed in this retrospective study. Preoperative haematological parameters, clinicopathological data and survival data were obtained. The cut-off points for ALC, ANC and NLR were based on the median values. Disease-free survival (DFS) and Overall survival (OS) were analysed by the Kaplan-Meier method. Multivariable Cox regression was used to determine the independent prognostic significance of ALC, ANC and NLR. Results: Survival analysis revealed that the 3-year DFS in patients with high ALC was 89.0%, which was significantly worse than 95.0% in patients with low ALC (p=0.014). Kaplan-Meier analysis also showed that patients with low NLR had a poorer 3-year DFS than patients with high NLR (89.7% vs 94.0%, respectively; p=0.047). Multivariate analysis showed that ALC was an independent prognostic factor for DFS (HR=2.723; 95% CI=1.211-6.122; p=0.015). Neither ANC, ALC nor NLR could predict OS independently. Conclusion: In HER-2-positive breast cancer patients who were treated with adjuvant trastuzumab, a high ALC is significantly associated with a poor DFS.

This manuscript has been retracted due to the identification of undeclared duplication of content, including Figure images, from a -previous publication by some of the authors: Wang C, Xie J, Zhao L, Fei X, Zhang H, Tan Y, Nie X, Zhou L, Liu Z, Ren Y, Yuan L, Zhang Y, Zhang J, Liang L, Chen X, Liu X, Wang P, Han X, Weng X, Chen Y, Yu T, Zhang X, Cai J, Chen R, Shi ZL, Bian XW. Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients. EBioMedicine. 2020; 57: 102833. All authors are requested to declare that manuscripts submitted to this journal are original. This journal makes clear that research fraud of any kind will not be tolerated and will result in immediate retraction.

PurposeBreast cancer (BC) patients with T1N0 tumors have relatively favorable clinical outcomes. However, it remains unclear whether molecular subtypes can aide in prognostic prediction for such small, nodal-negative BC cases and guide decision-making about escalating or de-escalating treatments.Patients and MethodsT1N0 BC patients diagnosed between 2009 and 2017 were included and classified into three subgroups according to receptor status: 1) hormonal receptor (HR)+/human epidermal growth factor receptor-2 (HER2)−; 2) HER2+; and 3) triple negative (TN) (HR−/HER2−). Patients’ characteristics and relapse events were reviewed. Kaplan–Meier analysis and Cox regression were used to assess the iDFS and BCSS. The effects of risk factors and adjuvant treatment benefits were evaluated by calculating hazard ratios (HRs) for invasive disease-free survival (iDFS) and breast cancer-specific survival (BCSS) with Cox proportional hazards models.ResultsIn total, 2,168 patients (1,435 HR+/HER2−, 427 HER2+, 306 TN) were enrolled. The 5-year iDFS rates were 93.6, 92.7, and 90.6% for HR+/HER2−, HER2+, and TN patients, respectively (P = 0.039). Multivariate analysis demonstrated that molecular subtype (P = 0.043), but not tumor size (P = 0.805), was independently associated with iDFS in T1N0 BC. TN patients [HRs = 1.77, 95% confidence interval (CI) = 1.11–2.84, P = 0.018] had a higher recurrence risk than HR+/HER2− patients. Adjuvant chemotherapy benefit was not demonstrated in all T1N0 patients but interacted with molecular subtype status. TN (adjusted HRs = 2.31, 95% CI = 0.68–7.54) and HER2+ (adjusted HRs = 2.26, 95% CI = 0.95–5.63) patients receiving chemotherapy had superior iDFS rates. Regarding BCSS, molecular subtype tended to be related to outcome (P = 0.053) and associated with chemotherapy benefit (P = 0.005).ConclusionMolecular subtype was more associated with disease outcome and chemotherapy benefit than tumor size in T1N0 BC patients, indicating that it may guide possible clinical de-escalating therapy in T1N0 BC.

BACKGROUND Coronavirus 2 (SARS-CoV-2) was declared a pandemic by the World Health Organization (WHO) in March 2020. To further reveal the pathologic associations between coronavirus and hypoxemia, we report the findings of 4 complete systematic autopsies of severe acute respiratory syndrome coronavirus 2-positive individuals who died of multiple organ failure caused by severe hypoxemia. MATERIAL AND METHODS We examined the donated corpses of 4 deceased patients who had been diagnosed with severe acute respiratory syndrome coronavirus 2. A complete post-mortem examination was carried out on each corpse, and multiple organs were macroscopically examined. RESULTS The 4 corpses were 2 males and 2 females, with an average age of 69 years. Bilateral lungs showed various degrees of atrophy and consolidation, with diffusely tough and solid texture in the sections. A thromboembolism was found in the main pulmonary artery extending into the atrium in 1 corpse, and significant atherosclerotic plaques tagged in the inner wall of the aortic arch were found in 2 corpses. Two corpses were found to have slightly atrophied bilateral renal parenchyma. Atrophic changes in the spleen were found in 2 corpses. Notably, there were significantly expanded alveolar septa and prominent fibroblastic proliferation. CONCLUSIONS The laboratory data of these corpses showed a progressive decrease in blood oxygen saturation, followed by refractory and irreversible hypoxemia. Clinical and laboratory information and autopsy and histologic presentations of multiple organs showed insufficient air exchange due to abnormalities in the respiratory system, and reduced erythropoiesis in bone marrow may play a role.

A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy., Postmortem analyses provide useful information for COVID-19 etiology. Here the authors profile 22 deceased severe COVID-19 patients with transcriptomic and histological approaches to find correlations between the presence of viral antigens with lymphocyte suppression yet myeloid activation, hinting distinct functions of these cells during pathogenesis.

Actin-binding protein Anillin plays a pivotal role in regulating cytokinesis during the cell cycle, and involves in tumorigenesis and progress. However, the exact regulation mechanism of Anillin in human hepatocellular carcinoma (HCC) remains largely unknown. In this study, we examined and verified the anomalous high expression of Anillin in both HCC patients' specimens and HCC cell lines. High expression of Anillin is associated with dismal clinicopathologic features of HCC patients and poor prognosis. We conducted loss-of and gain-of function studies in HCC Hep3B cells. Anillin presented a significantly facilitating effect on cell proliferation in vitro and induced remarkable tumor growth in vivo. We found that the over-expression of Anillin was driven by a potential axis of miR-138/SOX4. Transcription factor SOX4 presented a high expression profile positive correlated with Anillin, and ChIP assay validated the interaction between SOX4 and the specific sequence of the promoter region of Anillin gene. While, we verified miR-138 as an upstream regulator of SOX4, which is abrogated in HCC cells and exerts degenerating effect on SOX4 mRNA. In our conclusion, Anillin facilitates the cell proliferation and enhances tumor growth of HCC, and is modulated by miR-138/SOX4 axis which regulates the transcriptional activity of Anillin. Findings above demonstrate us a probable axis for HCC diagnosis and treatment. SUMMARY OF THE MAIN POINT: Anillin facilitates the cell proliferation and enhances tumor growth in HCC. The transcriptional activity of Anillin is modulated by miR-138/SOX4 axis. Findings above demonstrate us a probable axis for HCC diagnosis and treatment.

Systematic autopsy and comprehensive pathological analyses of COVID-19 decedents should provide insights into the disease characteristics and facilitate the development of novel therapeutics. In this study, we report the autopsy findings from the lungs and lymphatic organs of 12 COVID-19 decedents—findings that evaluated histopathological changes, immune cell signature and inflammatory factor expression in the lungs, spleen and lymph nodes. Here we show that the major pulmonary alterations included diffuse alveolar damage, interstitial fibrosis and exudative inflammation featured with extensive serous and fibrin exudates, macrophage infiltration and abundant production of inflammatory factors (IL-6, IP-10, TNFα and IL-1β). The spleen and hilar lymph nodes contained lesions with tissue structure disruption and immune cell dysregulation, including lymphopenia and macrophage accumulation. These findings provide pathological evidence that links injuries of the lungs and lymphatic organs with the fatal systematic respiratory and immune malfunction in critically ill COVID-19 patients.

Background: The 21-gene recurrence score (RS) assay has been proven prognostic and predictive for hormone receptor-positive/HER2-negative, node-negative early breast cancer patients. However, whether primary 21-gene RS can predict prognosis in recurrent breast cancer patients remained unknown.Patients and Methods: Consecutive breast cancer patients operated in Comprehensive Breast Health Center, Shanghai Ruijin Hospital between January 2009 and December 2018 were retrospectively analyzed. Patients with available 21-gene RS result for the primary tumor and reporting disease recurrence during follow-up were included. Association of 21-gene RS and overall survival (OS), post-recurrence overall survival (PR-OS), post-recurrence progression-free survival (PR-PFS), and first-line systemic treatment after recurrence were compared among different groups.Results: A total of 74 recurrent patients were included, with 10, 27, 37 patients in the RS

Potential functions of pseudogenes on tumorigenesis and development of human malignancies have been gradually revealed recently. However, the specific regulation and intracellular events associated with pseudogenes have not been illustrated clearly in hepatocellular carcinoma (HCC). AKR1B10P1 is an isoform pseudogene of oncogenic AKR1B10, and is barely transcribed in normal hepatocytes. In this study, anomalous transcript of AKR1B10P1 was detected in both HCC tissues and cell lines, and is positively correlated with its parental genes. High level of AKR1B10P1 transcript is correlated with dismal clinicopathologic features, including large tumor dimension, high level of serum Alpha-fetoprotein (AFP), advanced TNM stages, tumor microsatellite formation and venous invasion. Loss-of and gain-of function assays demonstrated the exact impact of AKR1B10P1 on promoting HCC cell proliferation. Furthermore, transcription factor SOX4 was discovered facilitating the activation of AKR1B10P1 transcription, and was validated as a down-stream target degraded by tumor-suppressing miR-138. Meanwhile, we discovered the existence of a positive feedback from AKR1B10P1, by which miR-138 interacts with AKR1B10P1 via a competing endogenous RNA (ceRNA) way. Thus, we suggest a positive feedback loop of AKR1B10P1/miR-138/SOX4, promoting HCC cell proliferation. In summary, the AKR1B10P1/miR-138/SOX4 loop in HCC cells provides us potential and probable targets contributing to HCC prevention and therapeutic treatment.

Given the histological special types (HST) of breast carcinoma accounted for minority of the Z0011 study population, this study aimed to assess the rates of axillary lymph node (ALN) involvement and non-sentinel lymph node (SLN) metastasis in patients with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), or other HST. Patients with cT1-2N0M0 breast cancer treated between 2009 and 2018 were retrospectively included from a multi-institutional database. Rates of nodal involvement were analyzed among different histological subgroups. The impact of ALN dissection (ALND) on adjuvant treatment decisions and prognosis were also analyzed among patients with 1–2 + SLNs. A total of 8294 patients were included: 6854 (82.6%), 257 (3.1%), and 1183 (14.3%) patients with IDC, ILC, and other HST, respectively. IDC patients had a significantly higher rate of ALN metastasis compared with ILC or other HST (31.9% vs. 22.6% vs. 16.4%, P

Background: Despite low aggressiveness in tumor biology and high responsiveness to endocrine therapy, subgroups of patients with estrogen receptor-positive/HER2-negative (ER+/HER2-) breast cancer relapse early in the first two years after initiation of endocrine therapy, indicating potential endocrine resistance. Accordingly, we attempted to establish a scoring system to inform the first-2-year prognosis (F2P Score). Methods: Patients with node-negative ER+/HER2- breast cancer and complete data of gene expressions in a 21-gene panel were retrospectively retrieved from Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB). The F2P Score was established based on the clinical and genomic variables associated with the first-2-year relapse after shrinkage correction and validated using the bootstrap resampling method. Model performance was quantified by Harrell's concordance-index (C-index) and Bayesian information criteria (BIC). Results: The F2P Score was established by integrating the clinical (age and tumor size) and genomic (ESR1, PGR, BCL2, CD68, GSTM1, and BAG1) variables with a C-index of 0.71 and BIC of 397.46. Bootstrap C-index was 0.72 (95% CI, 0.62-0.81) and BIC was 396.75 (95% CI, 252.37-541.13). A higher score indicated an increased likelihood of a first-2-year relapse, when used as continuous (HR, 2.94; 95% CI, 1.87-4.61) or categorical (HR, 3.68; 95% CI, 1.70-8.00) predictors in multivariate analysis. Both continuous and categorical F2P Score also remained prognostic for overall survival and other endpoints. No significant interaction was observed between the F2P Score and treatment subgroups. Additionally, the F2P Score outperformed the IHC4, clinical treatment score and 21-gene test in predicting first-2-year relapse. Conclusion: The F2P Score reported herein, integrating the clinicopathological and genomic variables, may inform prognosis and endocrine responsiveness. After the benefits and risks have been considered, treatment escalation may be an alternative strategy for patients with a higher score.

The coronavirus disease-19 (COVID-19) caused by SARS-CoV-2 infection can lead to a series of clinical settings from non-symptomatic viral carriers/spreaders to severe illness characterized by acute respiratory distress syndrome (ARDS)1,2. A sizable part of patients with COVID-19 have mild clinical symptoms at the early stage of infection, but the disease progression may become quite rapid in the later stage with ARDS as the common manifestation and followed by critical multiple organ failure, causing a high mortality rate of 7-10% in the elderly population with underlying chronic disease1-3. The pathological investigation in the lungs and other organs of fatal cases is fundamental for the mechanistic understanding of severe COVID-19 and the development of specific therapy in these cases. Gross anatomy and molecular markers allowed us to identify, in two fatal patients subject to necropsy, the main pathological features such as exudation and hemorrhage, epithelium injuries, infiltration of macrophages and fibrosis in the lungs. The mucous plug with fibrinous exudate in the alveoli and the activation of alveolar macrophages were characteristic abnormalities. These findings shed new insights into the pathogenesis of COVID-19 and justify the use of interleukin 6 (IL6) receptor antagonists and convalescent plasma with neutralizing antibodies against SARS-CoV-2 for severe patients.Authors Chaofu Wang, Jing Xie, Lei Zhao, Xiaochun Fei, Heng Zhang, and Yun Tan contributed equally to this work. Authors Chaofu Wang, Jun Cai, Rong Chen, Zhengli Shi, and Xiuwu Bian jointly supervised this work.

Background Advanced gastric cancer (GC) induces diamal prognosis and high mortality. Discovery of new biomarkers or differentially expressed genes (DEGs) is serving for early diagnosis, prevention and therapautic treatmen in GC. In this study, by combining with biostatistics analysis, we aimed to verify the aberrant high expression and enhancing effects of SPP1 on GC, and to explore the probable relative post-transcriptional regulation. Methods Three datasets (GSE13911, GSE19826 and GSE27342) from NCBI GEO database were explored. SPP1 was screened out and detected in 105 real GC patients through immunohistochemistry analysis and RT-qPCR assay. The patients’ clinicopathologic features were collected and analyzed. The expression of SPP1 was examinated in three GC cell lines (MKN-45, AGS and SNU-16) . MKN-45 cell model with SPP1 depletd was constrcted through shRNA transfection. CCK8 assay, cell cycle detection and apoptosis rate calculation were conducted to evaluate the ability of cell growth. MiR-4262 was filtered out as a potential up-streaming regulator of SPP1 mRNA through bioinformatic prediction, and the dual-luciferase reporter assay was used for validation. Rescue experiment was introduced to confirm the post-transcriptional regulation. Results Thirteen DEGs increased in GC were selected, among which SPP1 was screened out for its significant over-expression in GC. SPP1 expression profile was validated in both the 105 real GC patients’ samples and three GC cell liens. High SPP1 expression was found significantly associated with the patients’ clinicopathologic features related to unideal prognosis, including tumor size, lymph node metastasis, local invasion grade and TNM stage. Depletion of SPP1 remarkably suppressed the GC cell growth. Whilst, microRNA-4262 was validated directly binding to the 3’-UTR of SPP1 mRNA in GC cells, degenerating the expression of SPP1. Conclusions SPP1 probably functions as an oncogenic gene in GC, and provides us a new biomarker in GC hopeful to promote GC prevention, diagnose and therapeutic treatment.