Antibacterial, ROS scavenging and angiogenesis promotingϵ-Polylysine/gelatin based hydrogel containing CTLP to regulate macrophages for pressure ulcer healing.

Pressure ulcers (PUs) have emerged as a substantial burden on individuals and society. The introduction of innovative dressings that facilitate the healing of pressure ulcer wounds represents a cost-effective alternative for treatment. In this study, the emphasis is on the preparation of Carthamus tinctorius L. polysaccharide (CTLP) as hydrogel microspheres (MPs), which are then encapsulated within a hydrogel matrix crosslinked with phenylboronic acid gelatin (Gelatin-PBA) andϵ-polylysine-grafted catechol (ϵ-PL-Cat) to enable sustained release for promoting pressure ulcer healing. The presented Gelatin-PBA/ϵ-PL-Cat (GPL)/CTLP-MPs hydrogel demonstrated outstanding self-healing properties. In addition,in vitroexperiments revealed that the hydrogel exhibited remarkable antibacterial activity, excellent biocompatibility. And it showed the capacity to promote vascular formation, effectively scavenge reactive oxygen species, and facilitate macrophage polarization from the M1 to M2 phenotype.In vivowound healing of mice PUs indicated that the prepared GPL/CTLP-MPs hydrogel effectively accelerated the formation of granulation tissue and facilitated the healing of the wounds. In summary,in vivoandin vitroexperiments consistently highlight the therapeutic potential of GPL/CTLP-MPs hydrogel in facilitating the healing process of PUs.

EMP3 as a prognostic biomarker correlates with EMT in GBM.

BACKGROUND: Glioblastoma (GBM) is the most aggressive malignant central nervous system tumor with a poor prognosis.The malignant transformation of glioma cells via epithelial-mesenchymal transition (EMT) has been observed as a main obstacle for glioblastoma treatment. Epithelial membrane protein 3 (EMP3) is significantly associated with the malignancy of GBM and the prognosis of patients. Therefore, exploring the possible mechanisms by which EMP3 promotes the growth of GBM has important implications for the treatment of GBM. METHODS: We performed enrichment and correlation analysis in 5 single-cell RNA sequencing datasets. Differential expression of EMP3 in gliomas, Kaplan-Meier survival curves, diagnostic accuracy and prognostic prediction were analyzed by bioinformatics in the China Glioma Genome Atlas (CGGA) database and The Cancer Genome Atlas (TCGA) database. EMP3-silenced U87 and U251 cell lines were obtained by transient transfection with siRNA. The effect of EMP3 on glioblastoma proliferation was examined using the CCK-8 assay. Transwell migration assay and wound healing assay were used to assess the effect of EMP3 on glioblastoma migration. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to detect the mRNA and protein expression levels of EMT-related transcription factors and mesenchymal markers. RESULTS: EMP3 is a EMT associated gene in multiple types of malignant cancer and in high-grade glioblastoma. EMP3 is enriched in high-grade gliomas and isocitrate dehydrogenase (IDH) wild-type gliomas.EMP3 can be used as a specific biomarker for diagnosing glioma patients. It is also an independent prognostic factor for glioma patients' overall survival (OS). In addition, silencing EMP3 reduces the proliferation and migration of glioblastoma cells. Mechanistically, EMP3 enhances the malignant potential of tumor cells by promoting EMT. CONCLUSION: EMP3 promotes the proliferation and migration of GBM cells, and the mechanism may be related to EMP3 promoting the EMT process in GBM; EMP3 may be an independent prognostic factor in GBM.

PFKP is upregulated in 5-fluorouracil-resistant patients and suppresses the antitumor activity of 5-fluorouracil in colorectal cancer in vitro and in vivo.

As a long-established chemotherapy drug, 5-fluorouracil (5-FU) is widely used to clinically manage colorectal cancer (CRC). However, a substantial portion of patients develop 5-FU resistance at some stage, which poses a great challenge. Therefore, revealing the mechanisms that could guide the development of effective strategies to overcome 5-FU resistance is required. Here, we report that the expression of PFKP was higher in HCT116/5-FU CRC. Furthermore, genetic suppression of PFKP suppresses glycolysis, NF-κB activation, and expression of GLUT1 and HK2 in HCT116/5-FU cells. PFKP overexpression promotes glycolysis and expression of GLUT1 and HK2 via the NF-κB signaling pathway in HCT116 cells. Our functional assays demonstrated that PFKP silencing could sensitize HCT116/5-FU cells to 5-FU with an elevated population of apoptotic cells. In contrast, forced expression of PFKP conferred 5-FU resistance in HCT116 cells. Furthermore, PFKP silencing significantly inhibited CRC xenograft tumor growth. Notably, the combination of PFKP silencing and 5-FU inhibited tumor growth. Therefore, our results demonstrated that PFKP enhances 5-FU resistance by promoting glycolysis, indicating that PFKP could be a novel candidate for targeted therapy for 5-FU-resistant CRC.

Effects of Dietary Chlorogenic Acid Supplementation on Growth Performance, Meat Quality, and Muscle Flavor Substances in Finishing Pigs.

With the prohibition of antibiotics in feed, certain phytocompounds have been widely studied as feed additives. Chlorogenic acid (CGA), a natural polyphenol found in plants, possesses anti-inflammatory, antioxidant, and metabolic regulatory features. The objective of this study was to investigate the effects of dietary chlorogenic acid supplementation on growth performance and carcass traits, as well as meat quality, nutrient value and flavor substances of Duroc × Landrace × Yorkshire (DLY) pigs. Forty healthy DLY pigs (initial body weight (BW): 26.69 ± 0.37) were allotted to four treatment groups and were fed with the control diet, which was supplemented with 25 mg kg-1, 50 mg kg-1, and 100 mg kg-1 CGA, respectively. The trial lasted 100 days. The results suggested that dietary CGA supplementation had no effect (p < 0.05) on the average daily gain (ADG) and feed conversion ratio (FC). Herein, it was found that 50 mg kg-1 CGA-containing diet not only increased the dressing percentage and perirenal fat, but also reduced the rate of muscular pH decline (p < 0.05). In the longissimus thoracis (LT) muscle, the myofiber-type-related genes such as the MyHC IIa and MyHC IIX mRNA levels were increased by 100 mg kg-1 CGA. The results also indicated that the 100 mg kg-1 CGA-containing diet increased the content of crude fat, glycogen, total amino acids, and flavor amino acids, but decreased the inosine and hypoxanthine concentration in LT (p < 0.05). Meanwhile, the lipogenic gene ACC1 mRNA level was elevated by 50 mg kg-1 CGA. Instead, 100 mg kg-1 CGA downregulated the expression level of NT5C2, an enzyme responsible for inosine-5'-monophosphate (IMP) degradation. Additionally, 100 mg kg-1 CGA decreased the malondialdehyde (MDA) content, but increased the glutathione peroxidase (GSH-Px) content as well as antioxidant gene (HO-1, NQO-1, NRF2) mRNA levels in LT muscle. These findings showed that dietary CGA could partly improve carcass traits and muscle flavor without negatively affecting growth performance, and the underlying mechanism may be due to the antioxidant properties induced by CGA.

Adult granulosa cell tumor of the testis with malignant tendency: A case report with genetic analysis using high-throughput sequencing.

BACKGROUND: The adult granulosa cell tumor of the testis is a rare sex-cord/stromal tumor, with a potentiality for late recurrence and metastasis. Because of its rarity, this tumor is poorly understood, particularly in terms of its molecular features. As a result, it is necessary to register each occurrence in order to study the evolution of this rare malignancy and develop therapeutic strategies. METHODS: A 50-year-old man discovered a painless right testicular mass unexpectedly, and the mass steadily expanded for 2 months. Ultrasonography showed a 5.2 cm × 4.0 cm × 3.6 cm mass in the right testicle. A right radical orchiectomy was performed on September 7, 2016. The pathologic diagnosis was a testicular adult granulosa cell tumor. The post-computed tomography scans and bone scintigraphy ruled out distant metastases. A high-throughput sequencing of 520 cancer-related genes revealed FOXL2 C134W, CDKN2A E87Gfs*24, TP53 S183*, TERT c.-124C > T, and H3F3A K28R mutations in this case. Because the patient stated he would be unable to return to the hospital for a follow-up appointment on time, he elected to have 4 cycles of adjuvant chemotherapy BEP (bleomycin, etoposide, and cisplatin) after the right radical orchiectomy. RESULTS: The patient has not had a clinical recurrence or metastasis in 6 years. CONCLUSION: Surgery together with adjuvant chemotherapy may be useful treatment options for these individuals with malignant tendencies who are unable to visit the hospital for a follow-up appointment on time. Adult testicular granulosa cell tumors have a relatively complex genetic profile; their etiology is linked to a number of common driver genes, including TERT, CDKN2A, TP53, and H3F3A.

Secretory breast cancer in a boy: A case report with genetic analysis using next-generation sequencing and literature review.

RATIONALE: Male secretory breast cancer is a rare, low-grade carcinoma, especially in boys. Due to its rarity, not much is known about this disease. PATIENT CONCERNS: A 5-year-old boy presented with a 1.4 cm painless mass in the right breast. DIAGNOSES: Ultrasonography could not distinguish whether the breast tumor was benign or malignant. After a biopsy of the lumpectomy specimen, it was diagnosed to be secretory breast carcinoma. INTERVENTIONS: The patient underwent a modified radical mastectomy for his right breast. No postoperative chemotherapy or radiotherapy was performed. Next-generation sequencing of 211 cancer-related genes was detected, and the results revealed an ETV6-NTRK3 translocation and a PDGFRB c.2632A > G mutation. None of the most commonly altered molecules in male aggressive breast cancer (such as BRCA1-2, TP53, RAD51C, and RAD51D mutations) has been identified. OUTCOMES: The patient was still free from local recurrence or metastases at 6-month follow-up. LESSONS: The genomic profile of male pediatric SCB is relatively simple, no other known driver genes have been found except for the ETV6-NTRK3 fusion. Our report will improve our understanding of secretory breast cancer.

Sumoylated SnoN interacts with HDAC1 and p300/CBP to regulate EMT-associated phenotypes in mammary organoids.

Protein post-translational modification by the small ubiquitin-like modifier (SUMO) regulates the stability, subcellular localization, and interactions of protein substrates with consequences on cellular responses including epithelial-mesenchymal transition (EMT). Transforming growth factor beta (TGFß) is a potent inducer of EMT with implications for cancer invasion and metastasis. The transcriptional coregulator SnoN suppresses TGFß-induced EMT-associated responses in a sumoylation-dependent manner, but the underlying mechanisms have remained largely unknown. Here, we find that sumoylation promotes the interaction of SnoN with the epigenetic regulators histone deacetylase 1 (HDAC1) and histone acetylase p300 in epithelial cells. In gain and loss of function studies, HDAC1 suppresses, whereas p300 promotes, TGFß-induced morphogenetic changes associated with EMT-related events in three-dimensional multicellular organoids derived from mammary epithelial cells or carcinomas. These findings suggest that sumoylated SnoN acts via the regulation of histone acetylation to modulate EMT-related effects in breast cell organoids. Our study may facilitate the discovery of new biomarkers and therapeutics in breast cancer and other epithelial cell-derived cancers.

A novel exosome-derived prognostic signature and risk stratification for breast cancer based on multi-omics and systematic biological heterogeneity.

Tumor heterogeneity remains a major challenge for disease subtyping, risk stratification, and accurate clinical management. Exosome-based liquid biopsy can effectively overcome the limitations of tissue biopsy, achieving minimal invasion, multi-point dynamic monitoring, and good prognosis assessment, and has broad clinical prospects. However, there is still lacking comprehensive analysis of tumor-derived exosome (TDE)-based stratification of risk patients and prognostic assessment for breast cancer with systematic dissection of biological heterogeneity. In this study, the robust corroborative analysis for biomarker discovery (RCABD) strategy was used for the identification of exosome molecules, differential expression verification, risk prediction modeling, heterogenous dissection with multi-ome (6101 molecules), our ExoBCD database (306 molecules), and 53 independent studies (481 molecules). Our results showed that a 10-molecule exosome-derived signature (exoSIG) could successfully fulfill breast cancer risk stratification, making it a novel and accurate exosome prognostic indicator (Cox P = 9.9E-04, HR = 3.3, 95% CI 1.6-6.8). Interestingly, HLA-DQB2 and COL17A1, closely related to tumor metastasis, achieved high performance in prognosis prediction (86.35% contribution) and accuracy (Log-rank P = 0.028, AUC = 85.42%). With the combined information of patient age and tumor stage, they formed a bimolecular risk signature (Clinmin-exoSIG) and a convenient nomogram as operable tools for clinical applications. In conclusion, as an extension of ExoBCD, this study conducted systematic analyses to identify prognostic multi-molecular panel and risk signature, stratify patients and dissect biological heterogeneity based on breast cancer exosomes from a multi-omics perspective. Our results provide an important reference for in-depth exploration of the "biological heterogeneity - risk stratification - prognosis prediction".

ATF3 Modulates the Proliferation, Migration, and Apoptosis of Synovial Fibroblasts after Arthroscopy by Promoting RGS1 Transcription.

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease involving both cartilage and synovium. Activating transcription factor 3 (ATF3) and regulator of G protein signaling 1 (RGS1) have been reported to be up-regulated in OA. However, little is known regarding the relationship between these two genes and the mechanism of this relationship in OA development. Therefore, the present study explores the mechanism of ATF3-mediated RGS1 in the proliferation, migration, and apoptosis of synovial fibroblasts. METHODS: After the OA cell model was constructed with TGF-ß1 induction, human fibroblast-like synoviocytes (HFLSs) were transfected with ATF3 shRNA or RGS1 shRNA alone or co-transfected with ATF3 shRNA and pcDNA3.1-RGS1. Then, proliferation, migration, apoptosis, and the expression of ATF3, RGS1, α-SMA, BCL-2, caspase3, and cleaved-caspase3 were measured. Meanwhile, the potential relationship between ATF3 and RGS1 was predicted and validated. RESULTS AND DISCUSSION: Analysis of the GSE185059 dataset suggested that RGS1 was up-regulated in OA synovial fluid exosomes. Moreover, ATF3 and RGS1 were both highly expressed in TGF-ß1-induced HFLSs. Transfection of ATF3 shRNA or RGS1 shRNA significantly reduced proliferation and migration and promoted apoptosis of TGF- ß1-induced HFLSs. Mechanistically, ATF3 bound to the RGS1 promoter and elevated RGS1 expression. Silencing ATF3 repressed proliferation and migration and enhanced apoptosis of TGF-ß1-induced HFLSs by down-regulating RGS1. CONCLUSION: ATF3 binds to the RGS1 promoter and enhances RGS1 expression to accelerate cell proliferation and block cell apoptosis in TGF-ß1-induced synovial fibroblasts.

Effect of L-cysteine treatment to induce postharvest disease resistance of Monilinia fructicola in plum fruits and the possible mechanisms involved.

Plum is an important stone fruit in China, but the fruit is easily perishable and susceptible to infection by pathogens. Traditionally, synthetic fungicides are used to control diseases. However, the side effects of fungicides should not be ignored. Cysteine, generally recognized as safe (GRAS) amino acid, has been reported to play roles in the plant abiotic stress response, but little is known about the role of cysteine to control postharvest diseases in fruits. Therefore, this study was designed to investigate the effect of L-cysteine treatment on control of postharvest brown rot in artificially inoculated plum fruits and the possible biocontrol mechanisms involved. Postharvest plum fruits were inoculated with 1, 10, 100 and 1000 mg L-1 L-cysteine. 100 mg L-1 L-cysteine treatment effectively controlled brown rot in artificially inoculated plum fruits by inducing resistance. Furthermore, 100 mg L-1 L-cysteine treatment increased the activities of glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH), enhanced the content of NADPH of the pentose phosphate pathway, as well as improved the contents of H2O2 and some amino acids in the artificially inoculated plum fruits. 100 mg L-1 L-cysteine treatment also elevated the antioxidant content (AsA, GSH) and the antioxidant enzymes activities (APX, GR, MDAR, DHAR) of the ascorbate-glutathione (AsA-GSH) pathway. The protective effects of L-cysteine treatment on postharvest plum fruits likely be due to activating some defense-related responses of the fruit against infection. L-cysteine treatment is a safe promising method for controlling postharvest brown rot in plum fruits.

Metformin improves survival in patients with concurrent diabetes and small cell lung cancer: a meta-analysis.

INTRODUCTION: To compare survival outcome among the patients with concurrent small cell lung cancer (SCLC) and diabetes mellitus (DM) using metformin or without metformin. EVIDENCE ACQUISITION: A systematic literature search for relevant studies up to Oct 2020 was conducted. Outcome of the included studies included overall survival (OS) or disease-free survival (DFS). HR values were pooled to estimate the effect of metformin on survival outcomes. EVIDENCE SYNTHESIS: Six studies with 539 participants with both SCLC and diabetes were included in the analysis. The patients with metformin usage had significantly longer OS and DFS than those without metformin usage (OS: HR=0.72 [0.53-0.98], P=0.04; DFS: HR=0.59 [0.45-0.76], P<0.0001). The studies included were not significantly different in the two analyses by heterogeneity test. There was no obvious publication bias. CONCLUSIONS: Metformin may improve survival among patients with concurrent SCLC and DM. Further investigations especially randomized control trials are warranted, especially among the patients who do not have diabetes.

Biogeochemical niche conservatism relates to plant species diversification and life form evolution in a subtropical montane evergreen broad-leaved forest.

The evolutionary mechanisms underlying the biogeochemical niche conservatism in forests remain incompletely understood. Here we aimed to determine how the strengths of biogeochemical niche conservatism vary among elements and between life forms. We measured leaf concentrations of basal elements (C, N, P, K, Ca, and Mg) in a wide range of life forms in a subtropical montane evergreen broad-leaved forest. We found that differences in life forms such as evergreen/deciduous woody species and herbaceous/woody species significantly affected leaf elemental composition. The significant phylogenetic signal was present in leaf C, N, K, and Mg concentrations but absent in leaf P and Ca concentrations in all species. These contrasting strengths of biogeochemical niche conservatism were best generated by Ornstein-Uhlenbeck processes toward optima. Woody species were evolutionarily selected to show lower optimal leaf N, P, and K concentrations and higher optimal leaf C, Ca, and Mg concentrations than herbaceous species. The number of optima varied from the least in leaf C concentration to the most in leaf Ca concentration, suggesting the stronger convergent evolution of leaf Ca concentration. The positions of optima toward the tips were more selected in woody species, suggesting the more frequency of species-specific adaptations in woody species. The positions of optima were also selected at the nodes towards the species groupings from certain life forms (e.g., the group of 12 Polypodiales ferns in leaf Ca evolution and the group of three evergreen Theaceae species in leaf P evolution) that were converged to present similar leaf elemental composition. During the evolution of biogeochemical niche, strong correlations were found among leaf C, N, P, and K concentrations and between leaf Ca and Mg concentrations. In conclusion, the strengths of biogeochemical niche conservatism can vary among elements and between life forms due to the different tempo and mode of Ornstein-Uhlenbeck processes.

Protective effect and mechanism of baicalin on lung inflammatory injury in BALB/cJ mice induced by PM2.5.

The public health harms caused by fine particulate matter (PM2.5) have become a global focus, with PM2.5 exposure recognized as a critical risk factor for global morbidity and mortality. Chronic inflammation is the common pathophysiological feature of respiratory diseases induced by PM2.5 and is the most critical cause of all these diseases. However, presently there is a lack of effective preventive and therapeutic approaches for inflammatory lung injuries caused by PM2.5 exposure. Baicalin is a herb-derived effective flavonoid compound with multiple health benefits. This study established a murine lung inflammatory injury model via inhalation of PM2.5 aerosols. The data showed that after baicalin intervention, lung injury pathological score of baicalin (4.16 ± 0.54, 3.33 ± 0.76, 4.00 ± 0.45) and claricid (3.00 ± 0.78) treatments were markedly lower than PM2.5-treated mice (6.17 ± 0.31), and pathological damage was alleviated. Compared to the PM2.5 group, the spleen and lung indexes in the baicalin and claricid groups were significantly reduced. The inflammatory cytokines of TNF-α, IL-18, and IL-1ß in serum, alveolar lavage fluid, and lung tissue were significantly decreased in the baicalin and claricid groups. The expressions of inflammatory pathway-related genes and proteins HMGB1, NLRP3, ASC, and caspase-1 were up-regulated in the PM2.5 group. The expressions of these genes and proteins were significantly decreased following baicalin treatment. The lung function indicators showed that the MV (65.94 ± 8.19 mL), sRaw (1.79 ± 0.08 cm H2O.s), and FRC (0.52 ± 0.01 mL) in the PM2.5 group were higher than in the control and baicalin groups, and respiratory function was improved by baicalin. PM2.5 exposure markedly altered the bacterial composition at the genus level. The dominant flora relative abundances of uncultured_bacterium_f_Muribaculaceae, Streptococcus, and Lactobacillus, were decreased from the control group (9.20%, 8.53%, 6.21%) to PM2.5 group (6.26%, 5.49%, 4.77%), respectively. Following baicalin intervention, the relative abundances were 9.72%, 6.65%, and 3.57%, respectively. Therefore, baicalin could potentially prevent and improve mice lung inflammatory injury induced by PM2.5 exposure. Baicalin might provide a protective role by balancing oropharyngeal microbiota and affecting the expression of the HMGB1/Caspase1 pathway.

Combined anti-tumor efficacy of somatostatin fusion protein and vaccinia virus on tumor cells with high expression of somatostatin receptors.

Somatostatin, a growth hormone-release inhibiting peptide, exerts antiproliferative and antiangiogenic effects on tumor cells. However, the short half-life of somatostatin limits its application in human therapy, and long-acting somatostatin fusion protein is also limited by its severe terminal degradation. Therefore, oncolytic virus delivery system was introduced to express somatostatin fusion protein and the anti-tumor effects of both somatostatin and oncolytic virus were combined to destroy tumor tissues. Here, a vaccinia VG9/(SST-14)2-HSA recombinant was constructed by replacing somatostatin fusion gene into TK locus of attenuated VG9 strain via homologous recombination. Results showed that vaccinia VG9/(SST-14)2-HSA possessed a combined anti-tumor effect on sstr-positive tumor cells in vitro. In the tumor burden models, BALB/c mice with complete immunity are most suitable for evaluating tumor regression and immune activation. Complete tumor regression was observed in 3 out of 10 mice treated with vaccinia VG9/TK- or VG9/(SST-14)2-HSA, and the survival of all mice in both groups was significantly prolonged. Besides, vaccinia VG9/(SST-14)2-HSA is more effective in prolonging survival than VG9/TK-. Vaccinia VG9/(SST-14)2-HSA exerts a combined anti-tumor efficacy including the oncolytic ability provided by the virus and the anti-tumor effect contributed by (SST-14)2-HSA, which is expected to become a potent therapeutic agent for cancer treatment.

[Antitumor Effect of Dihydroartemisinin on Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To investigate the potential antitumor effect and its mechanism of dihydroartemisinin (DHA) on diffuse large B-cell lymphoma (DLBCL). METHODS: OCI-Ly7 cells were respectively treated with different concentrations of DHA (0, 12.5, 25, 50 and 100 µmol/L) , CCK-8 was used to detect the cells viability. Subsequently, OCI-Ly7 cells were divided into 5 groups : DHA 0,25,50,100 µmol / L and DHA (100 µmol / L) + Colivelin (STAT3 activator). Aldehyde dehydrogenase (ALDH) positive cells were sorted by flow cytometry, the sphere-forming ability of stem cells was detected. Transwell assay and scratch test were used to analyze the invasion and migration of cells. Western blot was used to detect the expression of migration and invasion-related proteins, as well as the phosphorylation levels of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3(STAT3). RESULTS: DHA induced obvious cytotoxicity to OCI-Ly7 cells. Compared with the control group, the stem cell-like properties, invasion and migration of OCI-Ly7 were significantly inhibited in DHA 50 µmol/L group and 100 µmol/L group, while the phosphorylation levels of JAK2 and STAT3 were significantly reduced. There was no significant difference in DHA 25 µmol/L group compared with the control group. Treated with Colivelin, the inhibition of DHA on OCI-Ly7 stem cell-like properties, invasion and migration was significantly reversed, and the expression of p-STAT3 was significantly up-regulated. CONCLUSION: DHA has antitumor effect on DLBCL, and its mechanism may be through inhibiting the activation of JAK2/STAT3 pathway to inhibit the stem cell-like properties, invasion and migration of DLBCL cells.