A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer.

Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.

Strategy of combining CDK4/6 inhibitors with other therapies and mechanisms of resistance.

Cell cycle-dependent protein kinase 4/6 (CDK4/6) is a crucial kinase that regulates the cell cycle, essential for cell division and proliferation. Hence, combining CDK4/6 inhibitors with other anti-tumor drugs is a pivotal clinical strategy. This strategy can efficiently inhibit the growth and division of tumor cells, reduce the side effects, and improve the quality of life of patients by reducing the dosage of combined anticancer drugs. Furthermore, the combination therapy strategy of CDK4/6 inhibitors could ameliorate the drug resistance of combined drugs and overcome the CDK4/6 resistance caused by CDK4/6 inhibitors. Various tumor treatment strategies combined with CDK4/6 inhibitors have entered the clinical trial stage, demonstrating their substantial clinical potential. This study reviews the research progress of CDK4/6 inhibitors from 2018 to 2022, the related resistance mechanism of CDK4/6 inhibitors, and the strategy of combination medication.

Immune profiling of mouse lung adenocarcinoma paraffin tissues using multiplex immunofluorescence panel: a pilot study.

BACKGROUND: Immune profiling has become an important tool for identifying predictive, prognostic and response biomarkers for immune checkpoint inhibitors from tumor microenvironment (TME). We aimed to build a multiplex immunofluorescence (mIF) panel to apply to formalin-fixed and paraffin-embedded tissues in mice tumors and to explore the programmed cell death protein 1/ programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. RESULTS: An automated eight-color mIF panel was evaluated to study the TME using seven antibodies, including cytokeratin 19, CD3e, CD8a, CD4, PD-1, PD-L1, F4-80 and DAPI, then was applied in six mice lung adenocarcinoma samples. Cell phenotypes were quantified by software to explore the co-localization and spatial distribution between immune cells within the TME. This mice panel was successfully optimized and applied to a small cohort of mice lung adenocarcinoma cases. Image analysis showed a sparse degree of immune cell expression pattern in this cohort. From the spatial analysis we found that T cells and macrophages expressing PD-L1 were close to the malignant cells and other immune cells. CONCLUSIONS: Comprehensive immune profiling using mIF in translational studies improves our ability to correlate the PD-1/PD-L1 axis and spatial distribution of lymphocytes and macrophages in mouse lung cancer cells to provide new cues for immunotherapy, that can be translated to human tumors for cancer intervention.

Exploring the Anticancer Properties of Sakuranin Flavanone in Human Oropharyngeal Squamous Carcinoma Cells by Studying Its Effects on Caspase-driven Apoptosis, Mitochondrial Membrane Potential (MMP) Loss, Cell Migratory and Invasiveness and m-TOR/PI3K/AKT Signalling Pathway.

Sakuranin is a flavanone which is a class of flavonoids found abundantly in Prunus species. Flavonoids have been long known for their anticancer properties against a range of human cancers. However, there are no previous reports on the anticancer effects of sakuranin flavanone molecule. This study was designed to study the anticancer effects of sakuranin against human oropharyngeal carcinoma cells along with investigating its effects on caspase-mediated apoptosis, mitochondrial membrane potential (MMP) loss, cell migration and invasion and m-TOR/PI3K/AKT signalling pathway. MTT assay was used to study effects on cell viability. The apoptotic studies were carried out through AO/EB staining, annexin V/FITC staining, comet assay and western blotting assay. Transwell chambers assay was used to study effects on cell migration and invasion. Flow cytometry was used to study effects of Sakuranin on mitochondrial membrane potential loss (MMP). Finally, western blotting was used to investigate m-TOR/PI3K/AKT signalling pathway. Results indicated that Sakuranin led to potent cell proliferation inhibition in a dose-dependent manner. Sakuranin also induced apoptotic cell death as indicated by fluorescence microscopy and annexin V/FITC staining assays. The apoptotic induction was mediated via activation of caspase-3, caspase-9, and Bax while as it led to downregulation of Bcl-2. Sakuranin also caused inhibition of cell migration and cell invasion along with causing significant decrease in MMP. Sakuranin also caused inhibition of expressions of proteins related with m-TOR/PI3K/AKT signalling pathway. In conclusion, the current findings clearly indicate anticancer effects of Sakuranin flavanone in human oropharyngeal cancer cells and are mediated via caspase activated apoptosis, inhibition of cell migration and invasion, loss of mitochondrial membrane potential and targeting m-TOR/PI3K/AKT signalling pathway.

Effect of moderate versus deep sedation on recovery following outpatient gastroscopy in older patients: a randomized controlled trial.

BACKGROUND: Although gastrointestinal endoscopy with sedation is increasingly performed in older patients, the optimal level of sedation remains open to debate. In this study, our objective was to compare the effects of moderate sedation (MS) and deep sedation (DS) on recovery following outpatient gastroscopy in elderly patients. METHODS: In this randomized, partially blinded, controlled trial, we randomly divided 270 patients older than 60 years who were scheduled for elective outpatient gastroscopy into the MS or DS group based on the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. The primary outcome was the duration of stay in the post-anesthesia care unit (PACU). Secondary outcomes included the duration of the total hospital stay, frequency of retching, bucking, and body movements during the examination, endoscopist and patient satisfaction, and sedation-associated adverse events during the procedure. RESULTS: A total of 264 patients completed the study, of whom 131 received MS and 133 received DS. MS was associated with a shorter PACU stay [16.15 ± 9.01 min vs. 20.02 ± 11.13 min, P < 0.01] and total hospital stay [27.32 ± 9.86 min vs. 30.82 ± 12.37 min, P < 0.05], lesser hypoxemia [2.3% (3/131) vs. 12.8% (17/133), P < 0.01], use of fewer vasoactive drugs (P < 0.001), and more retching (P < 0.001). There was no difference in the incidence of bucking and body movements or endoscopist and patient satisfaction between the two groups. CONCLUSION: Compared to deep sedation, moderate sedation may be a preferable choice for American Society of Anesthesiologists (ASA) Grade I-III elderly patients undergoing outpatient gastroscopies, as demonstrated by shorter PACU stays and total hospital stays, lower sedation-associated adverse events, and similar levels of endoscopist and patient satisfaction.

Life Events, Boredom Proneness and Mobile Phone Addiction Tendency: A Longitudinal Mediation Analysis Based on Latent Growth Modeling (LGM).

Purpose: Mobile phone addiction has motivated a widespread concern in recent years. From a developmental perspective, this study explored the predictive relations between life events, boredom proneness (BP), and mobile phone addiction tendency (MPAT) among undergraduate students. It also tested the longitudinal mediation of BP between life events and MPAT. Methods: Five hundred and eighty-four undergraduate students completed the Mobile Phone Addiction Tendency Scale, the Adolescent Self-Rating Life Events Checklist, and the Boredom Proneness Scale-Short Form. A longitudinal mediation analysis based on latent growth modeling was conducted to test the hypothesized relationships among life events, BP and MPAT. Results: Latent growth modeling (LGM) showed that the BP and MPAT of undergraduate students both increased linearly. A longitudinal model based on LGM showed that negative life events both directly and indirectly affected the initial level and the growth rate of the MPAT through the mediating effect of the initial level of BP. Conclusion: These results reveal that negative life events are an indicator of the development of MPAT. It has practical implications for calling for adopting health coping styles when facing negative life events. Supported for reducing college students' boredom proneness in order to lessen the tendency towards mobile phone addiction to improve their mental health.

Elevated serum phosphatidylcholine (16:1/22:6) levels promoted by fish oil and vitamin D3 are highly correlated with biomarkers of non-alcoholic fatty liver disease in Chinese subjects.

The aim of the present study was to investigate the relationship between the changes of serum lipid metabolites and the risk factors of non-alcoholic fatty liver disease (NAFLD) after fish oil (FO) or fish oil plus vitamin D (FO + D) intervention in Chinese NAFLD subjects. Seventy-four NAFLD subjects, aged 55.2 ± 15.9 years, were randomized to consume FO + D (n = 23), FO (n = 27) or corn oil (CO, n = 24) capsules for a 3-month intervention. Serum lipid-related metabolites were measured with ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based metabolomics approach together with multivariate data analysis. The differential metabolites were screened and identified with variable importance in projection (VIP) scores based on orthogonal partial least squares discriminant analysis models. Serum phosphatidylcholine (PC) (16:1/22:6) levels had the highest and second highest VIP scores following FO + D and FO interventions, respectively. Serum PC (16:1/22:6) levels were negatively correlated with circulating alanine transaminase (ALT) (r = -0.268, p = 0.021), triacylglycerol (TAG) (r = -0.236, p = 0.042), interleukin (IL)-1ß (r = -0.401, p < 0.001) and tumor necrosis factor (TNF)-α (r = -0.322, p = 0.005) concentrations, and were positively correlated with high-density lipoprotein cholesterol (HDL-C) (r = 0.272, p = 0.019) concentrations. The present study was the first to report that serum PC (16:1/22:6) levels were highly correlated with ALT, TAG, HDL-C, IL-1ß and TNF-α concentrations, indicating that PC (16:1/22:6) might ameliorate lipid metabolism and inflammation in NAFLD subjects.

Cancer-associated fibroblasts employ NUFIP1-dependent autophagy to secrete nucleosides and support pancreatic tumor growth.

Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for survival from pancreatic ductal adenocarcinoma (PDAC) on glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in a nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-dependent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.

Concentrated fish oil ameliorates non-alcoholic fatty liver disease by regulating fibroblast growth factor 21-adiponectin axis.

OBJECTIVES: The fibroblast growth factor 21 (FGF21)-adiponectin axis participates in energy hemostasis and obesity-related syndrome. The present study aimed to investigate whether concentrated fish oil (FO) intervention could alleviate non-alcoholic fatty liver disease (NAFLD) via the regulation of the FGF21-adiponectin axis. METHODS: In a randomized controlled trial, 61 patients with NAFLD, age 55.9 ± 15.6 y, were randomly divided into two groups: FO (3 g/d; n = 30) and corn oil (CO; 3 g/d; n = 31), which served as the control group. RESULTS: After a 3-mo intervention, there were significant net reductions in serum alanine transaminase (-5.4 ± 14.5 U/L vs. -0.25 ± 4.70 U/L; P = 0.001) and triacylglycerol (-0.70 ± 1.10 mmol/L vs. 0.11 ± 1.04 mmol/L; P = 0.018) levels in the FO group compared with the CO group. Furthermore, the mean changes of FGF21 levels (-16.3 ± 20.1 pg/mL vs. 7.2 ± 32.9 pg/mL; P = 0.002) were significantly decreased, but adiponectin levels (1.14 ± 1.53 µg/mL vs. -0.42 ± 2.04 pg/mL; P = 0.011) were significantly increased in the FO group compared with the CO group. In the animal study, the mice fed the high-fat diet demonstrated characteristics of NAFLD. The administration of FO significantly improved high-fat diet-induced hepatic steatosis, insulin resistance, and inflammation compared with the high-fat control group. In addition, FO improved the sensitivity of FGF21, and stimulated the expression levels of adiponectin in the liver. CONCLUSIONS: The present study suggested that FO could potentially ameliorate NAFLD through mediating the FGF21-adiponectin axis.

Branched chain and other amino acid intakes are inversely associated with sarcopenia among community elders in Qingdao, China.

BACKGROUND AND OBJECTIVES: The present study aimed to investigate the hypothesis that dietary amino acid intakes are associated with the risk of sarcopenia through a community-based observational study. METHODS AND STUDY DESIGN: A total of 1,140 participants (72.7±6.3 y) were recruited from an annual health check-up program in Qingdao, China. Skeletal muscle mass, muscle mass functions and biochemical parameters were measured by standard methods. Dietary intake was assessed by 3-day, 24-hour food records. The odds ratios (ORs) and 95% confidence intervals (CIs) of sarcopenic risk across quartiles of amino acid intakes were calculated using a multivariable- adjusted logistic regression model. Generalized linear models were used to assess the associations between dietary amino acid intakes and muscle mass functions. RESULTS: The prevalence of sarcopenia was 4.1%. Compared with the lowest category intake, the highest category of branched chain amino acids (BCAAs) (OR=0.11; 95% CI: 0.01, 0.90; p for trend=0.119), isoleucine (OR=0.11; 95% CI: 0.01, 0.89; p for trend=0.122) and tryptophan (OR=0.10; 95% CI: 0.01, 0.87; p for trend=0.176) was negatively correlated with sarcopenic risk with adjustment for potential confounding factors. Generalized linear model analysis showed that gait speed was positively correlated with dietary intakes of lysine, threonine, leucine, valine, tryptophan, BCAAs and aromatic amino acids (p<0.05). CONCLUSIONS: Higher intakes of BCAAs were associated with a lower risk of sarcopenia, which might beneficially protect against sarcopenia and improve physical function of the elderly.

The effects of fish oil plus vitamin D3 intervention on non-alcoholic fatty liver disease: a randomized controlled trial.

PURPOSE: The present study aimed to investigate fish oil plus vitamin D3 (FO + D) supplementation on biomarkers of non-alcoholic fatty liver disease (NAFLD). METHODS: In a 3-month randomized controlled trial, 111 subjects with NAFLD, aged 56.0 ± 15.9 y, were randomized into FO + D group (n = 37), fish oil group (FO, n = 37) or corn oil group (CO, n = 37). The subjects consumed the following capsules (3 g/day), which provided 2.34 g/day of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) + 1680 IU vitamin D3 (FO + D group), or 2.34 g/day of EPA + DHA (FO group), or 1.70 g/d linoleic acid (CO group). RESULTS: Using multivariable-adjusted general linear model, there were significant net reductions in serum alanine aminotransferase (ALT), and triacylglycerol (TAG) and TNF-α levels in the FO + D and FO groups, compared with the control group (P < 0.05). The supplemental FO + D also showed significant reductions in insulin (- 1.58 ± 2.00 mU/L vs. - 0.63 ± 1.55 mU/L, P = 0.050) and IL-1ß (- 6.92 ± 7.29 ng/L vs. 1.06 ± 5.83 ng/L, P < 0.001) in comparison with control group. Although there were no significant differences between FO + D and FO groups regarding biochemical parameters, supplemental FO + D showed decreases in ALT (from 26.2 ± 13.5 U/L to 21.4 ± 9.6 U/L, P = 0.007), aspartate aminotransferase (AST, from 22.5 ± 7.0 U/L to 20.2 ± 4.0 U/L, P = 0.029), HOMA-IR (from 3.69 ± 1.22 to 3.38 ± 1.10, P = 0.047), and TNF-α (from 0.43 ± 0.38 ng/L to 0.25 ± 0.42 ng/L, P < 0.001) levels following the intervention. CONCLUSION: The present study demonstrated that groups supplemented with FO + D and FO had similar beneficial effects on biomarkers of hepatocellular damage and plasma TAG levels in subjects with NAFLD, while in the FO + D group, there were some suggestive additional benefits compared with FO group on insulin levels and inflammation. TRIAL REGISTRATION: ChiCTR1900024866.

Effector memory cytotoxic CD3+/CD8+/CD45RO+ T cells are predictive of good survival and a lower risk of recurrence in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) with high tumour-infiltrating lymphocytes (TILs) has been associated with a promising prognosis. To better understand the prognostic value of immune cell subtypes in TNBC, we characterised TILs and the interaction between tumour cells and immune cell subtypes. A total of 145 breast cancer tissues were stained by multiplex immunofluorescence (mIF), including panel 1 (PD-L1, PD-1, CD3, CD8, CD68 and CK) and panel 2 (Foxp3, Granzyme B, CD45RO, CD3, CD8 and CK). Phenotypes were analysed and quantified by pathologists using InForm software. We found that in the ER-negative (ER <1% and HER2-negative) group and the ER/PR-low positive (ER 1-9% and HER2-negative) group, 11.2% and 7.1% of patients were PD-L1+ by the tumour cell score, 29.0% and 28.6% were PD-L1+ by the modified immune cell score and 30.8% and 32.1% were PD-L1+ by the combined positive score. We combined ER-negative and ER/PR-low positive cases for the survival analysis since a 10% cut-off is often used in clinical practice for therapeutic purposes. The densities of PD-L1+ tumour cells (HR: 0.366, 95% CI: 0.138-0.970; p = 0.043) within the tumour compartment and CD3+ immune cells in the total area (tumour and stromal compartments combined) (HR: 0.213, 95% CI: 0.070-0.642; p = 0.006) were favourable prognostic biomarkers for overall survival (OS) in TNBC. The density of effector/memory cytotoxic T cells (CD3+CD8+CD45RO+) in the tumour compartment was an independent prognostic biomarker for OS (HR: 0.232, 95% CI: 0.086-0.628; p = 0.004) and DFS (HR: 0.183, 95% CI: 0.1301-0.744; p = 0.009) in TNBC. Interestingly, spatial data suggested that patients with a higher density of PD-L1+ tumour cells had shorter cell-cell distances from tumour cells to cytotoxic T cells (p < 0.01). In conclusion, we found that phenotyping tumour immune cells by mIF is highly informative in understanding the immune microenvironment in TNBC. PD-L1+ tumour cells, total T cells and effector/memory cytotoxic T cells are promising prognostic biomarkers in TNBC.

Metastasis to Breast from Extramammary Solid Tumors and Lymphomas: A 20-Year Population-Based Study.

To discuss the clinicopathological features and prognosis of metastases to the breast from extramammary solid tumors and lymphomas, we reviewed Cancer Hospital of Chinese Academy of Medical Sciences database from 01/01/2000 to 12/31/2020. Fifty-nine patients were identified. The most common primary sites for breast metastases were lymph node and pulmonary, followed by nasal cavity, ovary, skin, etc. All the patients were treated with chemotherapy, 18 were operated, 14 accepted radiotherapy. Metastasis to breast should be considered in any patient with tumor history presenting a breast lump. Pathological with immunohistochemical examination should be performed to identify the original site.

Efficacy and Safety of Anti-PD-1/ PD-L1 Monotherapy for Metastatic Breast Cancer: Clinical Evidence.

Background: Success has been reported in PD-1/PD-L1 blockade via pembrolizumab, atezolizumab, or avelumab monotherapy in manifold malignancies including metastatic breast cancer. Due to lack of large-scale study, here we present interim analyses to evaluate the safety and efficacy of these promising strategies in patients with advanced breast cancer. Methods: Six studies including 586 advanced breast cancer patients treated with anti-PD-1/PD-L1 monotherapy agents before July 1, 2020, were included. The anti-PD-1/PD-L1 agents include pembrolizumab, atezolizumab, land avelumab. Statistics was analyzed by R software and IBM SPSS Statistics 22. Results: Global analysis showed that for this monotherapy, the complete response was 1.26%, partial response was 7.65%, objective response rate (ORR) was 9.85%, and disease control rate (DCR) was 18.33%. 1-year overall survival rate and 6-month progression-free survival rate were 43.34 and 17.24%. Overall incidence of adverse events (AEs) was 64.18% in any grade and 12.94% in severe grade, while the incidence of immune-related AEs (irAEs) was approximately 14.75%: the most common treatment-related AEs of any grade that occurred in at least 5% of patients were arthralgia and asthenia; the most common severe treatment-related AEs occurred in at least 1% of patients were anemia and autoimmune hepatitis; the most common irAEs were hypothyroidism. Besides, the incidence of discontinue and death due to treatment-related AEs was about 3.06 and 0.31%, respectively. Additionally, by comparing efficacy indicators between PD-L1-positive and PD-L1-negative groups, an implicated correspondence between efficacy and the expression of PD-L1 biomarker was found: the PR was 9.93 vs 2.69%; the ORR was 10.62 vs. 3.07%; the DCR was 17.95 vs. 4.71%. Conclusion: Anti-PD-1/PD-L1 monotherapy showed a manageable safety profile and had a promising and durable anti-tumor efficacy in metastatic breast cancer patients. Higher PD-L1 expression may be closely correlated to a better clinical efficacy.

Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples.

Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, numerous cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, serves as an alternative inhibitory receptor to be targeted in the clinic. The impacts of LAG3 on immune cell populations and coregulation of immune responses in breast cancer remain largely unknown. To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from 2,994 breast cancer patients. We estimated the landscape of the relationship between LAG3 and 10 types of cell populations of breast cancer. We investigated the correlation pattern between LAG3 and immune modulators in pancancer, particularly the synergistic role of LAG3 with other immune checkpoint members in breast cancer. LAG3 expression was closely related to the malignancy of breast cancer and may serve as a potential biomarker. LAG3 may play an important role in regulating the tumor immune microenvironment of T cells and other immune cells. More important, LAG3 may synergize with CTLA4, PD1/PDL1, and other immune checkpoints, thereby contributing more evidence to improve combination cancer immunotherapy by simultaneously targeting LAG3, PD1/PDL1, and CTLA4.

Molecular and Clinical Characterization of CCT2 Expression and Prognosis via Large-Scale Transcriptome Profile of Breast Cancer.

Molecular chaperones play important roles in regulating various cellular processes and malignant transformation. Expression of some subunits of molecular chaperone CCT/TRiC complex have been reported to be correlated with cancer development and patient survival. However, little is known about the expression and prognostic significance of Chaperonin Containing TCP1 Subunit 2 (CCT2). CCT2 is a gene encoding a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT), also known as the TCP1 ring complex (TRiC). Through the Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, we systematically reviewed a total of 2,994 cases with transcriptome data and analyzed the functional annotation of CCT2 by Gene ontology and KEGG analysis. Univariate and multivariate survival analysis were performed to investigate the prognostic value of CCT2 in breast cancer. We found CCT2 was significantly upregulated in various tumors. In breast cancer, CCT2 expression was significantly upregulated in HER2-positive (HER2+) group, and more malignant group. In addition, we investigated correlations between CCT2 and other CCT members. Interestingly, almost all CCTs expression were positively correlated with each other, but not CCT6B. Survival analysis suggested that CCT2 overexpression was independently associated with worse prognosis of patients with breast cancer, especially in luminal A subtype. In summary, our results revealed that CCT2 might be involved in regulating cell cycle pathway, and independently predicted worse prognosis in breast cancer patients. These findings may expand understanding of potential anti-CCT2 treatments. To our knowledge, this is the largest and most comprehensive study characterizing the expression pattern of CCT2 together with its prognostic values in breast cancer.

Identification of distinct immune landscapes using an automated nine-color multiplex immunofluorescence staining panel and image analysis in paraffin tumor tissues.

Immune profiling is becoming a vital tool for identifying predictive and prognostic markers for translational studies. The study of the tumor microenvironment (TME) in paraffin tumor tissues such as malignant pleural mesothelioma (MPM) could yield insights to actionable targets to improve patient outcome. Here, we optimized and tested a new immune-profiling method to characterize immune cell phenotypes in paraffin tissues and explore the co-localization and spatial distribution between the immune cells within the TME and the stromal or tumor compartments. Tonsil tissues and tissue microarray (TMA) were used to optimize an automated nine-color multiplex immunofluorescence (mIF) panel to study the TME using eight antibodies: PD-L1, PD-1, CD3, CD8, Foxp3, CD68, KI67, and pancytokeratin. To explore the potential role of the cells into the TME with this mIF panel we applied this panel in twelve MPM cases to assess the multiple cell phenotypes obtained from the image analysis and well as their spatial distribution in this cohort. We successful optimized and applied an automated nine-color mIF panel to explore a small set of MPM cases. Image analysis showed a high degree of cell phenotype diversity with immunosuppression patterns in the TME of the MPM cases. Mapping the geographic cell phenotype distribution in the TME, we were able to identify two distinct, complex immune landscapes characterized by specific patterns of cellular distribution as well as cell phenotype interactions with malignant cells. Successful we showed the optimization and reproducibility of our mIF panel and their incorporation for comprehensive TME immune profiling into translational studies that could refine our ability to correlate immunologic phenotypes with specific patterns of cells distribution and distance analysis. Overall, this will improve our ability to understand the behavior of cells within the TME and predict new treatment strategies to improve patient outcome.

Fatal outcome of malignant phyllodes tumor of the breast in pregnancy: a case and literature review.

Phyllodes tumor of the breast (PTB) is a rare fibroepithelial breast neoplasm that accounts for less than 1% of breast tumors. Only a few cases related to pregnancy have been reported. It is not known how pregnancy affects the diagnosis, treatment and prognosis of breast tumors. Here we report a case of a 38-year-old female patient with a small, mobile palpable lump in the left breast for about 15 years. it was considered a benign lesion and no surgical treatment was performed at the beginning. The left breast mass became larger suddenly during pregnancy, However, she did not see the doctor and receive any treatment in time. The lump was resected one year after labor and confirmed to be malignant phyllodes of the breast by histopathology and immunohistochemistry. Unfortunately, local recurrence occurred within six months after the first operation, and lung metastasis occurred eight months later. And this patient finally died 13 months after the operation due to tumor progression. This is the first report of pregnancy-related malignant PTB, with local recurrence and distant metastasis in a short period. This case report highlights a situation: the patient should be diagnosed early and treated in time when she has a previous breast fibroadenoma, but suddenly increased during pregnancy.

Effect of n-3 polyunsaturated fatty acid supplementation on muscle mass and function with aging: A meta-analysis of randomized controlled trials✰.

The results of randomized controlled trials (RCTs) investigating supplemental n-3 polyunsaturated fatty acids (PUFA) on muscle mass and function have been inconsistent. The present study aimed to quantitatively evaluate the effect of n-3 PUFA supplementation on indicators of muscle mass and function in healthy subjects. A systematic literature search was conducted up to July 2020 with databases of PubMed and Web of science. The random-effects model was implemented to calculate the weighted mean difference of net change of indicators regarding muscle mass and function. A total of nine studies (thirteen treatment groups) with 2067 participants were included for data analysis. The summary estimate showed that n-3 PUFA supplementation significantly increased the grip strength (1.17 kg; 95% CI: 0.27, 2.08 kg). Non-significant effect was observed with respect to muscle mass parameters, including fat mass (-0.67 kg; 95% CI: -2.20, 0.87 kg) and lean mass (0.33 kg; 95% CI: -0.35, 1.00 kg). Regarding muscle function indicators, there were non-significant effects on walking speed (-0.01 m•s-1; 95% CI: -0.03, 0.01 m•s-1), time up and go test (-0.25 s; 95% CI: -0.55, 0.04 s), respectively. The findings of this study indicated that supplementation with n-3 PUFA might have beneficial effects to improve muscle mass and function in healthy participants. However, there was no significant improvement in the subjects' muscle mass. Whether n-3 PUFA supplementation has favorable effects in participants with sarcopenia are warranted to be further investigated.

Changes in oxidation-antioxidation function on the thymus of chickens infected with reticuloendotheliosis virus.

BACKGROUND: Reticuloendotheliosis virus (REV) is a retrovirus that causes severe immunosuppression in poultry. Animals grow slowly under conditions of oxidative stress. In addition, long-term oxidative stress can impair immune function, as well as accelerate aging and death. This study aimed to elucidate the pathogenesis of REV from the perspective of changes in oxidative-antioxidative function following REV infection. METHODS: A total of 80 one-day-old specific pathogen free (SPF) chickens were randomly divided into a control group (Group C) and an REV-infected group (Group I). The chickens in Group I received intraperitoneal injections of REV with 104.62/0.1 mL TCID50. Thymus was collected on day 1, 3, 7, 14, 21, 28, 35, and 49 for histopathology and assessed the status of oxidative stress. RESULTS: In chickens infected with REV, the levels of H2O2 and MDA in the thymus increased, the levels of TAC, SOD, CAT, and GPx1 decreased, and there was a reduction in CAT and Gpx1 mRNA expression compared with the control group. The thymus index was also significantly reduced. Morphological analysis showed that REV infection caused an increase in the thymic reticular endothelial cells, inflammatory cell infiltration, mitochondrial swelling, and nuclear damage. CONCLUSIONS: These results indicate that an increase in oxidative stress enhanced lipid peroxidation, markedly decreased antioxidant function, caused thymus atrophy, and immunosuppression in REV-infected chickens.