Crenobacter oryzisoli sp. nov., a novel phosphate-solubilizing bacterium isolated from the paddy soil.

Two Gram-staining-negative, facultative anaerobic, rod-shaped and phosphate-solubilizing strains designated SG2303T and SG2305, were isolated from paddy soil in China. Phylogenetic analysis based on 16 S rRNA gene sequences indicated that SG2303T and SG2305 represented a member of the genus Crenobacter within the family Neisseriaceae of the phylum Pseudomonadota. Strain SG2303T displayed higher 16 S rRNA gene sequence similarities with members of the genus Crenobacter ranging from 93.5 to 94.0%. Strains C. luteus YIM 78141T and C. cavernae K1W11S-77T were closest related to the isolated strains and were considered as type strains. Growth of strain SG2303T occurred at 10-55 °C (optimum 37 °C), pH 5.0-9.0 (optimum pH 6.0-7.0) and 0-1% (w/v) NaCl (optimum 0%). The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain SG2303T and its closely related taxa were 76.1-78.2% and 20.5-22.1%, respectively. The genomic DNA G + C content was 62.2%. The quinone of strain SG2303T was Q-8. The major fatty acids (> 10%) of strain SG2303T were C16:0 (30.6%), summed feature 3 (C16:1ω7c and/or C16:1ω6c) (26.0%) and C12:0 3OH (12.1%). The polar lipids were phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), phospholipids (PL), glycolipid (GL) and unidentified lipids (UL). Based on the results of the phylogenetic, physiological, biochemical, and morphological analysis, strain SG2303T is recognized as a novel species of the genus Crenobacter, for which the name Crenobacter oryzisoli sp. nov. is proposed. The type strain is SG2303T (= GDMCC 1.3970T = JCM 36468T). In addition, SG2303T was also able of phosphorus solubilization and promoting the growth of rice seeds. Strain SG2303T exhibited a relatively high dissolvable phosphorus content of 2.52 µg·mL- 1.

PKMYT1 knockdown inhibits cholesterol biosynthesis and promotes the drug sensitivity of triple-negative breast cancer cells to atorvastatin.

Triple negative breast cancer (TNBC) as the most aggressive molecular subtype of breast cancer is characterized by high cancer cell proliferation and poor patient prognosis. Abnormal lipid metabolism contributes to the malignant process of cancers. Study observed significantly enhanced cholesterol biosynthesis in TNBC. However, the mechanisms underlying the abnormal increase of cholesterol biosynthesis in TNBC are still unclear. Hence, we identified a member of the serine/threonine protein kinase family PKMYT1 as a key driver of cholesterol synthesis in TNBC cells. Aberrantly high-expressed PKMYT1 in TNBC was indicative of unfavorable prognostic outcomes. In addition, PKMYT1 promoted sterol regulatory element-binding protein 2 (SREBP2)-mediated expression of enzymes related to cholesterol biosynthesis through activating the TNF/ TNF receptor-associated factor 1 (TRAF1)/AKT pathway. Notably, downregulation of PKMYT1 significantly inhibited the feedback upregulation of statin-mediated cholesterol biosynthesis, whereas knockdown of PKMYT1 promoted the drug sensitivity of atorvastatin in TNBC cells. Overall, our study revealed a novel function of PKMYT1 in TNBC cholesterol biosynthesis, providing a new target for targeting tumor metabolic reprogramming in the cancer.

Chronic stress influences the macrophage M1-M2 polarization balance through ß-adrenergic signaling in hepatoma mice.

Chronic stress negatively affects the immune system and promotes tumor progression. Tumor-associated macrophage (TAM) is an important component of the tumor immune microenvironment. However, the influence of chronic stress on M1-M2 polarization of TAM is unclear. We used flow cytometry to measure the M1-M2 polarization of TAM in chronic stress hepatocellular carcinoma (HCC) bearing mice. We also measured the level of norepinephrine and blocked ß-adrenergic signaling to explore the role of ß-adrenergic receptor in the effect of chronic stress on M1-M2 polarization of TAM. We found that chronic stress disrupts the M1-M2 polarization in tumor tissues, increased the level of CD11b+Ly6C+CCR2+ monocyte and interleukin-1beta in blood and promoted the growth of HCC. Furthermore, chronic stress upregulated the level of CCL2 in tumor tissues. Finally, we found chronic stress increased norepinephrine level in serum and propranolol, a blocker of ß-adrenergic signaling, inhibited HCC growth, recovered the M1-M2 polarization balance of TAM in tumor tissues, blocked the increase of CD11b+Ly6C+CCR2+ monocytes in blood, and blocked the increase of CCL2 in tumor tissues induced by chronic stress. Our study indicated that chronic stress disrupts the M1-M2 polarization balance of TAMs through ß-adrenergic signaling, thereby promoting the growth of HCC.

Effects of sintilimab plus chemotherapy as first-line treatment on health-related quality of life in patients with advanced esophageal squamous cell carcinoma: results from the randomized phase 3 ORIENT-15 study.

Background: In ORIENT-15 study, sintilimab plus chemotherapy demonstrated significant improvement on overall survival (OS) versus placebo plus chemotherapy in first-line treatment of advanced esophageal squamous cell carcinoma (ESCC). Here, we report effect of sintilimab plus chemotherapy on health-related quality of life (HRQoL) in patients with advanced ESCC. Methods: From December 14, 2018 to August 28, 2022, HRQoL was evaluated in all randomized patients using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), EORTC Quality of Life Questionnaire Oesophageal Cancer Module 18 items (QLQ-OES18), and visual analogue scale (VAS) of the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L). Mean scores of each scale were described by treatment group through week 60. Least-squares mean (LSM) score change from baseline through week 24 were analyzed using the mixed-model repeated-measures method. Time to the first onset of deterioration (TTD) and OS for each scale were estimated. Clinical Trials Registration: NCT03748134. Findings: As of August 28, 2022, 689 of 690 enrolled patients were assessed for HRQoL analysis (sintilimab group: 340, placebo group: 349). Median follow-up was 32.2 months. Differences in LSM favored sintilimab over placebo for QLQ-C30 social functioning (LSM difference: 3.06, 95% CI: 0.55 to 5.57; P = 0.0170), pain (-2.24, 95% CI: -4.30 to -0.17; P = 0.0337), fatigue (-2.24, 95% CI: -4.46 to -0.02; P = 0.0479), constipation (-3.27, 95% CI -5.49 to -1.05; P = 0.0039), QLQ-OES18 pain (-1.77, 95% CI -3.11 to -0.43; P = 0.0097), trouble swallowing saliva (-2.09, 95% CI: -3.77 to -0.42; P = 0.0146), and choked when swallowing (-3.23, 95% CI: -5.60 to -0.86; P = 0.0076). TTD favored sintilimab over placebo for QLQ-OES18 dysphagia (Hazard ratio [HR]: 0.76, 95% CI: 0.61-0.94, P = 0.0104), and trouble swallowing saliva (HR: 0.48, 95% CI: 0.35-0.67, P < 0.0001). Improved OS were observed in patients with better performance in several functioning and symptom scales of QLQ-C30 and QLQ-QES18. Interpretation: The statistically significant differences of several HRQoL scales and improvements in delayed deterioration observed in our study further support the use of sintilimab plus chemotherapy as first-line treatment for advanced ESCC. Funding: This study was funded by Innovent Biologics and was co-funded by Eli Lilly.

Sporophytic control of tapetal development and pollen fertility by a mitogen-activated protein kinase cascade in rice.

Tapetum, the innermost layer of the anther wall, provides essential nutrients and materials for pollen development. Timely degradation of anther tapetal cells is a prerequisite for normal pollen development in flowering plants. Tapetal cells facilitate male gametogenesis by providing cellular contents after highly coordinated programmed cell death (PCD). Tapetal development is regulated by a transcriptional network. However, the signaling pathway(s) involved in this process are poorly understood. In this study, we report that a mitogen-activated protein kinase (MAPK) cascade composed of OsYDA1/OsYDA2-OsMKK4-OsMPK6 plays an important role in tapetal development and male gametophyte fertility. Loss of function of this MAPK cascade leads to anther indehiscence, enlarged tapetum, and aborted pollen grains. Tapetal cells in osmkk4 and osmpk6 mutants exhibit an increased presence of lipid body-like structures within the cytoplasm, which is accompanied by a delayed occurrence of PCD. Expression of a constitutively active version of OsMPK6 (CA-OsMPK6) can rescue the pollen defects in osmkk4 mutants, confirming that OsMPK6 functions downstream of OsMKK4 in this pathway. Genetic crosses also demonstrated that the MAPK cascade sporophyticly regulates pollen development. Our study reveals a novel function of rice MAPK cascade in plant male reproductive biology.

Identification of novel GSPT1 degraders by virtual screening and bioassay.

GSPT1 plays crucial physiological functions, such as terminating protein translation, overexpressed in various tumors. It is a promising anti-tumor target, but is also considered as an "undruggable" protein. Recent studies have found that a class of small molecules can degrade GSPT1 through the "molecular glue" mechanism with strong antitumor activity, which is expected to become a new therapy for hematological malignancies. Currently available GSPT1 degraders are mostly derived from the scaffold of immunomodulatory imide drug (IMiD), thus more active compounds with novel structure remain to be found. In this work, using computer-assisted multi-round virtual screening and bioassay, we identified a non-IMiD acylhydrazone compound, AN5782, which can reduce the protein level of GPST1 and obviously inhibit the proliferation of tumor cells. Some analogs were obtained by a substructure search of AN5782. The structure-activity relationship analysis revealed possible interactions between these compounds and CRBN-GSPT1. Further biological mechanistic studies showed that AN5777 decreased GSPT1 remarkably through the ubiquitin-proteasome system, and its effective cytotoxicity was CRBN- and GSPT1-dependent. Furthermore, AN5777 displayed good antiproliferative activities against U937 and OCI-AML-2 cells, and dose-dependently induced G1 phase arrest and apoptosis. The structure found in this work could be good start for antitumor drug development.

MyoD1 promotes the transcription of BIK and plays an apoptosis-promoting role in the development of gastric cancer.

Myogenic differentiation (MyoD) 1, which is known as a pivotal transcription factor during myogenesis, has been proven dysregulated in several cancers. However, litter is known about the precise role and downstream genes of MyoD1 in gastric cancer (GC) cells. Here, we report that MyoD1 is lowly expressed in primary GC tissues and cells. In our experiments, overexpression of MyoD1 inhibited cell proliferation. Downstream genes of MyoD1 regulation were investigated using RNA-Seq. As a result, 138 up-regulated genes and 20 down-regulated genes and 27 up-regulated lncRNAs and 20 down-regulated lncRNAs were identified in MyoD1 overexpressed MKN-45 cells, which participated in epithelial cell signaling in Helicobacter pylori infection, glycosaminoglycan biosynthesis (keratan sulfate), notch signaling pathway, and others. Among these genes, BIK was directly regulated by MyoD1 in GC cells and inhibited cancer cell proliferation. The BIK knockdown rescued the effects of MyoD1 overexpression on GC cells. In conclusion, MyoD1 inhibited cell proliferation via 158 genes and 47 lncRNAs downstream directly or indirectly that participated in multiple signaling pathways in GC, and among these, MyoD1 promotes BIK transcription by binding to its promoter, then promotes BIK-Bcl2-caspase 3 axis and regulates GC cell apoptosis.

Identification of genetic modifiers enhancing B7-H3-targeting CAR T cell therapy against glioblastoma through large-scale CRISPRi screening.

BACKGROUND: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Current treatment options are limited and often ineffective. CAR T cell therapy has shown success in treating hematologic malignancies, and there is growing interest in its potential application in solid tumors, including GBM. However, current CAR T therapy lacks clinical efficacy against GBM due to tumor-related resistance mechanisms and CAR T cell deficiencies. Therefore, there is a need to improve CAR T cell therapy efficacy in GBM. METHODS: We conducted large-scale CRISPR interference (CRISPRi) screens in GBM cell line U87 MG cells co-cultured with B7-H3 targeting CAR T cells to identify genetic modifiers that can enhance CAR T cell-mediated tumor killing. Flow cytometry-based tumor killing assay and CAR T cell activation assay were performed to validate screening hits. Bioinformatic analyses on bulk and single-cell RNA sequencing data and the TCGA database were employed to elucidate the mechanism underlying enhanced CAR T efficacy upon knocking down the selected screening hits in U87 MG cells. RESULTS: We established B7-H3 as a targetable antigen for CAR T therapy in GBM. Through large-scale CRISPRi screening, we discovered genetic modifiers in GBM cells, including ARPC4, PI4KA, ATP6V1A, UBA1, and NDUFV1, that regulated the efficacy of CAR T cell-mediated tumor killing. Furthermore, we discovered that TNFSF15 was upregulated in both ARPC4 and NDUFV1 knockdown GBM cells and revealed an immunostimulatory role of TNFSF15 in modulating tumor-CAR T interaction to enhance CAR T cell efficacy. CONCLUSIONS: Our study highlights the power of CRISPR-based genetic screening in investigating tumor-CAR T interaction and identifies potential druggable targets in tumor cells that confer resistance to CAR T cell killing. Furthermore, we devised targeted strategies that synergize with CAR T therapy against GBM. These findings shed light on the development of novel combinatorial strategies for effective immunotherapy of GBM and other solid tumors.

Pan-Cancer Analysis of the Prognostic and Immunological Role of TOMM40 to Identify Its Function in Breast Cancer.

Breast cancer (BRCA) is currently the most commonly diagnosed malignancy in women worldwide. Previous studies have demonstrated that mitophagy is important for the prevention and treatment of BRCA. However, few studies have focused on the individual mitochondrial autophagy-related genes (MARG) in human cancers. Based on bioinformatics analyses, TOMM40 was identified as a prognostic DEMARG (PDEMARGs); Kaplan-Meier (KM) survival analysis also indicates that TOMM40 can be useful as a prognostic indicator in BRCAs, with patients in the high expression group having a poorer prognosis. For 20 distinct cancer kinds, there were appreciable differences in the expression of TOMM40 between tumor and normal tissues; in addition, in 21 different cancer types, there were associations between the expression profile of TOMM40 and patient prognosis. Gene Set Enrichment Analysis (GSEA), functional enrichment analysis, and immunological and drug sensitivity analyses of TOMM40 have indicated its biological significance in pan-cancers. Knockdown of TOMM40 in MDA-MB-231 cells inhibited their proliferation, migration, and invasiveness. In conclusion, we found that TOMM40 has prognostic value in 21 cancers, including breast cancer, by bioinformatics analysis. Based on immune correlation analysis, TOMM40 may also be a potential immunotherapeutic target for the treatment of BRCA. Therefore, our results may provide researchers to further explore the role of MARGs, especially TOMM40, in the developmental process of breast cancer, which may provide new directions and targets for the improvement of prognosis of breast cancer patients and their treatment.

The Efficiency and Toxicity Of Anlotinib in Combination With Docetaxel Followed by Epirubicin and Cyclophosphamide Regimen as Neoadjuvant Treatment in IIB to IIIA Triple Negative Breast Cancer: A Single-Arm, Multicenter, Open-Label, Phase II Study.

BACKGROUND: The combination of neoadjuvant chemotherapy and anti-angiogenesis therapy for patients with triple-negative breast cancer (TNBC) remains inadequately supported by evidence. We conducted a single-arm, open-label, multicenter, phase II trial to evaluate the efficacy and toxicity of anlotinib plus epirubicin and cyclophosphamide followed by paclitaxel in patients with IIB to IIIA stage TNBC. METHODS: Newly diagnosed patients received epirubicin at 90 mg/m2 and cyclophosphamide at 600 mg/m2 followed by docetaxel at 100 mg/m2 (21 days per cycle; total of 4 cycles), along with oral anlotinib (12 mg qd, d1-14; 21 days per cycle; total of 4 cycles). Subsequently, patients underwent surgery. The primary endpoint of this study was pathologic complete response (pCR). RESULTS: Among the 34 included patients, the median age was 46.5 years (range: 27-72); all were female. Pathological assessment revealed that 17 patients achieved RCB 0 response, which is currently defined as pathologic complete response; 3 patients achieved RCB 1; 12 patients achieved RCB 2; and 1 patient achieved RCB 3. The probability of a grade 3 adverse reaction was 17.6%, and no grade 4 adverse reactions occurred. The most common hematological adverse reaction was leukopenia (13/34, 38.2%), of which 5.9% (2/34) were grade 3. The most common non-hematological adverse reactions were oral mucositis (16/34, 58.8%), fatigue (50.0%), hand-foot syndrome (50.0%), hypertension (44.1%), bleeding (44.1%), and alopecia (32.4%). CONCLUSION: The combination of anlotinib and EC-T chemotherapy demonstrated tolerable side effects in the neoadjuvant treatment of early TNBC. pCR was higher than what has been reported in previous clinical studies of chemotherapy alone. This study provides additional rationale for using anlotinib plus docetaxel-epirubicin-based chemotherapy regimen in patients with early-stage TNBCs.

Quantitative Assessment of Breast Tumor: Comparison of Four Methods of Positioning Region of Interest for Synthetic Relaxometry and Diffusion Measurement.

RATIONALE AND OBJECTIVES: To compare the differences in apparent diffusion coefficient (ADC) and synthetic magnetic resonance (MR) measurements of four region of interest (ROI) placement methods for breast tumor and to investigate their diagnostic performance. METHODS: 110 (70 malignant, 40 benign) newly diagnosed breast tumors were evaluated. The patients underwent 3.0 T MR examinations including diffusion-weighted imaging and synthetic MR. Two radiologists independently measured ADCs, T1 relaxation time (T1), T2 relaxation time (T2), and proton density (PD) using four ROI methods: round, square, freehand, and whole-tumor volume (WTV). The interclass correlation coefficient (ICC) was used to assess their measurement reliability. Diagnostic performance was evaluated using multivariate logistic regression analysis and the receiver operating characteristic (ROC) curves. RESULTS: The mean values of all ROI methods showed good or excellent interobserver reproducibility (0.79-0.99) and showed the best diagnostic performance compared to the minimum and maximum values. The square ROI exhibited superior performance in differentiating between benign from malignant breast lesions, followed by the freehand ROI. T2, PD, and ADC values were significantly lower in malignant breast lesions compared to benign ones for all ROI methods (p < 0.05). Multiparameters of T2 + ADC demonstrated the highest AUC values (0.82-0.95), surpassing the diagnostic efficacy of ADC or T2 alone (p < 0.05). CONCLUSION: ROI placement significantly influences ADC and synthetic MR values measured in breast tumors. Square ROI and mean values showed superior performance in differentiating benign and malignant breast lesions. The multiparameters of T2 + ADC surpassed the diagnostic efficacy of a single parameter.

Establishment of patient-derived organoids for guiding personalized therapies in breast cancer patients.

Breast cancer has become the most commonly diagnosed cancer. The intra- and interpatient heterogeneity induced a considerable variation in treatment efficacy. There is an urgent requirement for preclinical models to anticipate the effectiveness of individualized drug responses. Patient-derived organoids (PDOs) can accurately recapitulate the architecture and biological characteristics of the origin tumor, making them a promising model that can overtake many limitations of cell lines and PDXs. However, it is still unclear whether PDOs-based drug testing can benefit breast cancer patients, particularly those with tumor recurrence or treatment resistance. Fresh tumor samples were surgically resected for organoid culture. Primary tumor samples and PDOs were subsequently subjected to H&E staining, immunohistochemical (IHC) analysis, and whole-exome sequencing (WES) to make comparisons. Drug sensitivity tests were performed to evaluate the feasibility of this model for predicting patient drug response in clinical practice. We established 75 patient-derived breast cancer organoid models. The results of H&E staining, IHC, and WES revealed that PDOs inherited the histologic and genetic characteristics of their parental tumor tissues. The PDOs successfully predicted the patient's drug response, and most cases exhibited consistency between PDOs' drug susceptibility test results and the clinical response of the matched patient. We conclude that the breast cancer organoids platform can be a potential preclinical tool used for the selection of effective drugs and guided personalized therapies for patients with advanced breast cancer.

Multi-omics analysis elucidates the relationship between intratumor microbiome and host immune heterogeneity in breast cancer.

Research has indicated that intratumor microbiomes affect the occurrence, progression, and therapeutic response in many cancer types by influencing the immune system. We aim to evaluate the characteristics of immune-related intratumor microbiomes (IRIMs) in breast cancer (BC) and search for potential prognosis prediction factors and treatment targets. The clinical information, microbiome data, transcriptomics data of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) patients were obtained from Kraken-TCGA-Raw-Data and TCGA portal. The core tumor-infiltrating immune cell was identified using univariate Cox regression analysis. Based on consensus clustering analysis, BC patients were categorized into two immune subtypes, referred to as immune-enriched and immune-deficient subtypes. The immune-enriched subtype, characterized by higher levels of immune infiltration of CD8+ T and macrophage M1 cells, demonstrated a more favorable prognosis. Furthermore, significant differences in alpha-diversity and beta-diversity were observed between the two immune subtypes, and the least discriminant analysis effect size method identified 33 types of IRIMs. An intratumor microbiome-based prognostic signature consisting of four prognostic IRIMs (Acidibacillus, Succinimonas, Lachnoclostridium, and Pseudogulbenkiania) was constructed using the Cox proportional-hazard model, and it had great prognostic value. The prognostic IRIMs were correlated with immune gene expression and the sensitivity of chemotherapy drugs, specifically tamoxifen and docetaxel. In conclusion, our research has successfully identified two distinct immune subtypes in BC, which exhibit contrasting prognoses and possess unique epigenetic and intratumor microbiomes. The critical IRIMs were correlated with prognosis, tumor-infiltrating immune cell abundance, and immunotherapeutic efficacy in BC. Consequently, this study has identified potential IRIMs as biomarkers, providing a novel therapeutic approach for treating BC.IMPORTANCERecent research has substantiated the presence of the intratumor microbiome in tumor immune microenvironment, which could influence tumor occurrence and progression, as well as provide new opportunities for cancer diagnosis and treatment. This study identified the critical immune-related intratumor microbiome (Acidibacillus, Succinimonas, Lachnoclostridium, and Pseudogulbenkiania), which were correlated with prognosis, tumor-infiltrating immune cell abundance, and immunotherapeutic efficacy in breast cancer and might be the novel target to regulate immunotherapy in BC.

Machine learning predicts the risk of osteoporosis in patients with breast cancer and healthy women.

OBJECTIVE: In this study, we investigated the effects of endocrine therapy and related drugs on the body composition and bone metabolism of patients with breast cancer. Additionally, using body composition-related indicators in machine learning algorithms, the risks of osteoporosis in patients with breast cancer and healthy women were predicted. METHODS: We enrolled postmenopausal patients with breast cancer who were hospitalized in a tertiary hospital and postmenopausal women undergoing health checkups in our hospital between 2019 and 2021. The basic information, body composition, bone density-related indicators, and bone metabolism-related indicators of all the study subjects were recorded. Machine learning models were constructed using cross-validation. RESULTS: Compared with a healthy population, the body composition of patients with breast cancer was low in bone mass, protein, body fat percentage, muscle, and basal metabolism, whereas total water, intracellular fluid, extracellular fluid, and waist-to-hip ratio were high. In patients with breast cancer, the bone mineral density (BMD), Z value, and T value were low and the proportion of bone loss and osteoporosis was high. BMD in patients with breast cancer was negatively correlated with age, endocrine therapy status, duration of medication, and duration of menopause, and it was positively correlated with body mass index (BMI) and basal metabolism. The parameters including body composition, age, hormone receptor status, and medication type were used for developing the machine learning model to predict osteoporosis risk in patients with breast cancer and healthy populations. The model showed a high accuracy in predicting osteoporosis, reflecting the predictive value of the model. CONCLUSIONS: Patients with breast cancer may have changed body composition and BMD. Compared with the healthy population, the main indicators of osteoporosis in patients with breast cancer were reduced nonadipose tissue, increased risk of edema, altered fat distribution, and reduced BMD. In addition to age, duration of treatment, and duration of menopause, body composition-related indicators such as BMI and basal metabolism may be considerably associated with BMD of patients with breast cancer, suggesting that BMD status can be monitored in clinical practice by focusing on changes in the aforementioned indexes, which may provide a way to prevent preclinical osteoporosis.

Stomatal development: NRPM proteins in dynamic localization of ERECTA receptor.

Dynamic cellular localization of receptors is key to the perception of their peptide ligands and the activation of downstream signaling pathways. A new study identifies NRPMs as novel regulators of ERECTA receptor localization and stomatal formation downstream of the EPF1/EPF2 peptide ligands and upstream of the YDA MAPK cascade.

Exploring the resistance mechanism of triple-negative breast cancer to paclitaxel through the scRNA-seq analysis.

BACKGROUND: The triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer with high aggressiveness. Although paclitaxel-based chemotherapy scenario present the mainstay in TNBC treatment, paclitaxel resistance is still a striking obstacle for cancer cure. So it is imperative to probe new therapeutic targets through illustrating the mechanisms underlying paclitaxel chemoresistance. METHODS: The Single cell RNA sequencing (scRNA-seq) data of TNBC cells treated with paclitaxel at different points were downloaded from the Gene Expression Omnibus (GEO) database. The Seurat R package was used to filter and integrate the scRNA-seq expression matrix. Cells were further clustered by the FindClusters function, and the gene marker of each subset was defined by FindAllMarkers function. Then, the hallmark score of each cell was calculated by AUCell R package, the biological function of the highly expressed interest genes was analyzed by the DAVID database. Subsequently, we performed pseudotime analysis to explore the change patterns of drug resistance genes and SCENIC analysis to identify the key transcription factors (TFs). Finally, the inhibitors of which were also analyzed by the CTD database. RESULTS: We finally obtained 6 cell subsets from 2798 cells, which were marked as AKR1C3+, WNT7A+, FAM72B+, RERG+, IDO1+ and HEY1+HCC1143 cell subsets, among which the AKR1C3+, IDO1+ and HEY1+ cell subsets proportions increased with increasing treatment time, and then were regarded as paclitaxel resistance subsets. Hallmark score and pseudotime analysis showed that these paclitaxel resistance subsets were associated with the inflammatory response, virus and interferon response activation. In addition, the gene regulatory networks (GRNs) indicated that 3 key TFs (STAT1, CEBPB and IRF7) played vital role in promoting resistance development, and five common inhibitors targeted these TFs as potential combination therapies of paclitaxel were identified. CONCLUSION: In this study, we identified 3 paclitaxel resistance relevant IFs and their inhibitors, which offers essential molecular basis for paclitaxel resistance and beneficial guidance for the combination of paclitaxel in clinical TNBC therapy.

Rotational gland dissection for refractory granulomatous mastitis: A single-center retrospective study.

BACKGROUND: Refractory granulomatous mastitis (RGM) is a chronic benign breast disease that commonly occurred in women of childbearing age and is usually treated with surgery, with numerous cases suffering from unsatisfied postoperative recovery of breast shape, high rates of surgical complications, and even high recurrence. This study tries to evaluate the efficacy of an innovative surgical procedure, the rotational gland dissection for the treatment of RGM. METHODS: 129 patients with RGM who underwent surgical treatment at the Second Affiliated Hospital of Xi'an Jiaotong University between Apr. 2017 and May. 2021 were retrospectively included in this study. The article analyzed the age, local symptoms, lesion location, and size, days in hospital, recurrence rate, and satisfaction rate of the patients. RESULTS: Patients ranged in age from 19 to 58 years, with a median age of onset of 32 years. In 63 patients (48.84%), their lesions coverage exceeded two quadrants, and 52.71% of patients had lesions larger than 10 cm2. The average days in hospital of patients was 7.5 days, and 85.27% of them were satisfied with their post-surgery breast appearance. Within the median follow-up of 56 months, only 3.10% of patients experienced a recurrence of mastitis on the operation side. CONCLUSION: This novel surgical procedure we created is an effective treatment for RGM with a high success rate, high patient satisfaction, and low recurrence rate, and is significantly superior to other studies for it has the largest sample size and longest follow-up in this field.

High dose Vitamin C inhibits PD-L1 by ROS-pSTAT3 signal pathway and enhances T cell function in TNBC.

Vitamin C (VitC) presents excellent anti-tumor effect for long time. Recently, high dose VitC achieved by intravenous administration manifests superior anti-tumor effect. However, the functions and detailed mechanisms of high dose VitC's role in cancer immunity are not fully understood. This study investigates the effect of high dose VitC on PD-L1 expression in triple negative breast cancer (TNBC) and the potential mechanism. Results showed VitC inhibited PD-L1 expression in breast cancer cell lines and enhanced anti-tumor effects of T cells. Furthermore, we found VitC inhibited PD-L1 transcription through ROS-pSTAT3 signal pathways. Consistent with in vitro results, in vivo study showed VitC suppressed tumor growth in immunocompetent mice and enhanced CD8+ T cells infiltration and function in tumor microenvironment. Our findings identify the effects of high dose VitC on PD-L1 expression and provide a rationale for the use of high dose VitC as immunomodulator for cancer therapy.