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The mechanisms by which AML1/ETO (A/E) fusion protein induces leukemogenesis in acute myeloid leukemia (AML) without mutagenic events remain elusive. Here we show that interactions between A/E and hypoxia-inducible factor 1α (HIF1α) are sufficient to prime leukemia cells for subsequent aggressive growth. In agreement with this, HIF1α is highly expressed in A/E-positive AML patients and strongly predicts inferior outcomes, regardless of gene mutations. Co-expression of A/E and HIF1α in leukemia cells causes a higher cell proliferation rate in vitro and more serious leukemic status in mice. Mechanistically, A/E and HIF1α form a positive regulatory circuit and cooperate to transactivate DNMT3a gene leading to DNA hypermethylation. Pharmacological or genetic interventions in the A/E-HIF1α loop results in DNA hypomethylation, a re-expression of hypermethylated tumor-suppressor p15(INK4b) and the blockage of leukemia growth. Thus high HIF1α expression serves as a reliable marker, which identifies patients with a poor prognosis in an otherwise prognostically favorable AML group and represents an innovative therapeutic target in high-risk A/E-driven leukemia.

Introduction: In order to find the early diagnostic markers of AIDS combined with TM infection, we detected and analyzed the serum exosomal miRNAs of AIDS patients with or without TM infection., Materials and Methods: We profiled the expression levels of miRNAs via RNA sequencing in serum exosomes from the pooled samples of 17 AIDS patients combined without TM infection and 15 AIDS combined with TM infection patients. For external validation, we validated these results using real-time quantification polymerase chain reaction (qRT-PCR) in an independent cohort of 35 AIDS patients combined without TM infection and 33 AIDS combined with TM infection patients. Finally, bioinformatics was used to predict the target genes and pathways of meaningful miRNAs., Results: A total of 131 serum exosomal miRNAs including 73 up-regulated and 59 down-regulated miRNAs were found to be differentially expressed (log2FC≥1 and FDR <0.01) in the two groups. A validation analysis revealed that three miRNAs (miR-192-5p, miR-194-5p and miR-1246) were upregulated in exosomes from AIDS combined with TM infection patients. ROC analyses showed that the AUC in combined diagnosis of the three miRNAs was 0.742, and the diagnostic sensitivity and specificity were 0.568 and 0.861, respectively. In the biological process analysis, all the 3 miRNAs were involved in transcription, DNA-templated and positive regulation of transcription from RNA polymerase II promoter. At the same time, the related pathways were involved in TGF-β signaling pathway, AMPK signaling pathway, Wnt signaling pathway, MAPK signaling pathway, cGMP-PKG and cAMP signaling pathway, etc., Conclusion: miR-192-5p, miR-194-5p and miR-1246 in serum exosomes might be a potential biomarker for AIDS combined with TM infection patients, which may be involved in TGF-β signaling pathway, AMPK signaling pathway, Wnt signaling pathway, MAPK signaling pathway, cGMP-PKG and cAMP signaling pathway, etc. Further research is needed on the biological functions and mechanisms of these miRNAs., Competing Interests: The authors declare no conflicts of interest in this work., (© 2021 Ning et al.)

Objective: This study aims to investigate the clinical features and prognostic factors of patients with diffuse large B-cell lymphoma (DLBCL) and assess the prognostic value of diabetes mellitus (DM) and hyperglycemia during DLBCL treatment in DLBCL. Methods: The clinical data of 481 newly diagnosed DLBCL patients from January 1, 2009 to December 31, 2019 at Tianjin Medical University Cancer Institute and Hospital and Sun Yat-sen University Cancer Center were retrospectively collected, focusing on their blood glucose levels before and during treatment. Cox regression method was used for univariate analysis to assess prognostic factors, and the Kaplan-Meier method was used to draw survival curves to assess the prognostic value of DM and hyperglycemia during DLBCL treatment in patients with DLBCL. Results: Eighty-two (17.0%) patients had DM before DLBCL diagnosis and treatment, and 88 (18.3%) patients had at least one blood glucose increase during DLBCL treatment. Cox univariate analysis showed that age, Ann Arbor stage, international prognostic index, and DM were associated with overall survival (OS) and progression-free survival (PFS) (all P <0.05) . The pairwise comparison between the two groups showed that the OS ( P =0.001) and PFS ( P <0.001) of patients with pre-existing DM were significantly worse than those of patients without abnormal blood glucose. Moreover, the OS ( P =0.003) and PFS ( P <0.001) of patients with hyperglycemia during DLBCL treatment were significantly worse than those of patients without abnormal blood glucose. No significant difference exists between patients with DM and patients with hyperglycemia during DLBCL treatment (OS, P =0.557; PFS, P =0.463) . Additionally, patients with adequate glycemic control during chemotherapy had a better prognosis compared with patients with poor glycemic control (OS, P =0.037; PFS, P =0.007) . Conclusion: DM is an important factor affecting the prognosis of patients with DLBCL. Moreover, hyperglycemia during treatment is related to the poor prognosis of patients with DLBCL.

Objective: To compare the prognostic efficiency of Lugano staging, TNM staging and Musshoff staging systems in patients with primary gastrointestinal diffuse large B-cell lymphoma(PGI-DLBCL) and investigate its clinical features and prognosis. Methods: The clinical data of 110 patients with PGI-DLBCL in Tianjin Medical University Cancer Institute and Hospital from May 2008 to August 2017 was retrospectively analyzed. The stage of lymphoma was assessed following Lugano staging, TNM staging and Musshoff staging systems respectively. The prognostic value was compared mainly according to the situation of 5-year overall survival (OS)and the influence of different clinical features on prognosis of patients was also investigated. Results: The median age of the whole study was 55(range 17-92) years old. With a median follow-up time of 36 (range 1-115) months, the median progression-free survival (PFS) was 35 (range 0-86) months, and the median overall survival was 37 (range 2-104) months. The 5-year OS rate of Lugano stagingⅠ, Ⅱ, Ⅲ and Ⅳ were 77.6%, 73.4%, 69.7%, 12.2% (χ(2)=63.395, P< 0.001) respectively. The 5-year OS rate of TNM staging Ⅰ, Ⅱ, Ⅲ and Ⅳ were 77.6%, 75.9%, 25.0%, 9.3% (χ(2)=65.802, P< 0.001) respectively. The 5-year OS rate of Musshoff stagingⅠ, Ⅱ, Ⅲ and Ⅳ were 84.5%, 68.4%, 25.0%, 9.3% (χ(2)=66.966, P< 0.001) respectively. By Cox multiple-factors analysis, Lugano staging system was the only independent prognosis risk factor for PFS ( HR =4.987, 95 %CI : 1.421-17.498, P= 0.009) and OS ( HR =5.659, 95 %CI : 1.563-20.485, P= 0.008) of PGI-DLBCL. Univariated analysis revealed that the factors affecting PFS and OS of patients with PG-DLBCL include B-symptom, Eastern Cooperative Oncology Group performance status (ECOG PS), the number of extranodal lesions, serum lactate dehydrogenase (LDH), International prognostic index (IPI) score, staging and therapeutic regimen(all P values of PFS and OS<0.05). Patients with PG-DLBCL who received chemotherapy alone showed a better survival than others (PFS P= 0.004; OS P< 0.001); the factors affecting PFS and OS of patients with PI-DLBCL include β2-microglobulin(β2-MG), serum albumin(ALB) levels, LDH and staging (all P values of PFS and OS<0.05). Therapeutic regimen didn't affect those patients' survival (PFS P= 0.661, OS P= 0.720). The additional use of Rituximab failed to improve the survival of patients with PG-DLBCL and PI-DLBCL respectively (all P values of PFS and OS>0.05). Conclusions: Compared with TNM staging and Musshoff staging systems, Lugano staging system provides the best prognostic value in PFS and OS for patients with PGI-DLBCL. Accompany with B-sympto, higher ECOG PS score, more extranodal lesions, increased LDH, higher IPI score and later period are negative factors for PG-DLBCL. Increased β2-MG and LDH, lower ALB level and later period are negative factors of PI-DLBCL.

Objective: To evaluate the therapeutic efficacy and prognosis of autologous stem Hematopoietic cell transplantation (auto-HSCT) in multiple myeloma (MM) patients., Methods: A retrospective study was conducted for 56 patients diagnosed with MM and then received auto-HSCT in our hospital from December 2008 to September 2016., Results: All the patients successfully underwent hematopoietic reconstruction without transplantation-related mortality (TRM). The complete response (CR) rate of all the patients after induction chemotherapy was 23.2% (13/56), while the CR rate of these patients with auto-HSCT increased to 78.6% (44/56) (P<0.01). The CR plus VGPR (very good partial response) rates of these 56 patients after induction chemotherapy and auto-HSCT were 53.6%（30/56）and 94.6%（53/56） respectively (P<0.01). The median progression-free survival (PFS) time and median overall survival (OS) time were 37 and 71 months, respectively. The median PFS time in the patients with induction therapy containing bortezomib was 37 months, however, the median OS time did not reach to 71 months; the median PFS (P<0.01) and the median OS (P<0.01) in the patients with the induction chemotherapy without bortezomib was 27 and 51 months, respectively. Univariate analysis demonstrated that the patients maintained CR or VGPR after auto-HSCT or with less than 6 cycles of induction chemotherapy significantly correlated with PFS (P<0.01)., Conclusion: auto-HSCT can further increase the CR rate, prolong PFS and OS time. Sequential auto-HSCT after bortezomib-based therapy is the first line therapy for the transplant-eligible MM patients. Maintenance treatment is beneficial to the sustained CR+VGPR patients after auto-HSCT.

This paper aimed to investigate the effects of Jinwu Jiangu recipe total extract on the IL-17/STAT3 signals in rheumatoid arthritis synovial fibroblasts(RASF). The primary RASFs were cultured by tissue piece method in vitro ， and divided into blank control group， Jinwu Jiangu recipe low dose group， Jinwu Jiangu recipe middle dose group， Jinwu Jiangu recipe high dose group， and tripterygium glycosides control group. They were then treated with corresponding serum free medium， different doses of Jinwu Jiangu recipe total extract(0.06， 0.6， 6.0 g·L⁻¹)， and tripterygium glycosides(0.03 g·L⁻¹) respectively for 24 hours. The gene expression levels of RORα， RORγt， and STAT3 mRNA were detected by polymerase chain reaction(PCR)， and the protein activity of IL-17R and pSTAT3 were measured by Western blot assay. The results showed that as compared with blank control group， the expression levels of RORα， RORγt， IL-17R and STAT3 mRNA in RASF were significantly declined( P <0.01). As compared with tripterygium glycosides control group， Jinwu Jiangu recipe total extract middle dose group and high dose group can down-regulate the expression levels of RORα， RORγt， IL-17R and STAT3 mRNA( P <0.05)， and the effect was more obvious in high dose group( P <0.01). As compared with blank control group， the protein expression levels of IL-17R and pSTAT3 in each treatment group were obviously decreased( P <0.01). As compared with tripterygium glycosides control group， Jinwu Jiangu recipe high dose group had more obvious effect in down-regulating the protein expression of pSTAT3( P <0.01). Therefore， Miao medicine Jinwu Jiangu recipe total extract can down-regulate the expressions of RORα， RORγt， and STAT3 mRNA， and inhibit the protein activity of IL-17R and pSTAT3 in RASF., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Objective: To document the long-term exposure rate of unwrapped coralline hydroxyapatite (HA) orbital implants and explore possible risk factors., Design: This retrospective case series (May 2008-April 2013) reviewed the 234 patients with anophthalmia who underwent insertion of an unwrapped HA orbital implant by one of two different surgical closing techniques., Results: Of the 234 cases, 151 underwent a rectus end-to-end suturing closure technique and 83 underwent a rectus orthotopic suturing closure technique. The time of follow-up ranged from 25 months to 69 months (mean 41.9 months). Implant exposure developed in 11 cases. Three in the rectus end-to-end suturing closure group (2.0%) and eight in the rectus orthotopic suturing closure group (9.6%). In the rectus end-to-end suturing technique, a crosswise fixation of vascularised rectus muscle tissue is formed across the front of the implant; in this group the incidence of implant exposure was reduced (OR=8.11, p=0.013). Prior ocular surgery was found to be a factor increasing the incidence of HA exposure (OR=2.73, p=0.032)., Conclusions: The placement of an unwrapped HA orbital implant with rectus end-to-end suturing in enucleation surgery was associated with a low rate of exposure in most cases. The end-to-end suturing creates a joint-like structure over the HA sphere, protecting the Tenon's capsule and conjunctiva from its rough surface and reducing the risk of implant exposure. Prior ocular surgery may be another risk factor for HA exposure., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The goal of present study was to investigate the relationship between polymorphisms of TGF-β1 and familial aggregation of liver cancer in Guangxi Zhuang, Han, and Yao populations. We conducted a population-based case-control family study of liver cancer in Guanxi, China. A total of 214 individuals from 37 case families were surveyed for polymorphisms in TGF-β1. We genotyped six functional TGF-β1 polymorphisms: rs1800469, rs2241715, rs2241716, rs11466345, rs8105161, and rs747857. Levels of TGF-β1, hepatitis B surface antigen, and anti-hepatitis C virus in all serum samples were detected using the enzyme-linked immunoassay method, and presence of hepatitis B virus (HBV) DNA was determined using polymerase chain reaction amplification. A standardized questionnaire was used to collect information from subjects, including alcohol consumption, smoking, eating, and water drinking habits. The results were compared with those from 214 control individuals. The results showed that the TGF-β1 genotypes rs1800469, rs2241715, rs2241715, and rs8105161 were more frequent in patients than in controls. The risk factors for familial aggregation of liver cancer in Guangxi were determined, from high to low, to be: drinking sugared beverages > alcohol consumption > HBV DNA-positive > rs1800469 TT homozygous genotype > rs2241715 TT homozygous genotype. The results suggested that TGF-β1 rs1800469 TT and rs2241715 TT homozygote genotypes represent the genetic factors underlying familial clustering of liver cancer in Guangxi, and that drinking water use, alcohol consumption, and testing positive for HBV DNA are the main environmental factors contributing to familial aggregation of liver cancer in Guangxi.

We report on the generation of a high-repetition-rate pulse in a fiber laser using a graphene-deposited microfiber photonic device (GMPD) and a Fabry-Perot filter. Taking advantage of the unique nonlinear optical properties of the GMPD, dissipative four-wave mixing effect (DFWM) could be induced at low pump power. Based on DFWM mode-locking mechanism, the fiber laser delivers a 100 GHz repetition rate pulse train. The results indicate that the small sized GMPD offers an alternative candidate of highly nonlinear optical component to achieve high-repetition rate pulses, and also opens up possibilities for the investigation of other abundant nonlinear effects or related fields of photonics.

We report on the trapping of noise-like pulse in a figure-eight fiber laser mode locked by nonlinear amplifier loop mirror (NALM). After achievement of noise-like vector pulse, it was found that the wavelength shift of the two resolved polarization components responsible for the pulse trapping was very sensitive to the cavity birefringence. By properly rotating the polarization controllers (PCs), the wavelength shift could be up to 4.8 nm, which is much larger than that of conventional soliton trapping. The observed results would shed some light on the fundamental physics of noise-like pulse as well as its vector features in fiber lasers.

The vector nature of multi-soliton dynamic patterns was investigated in a passively mode-locked figure-eight fiber laser based on the nonlinear amplifying loop mirror (NALM). By properly adjusting the cavity parameters such as the pump power level and intra-cavity polarization controllers (PCs), in addition to the fundamental vector soliton, various vector multi-soliton regimes were observed, such as the random static distribution of vector multiple solitons, vector soliton cluster, vector soliton flow, and the state of vector multiple solitons occupying the whole cavity. Both the polarization-locked vector solitons (PLVSs) and the polarization-rotating vector solitons (PRVSs) were observed for fundamental soliton and each type of multi-soliton patterns. The obtained results further reveal the fundamental physics of multi-soliton patterns and demonstrate that the figure-eight fiber lasers are indeed a good platform for investigating the vector nature of different soliton types.

We reported on the generation of dual-wavelength rectangular pulses in a Yb-doped fiber laser (YDFL) by using a microfiber-based graphene saturable absorber (GSA). The duration of dual-wavelength rectangular pulse could be varied from 1.41 ns to 4.23 ns with the increasing pump power. With a tunable bandpass filter, it was found that the characteristics of the rectangular pulses centered at 1061.8 nm and 1068.8 nm are similar to each other. Moreover, the dual-wavelength switchable operation was also realized by properly rotating the polarization controllers (PCs). The demonstration of the dual-wavelength rectangular pulses from a YDFL would open some applications for fields such as spectroscopy, biomedicine and sensing research.

We reported on the dissipative soliton resonance (DSR) phenomenon in a mode-locked Yb-doped fiber laser by using the nonlinear polarization rotation technique. It was found that the multi-pulse oscillation under high pump power could be circumvented by properly adjusting the polarization controllers, namely, the wave-breaking-free rectangular pulse in DSR region was achieved. As the DSR signature, the pulse duration varied from 8.8 ps to 22.92 ns with the increasing pump power. Correspondingly, the maximum pulse energy was 3.24 nJ. The results demonstrated that the DSR phenomenon could exist in Yb-doped fiber lasers, which could be used to achieve wave-breaking-free, ultrahigh-energy pulse.

Prostate cancer is one of the most commonly diagnosed male malignancies. Genome wide association studies have revealed HNF1b to be a major risk gene for prostate cancer susceptibility. We examined the mechanisms of involvement of HNF1b in prostate cancer development. We integrated data from Gene Expression Omnibus prostate cancer genes from the Dragon Database of Genes Implicated in Prostate Cancer, and used meta-analysis data to generate a panel of HNF1b-associated prostate cancer risk genes. An RT-PCR was used to assess expression levels in DU145, PC3, LNCaP, and RWEP-1 cells. Twelve genes (BAG1, DDR1, ERBB4, ESR1, HSPD1, IGFBP2, IGFBP5, NR4A1, PAWR, PIK3CG, RAP2A, and TPD52) were found to be associated with both HNF1b and prostate cancer risk. Six of them (BAG1, ERBB4, ESR1, HSPD1, NR4A1, and PIK3CG) were mapped to the KEGG pathway, and submitted to further gene expression assessment. HNF1b, NR4A1, and HSPD1 were found to be highly expressed in the LNCaP androgenic hormone-dependent cell line. Compared to expression levels in wild-type prostate cancer cells, NR4A1, HSPD1, ERBB4, and ESR1 expression levels were also found to be significantly increased in the HNF1b-transfected cells. We conclude that the mechanism of action of HNF1b in prostate cancer involves modulation of the association between androgenic hormone and prostate cancer cells. Gene-gene interaction and coordination should be taken into account to determine relationships between specific loci and diseases.

We report on the vector nature of rectangular pulse operating in dissipative soliton resonance (DSR) region in a passively mode-locked fiber laser. Apart from the typical signatures of DSR, the rectangular pulse trapping of two polarization components centered at different wavelengths was observed and they propagated as a group-velocity locked vector soliton. Moreover, the polarization resolved soliton spectra show different spectral distributions. The observed results will enhance the understanding of fundamental physics of DSR phenomenon.

The generation of mode-locked rectangular pulses operating in dissipative soliton resonance (DSR) region is demonstrated in an erbium-doped figure-eight fiber laser with net anomalous dispersion. The duration of the wave-breaking-free rectangular pulse broadens with the increase of pump power. At a maximum pump power of 341 mW, the pulse energy can be up to 3.25 nJ with a repetition rate of 3.54 MHz. Particularly, the spectrum of rectangular pulse operating in DSR exhibits conventional soliton sidebands. The observed results show that the formation of pulse operating in DSR region is independent of mode-locking techniques, which may be helpful for further understanding the DSR phenomenon.

AML1-ETO fusion protein (AE) is generated by t(8;21)(q22;q22) chromosomal translocation, which is one of the most frequently observed structural abnormalities in acute myeloid leukemia (AML) and displays a pivotal role in leukemogenesis. The histone acetyltransferase p300 promotes self-renewal of leukemia cells by acetylating AE and facilitating its downstream gene expression as a transcriptional coactivator, suggesting that p300 may be a potential therapeutic target for AE-positive AML. However, the effects of p300 inhibitors on leukemia cells and the underlying mechanisms have not been extensively investigated. In the current study, we analyzed the anti-leukemia effects of C646, a selective and competitive p300 inhibitor, on AML cells. Results showed that C646 inhibited cellular proliferation, reduced colony formation, evoked partial cell cycle arrest in G1 phase, and induced apoptosis in AE-positive AML cell lines and primary blasts isolated from leukemic mice and AML patients. Nevertheless, no significant inhibitory effects were observed in granulocyte colony-stimulating factor-mobilized normal peripheral blood stem cells. Notably, AE-positive AML cells were more sensitive to lower C646 doses than AE-negative ones. And C646-induced growth inhibition on AE-positive AML cells was associated with reduced global histone H3 acetylation and declined c-kit and bcl-2 levels. Therefore, C646 may be a potential candidate for treating AE-positive AML.

Familial aggregation of hepatocellular carcinoma (HCC), the third leading cause of cancer death worldwide, has shown to be a common phenomenon. We investigated the association between the genetic background and HCC familial aggregation. Serum samples were collected from HCC family members and normal control family members for screening the differentially expressed protein peaks with the approach of surface-enhanced laser desorption ionization time-of-flight mass spectrometry. Potential genetically associated protein peaks were selected and further identified by matrix assisted laser desorption ionization-time of flight mass spectrometry. A panel of six protein peaks (m/z 6432.94, 8478.35, 9381.91, 17284.67, 17418.34, and 18111.04) were speculated to reflect the genetic susceptibility of HCC familial aggregation. Three of them (m/z 6432.94, 8478.35, and 9381.91) were selected to identify as the candidate proteins. Nine identified proteins, including mostly apolipoprotein family (ApoA1, ApoA2, ApoC3, ApoE) and serum amyloid A protein (SAA), were found overexpressed in the multiple HCC cases family members. The comparative proteomic profiles have suggested that genetic factors ought to be taken into account for familial aggregation of HCC., (© 2012 Japanese Cancer Association.)

Objective: To assess the correlation between familial clustering of hepatocellular carcinoma (HCC) and the level of anti-P53 in human serum in Guangxi., Methods: Enzyme-linked immunosorbent assay (ELISA) was used to detect anti-P53 in 164 members from 20 HCC families and 164 members from non-cancer control families. Univariate analysis was performed to assess the correlation between seral level of P53 antibody and familial clustering of HCC., Results: The level of P53 antibody was significantly higher in the members of HCC families than controls (Z=-3.04, P=0.002). After eliminating the interference of hepatitis B virus infection, this tendency still remains (P=0.011). And there was a significant difference between relatives of different degrees from HCC families (chi-square=11.593, P=0.021), with the expression of anti-P53 declining along with decrease in relationship coefficient. Furthermore, the number of individuals with high anti-P53 expression was also significantly greater in HCC families (95/164) than controls (71/164) (P=0.006). And the expression was rising along with the increasing HCC numbers (chi-square=16.068, P=0.000). Anti-P53 level was also greater in HCC families featuring sibling affection than parental affection (chi-square=12.679, P=0.002). Univariate analysis indicated that high expression of anti-P53 is a risk factor for development of HCC (OR=2.087, 95%CI: 1.270-3.431)., Conclusion: High level of anti-P53 expression may be a factor for the clustering of HCC families in Guangxi, China.

Prostate cancer is one of the most common male malignant neoplasms; however, its causes are not completely understood. A few recent studies have used gene expression profiling of prostate cancer to identify differentially expressed genes and possible relevant pathways. However, few studies have examined the genetic mechanics of prostate cancer at the pathway level to search for such pathways. We used gene set enrichment analysis and a meta-analysis of six independent studies after standardized microarray preprocessing, which increased concordance between these gene datasets. Based on gene set enrichment analysis, there were 12 down- and 25 up-regulated mixing pathways in more than two tissue datasets, while there were two down- and two up-regulated mixing pathways in three cell datasets. Based on the meta-analysis, there were 46 and nine common pathways in the tissue and cell datasets, respectively. Three up- and 10 down-regulated crossing pathways were detected with combined gene set enrichment analysis and meta-analysis. We found that genes with small changes are difficult to detect by classic univariate statistics; they can more easily be identified by pathway analysis. After standardized microarray preprocessing, we applied gene set enrichment analysis and a meta-analysis to increase the concordance in identifying biological mechanisms involved in prostate cancer. The gene pathways that we identified could provide insight concerning the development of prostate cancer.