Feasibility Study of Single-Photon Emission Computed Tomography with Iodine-123 Labeled Metaiodobenzylguanidine for Preclinical Evaluation of Labetalol as a ß-Adrenergic Receptor Blocker.

Among clinically used radiopharmaceuticals, iodine-123 labeled metaiodobenzylguanidine ([123I]mIBG) serves for diagnosing neuroendocrine tumors and obtaining images of myocardial sympathetic innervation. mIBG, a structural analogue of norepinephrine (NE), a neurotransmitter acting in peripheral and central nerves, follows a pathway similar to NE, transmitting signals through the NE transporter (NET) located at synaptic terminals. It moves through the body without decomposing, enabling noninvasive image evaluation. In this study, we aimed to quantify [123I]mIBG uptake in the adrenal glands using small animal single-photon emission computed tomography/computed tomography (SPECT/CT) images post [123I]mIBG administration. We investigated the possibility of assessing the effectiveness of ß-adrenergic receptor blockers by quantifying SPECT/CT images and biodistribution results to determine the degree of [123I]mIBG uptake in the adrenal glands treated with labetalol, a known ß-adrenergic receptor blocker. Upon intravenous administration of [123I]mIBG to mice, SPECT/CT images were acquired over time to confirm the in vivo distribution pattern, revealing a clear uptake in the adrenal glands. Labetalol inhibited the uptake of [123I]mIBG in cell lines expressing NET. A decrease in [123I]mIBG uptake in the adrenal glands was observed in the labetalol-treated group compared with the normal group through SPECT/CT imaging and biodistribution studies. These results demonstrate that SPECT/CT imaging with [123I]mIBG could be applicable for evaluating the preclinical efficacy of new antihypertensive drug candidates such as labetalol, a ß-adrenergic receptor blocker.

The assessment of halitosis with a new screening tool in medication-related osteonecrosis of the jaw.

OBJECTIVES: This study aimed to identify the levels of halitosis in patients with Medication-related osteonecrosis of the jaw (MRONJ) and osteoporosis and to suggest a new MRONJ screening method using halitosis measurement. MATERIALS AND METHODS: From October 2019 to April 2023, participants aged 19 years or older without periodontal disease were selected. Seventy-five participants, 25 in each group, were divided into an MRONJ group, an osteoporosis group without MRONJ, and a control group without osteoporosis and not taking osteoporosis drugs or antibiotics. Each participant underwent halitosis assessment twice using an exhaled breath analyzer to measure halitosis twice by blowing a straw for 1 min. Measured concentrations of hydrogen, hydrogen sulfide, and methyl mercaptan were compared between groups. RESULTS: Data from 22 patients in the MRONJ group, 25 in the osteoporosis group, and 25 in the control group were analyzed. The concentrations of hydrogen sulfide and methyl mercaptan were significantly higher in the MRONJ group than in the other groups, but the concentrations of hydrogen did not differ between the groups. When comparing the concentrations of hydrogen sulfide and methyl mercaptan in osteoporosis patients and solid cancer patients in the MRONJ group, there was a significant difference in hydrogen sulfide concentration, but there was no significant difference in methyl mercaptan. CONCLUSIONS: Quantifying the level of halitosis can be used to screen for MRONJ in patients taking bisphosphonates, such as patients with osteoporosis, prostate cancer, and breast cancer. CLINICAL RELEVANCE: MRONJ is accompanied by bad breath, and the concentrations of hydrogen sulfide and methyl mercaptan are associated with MRONJ.

Dentists' Intention to Use Teleconsultation for the Treatment of Patients With Osteoporosis: An Online Survey Study.

Introduction: To properly combine osteoporosis treatment with dental treatment and to prevent medication-related osteonecrosis of the jaw (MRONJI), a system of communication between health providers can be smoothly made within a short time is required. With the recent increase in the possibility of telemedicine being introduced in Korea, it is expected that the introduction of teleconsultation between health providers treating osteoporosis will reduce the discomfort of patients and health providers and improve satisfaction. In this study, a survey was conducted on the knowledge and experience of MRONJ to find out the willingness of dentists treating osteoporosis patients for teleconsultation. Methods: An online questionnaire-based survey was conducted to investigate the intention for teleconsultation for MRONJ with a total of 516 dentists between September and October 2021. Results: Two-thirds of the respondents had experience of requesting consultation other dentists or doctors for the osteoporosis or MRONJ patients. They answered that the referral letter was the most used consultation request method and that it took a long time to get a reply. As for the intention of teleconsultation, 70% of the respondents answered that they were willing. The more experienced or the higher the educational level, the higher the intention for teleconsultation. Although the intention of dentists for teleconsultation was high, satisfaction with the cost of teleconsultation was low. Discussion: Although dentists' intention to use teleconsultation was high, satisfaction with the cost of medical care for teleconsultation was low, so it seems that this should be coordinated.

Assessment of subjective and objective masticatory function among elderly individuals with mild cognitive impairment.

BACKGROUND: Masticatory function is known to be related to cognitive ability; therefore, factors for improving masticatory function should be identified. AIMS: This study aimed to identify factors influencing masticatory function associated with mild cognitive impairment (MCI) in elderly individuals. METHODS: A total of 123 elderly participants [mean age: 76.5 ± 6.5 years; 82 females (66.7%), 41 males (33.3%)] were included. Cognitive function was evaluated by the Korean version of the Mini-Mental State Examination (KMMSE). Questionnaires for subjective evaluation were administered, and dynamic objective masticatory function evaluations, including chewing tests and bite force measurements, were performed. Intergroup differences were evaluated by the Wilcoxon rank-sum and chi-square test, and correlations between cognitive ability and masticatory function were evaluated by multilinear logistic regression. RESULTS: The number of teeth, number of posterior teeth, bite force, masticatory ability index (MAI) and posterior support status showed significant differences between the normal (KMMSE > 23) and MCI (KMMSE ≤ 23) groups. However, only the MAI, representing dynamic masticatory performance, was significantly associated with MCI regardless of age, sex and removable prostheses. The number of teeth and posterior teeth, bite force, subjective masticatory ability and posterior occlusal support showed no significant association with MCI. DISCUSSION: These results suggested the importance of chewing function for preventing the progression of cognitive impairment. CONCLUSIONS: Considering that only the MAI was significantly associated with MCI, it is more important to improve chewing efficiency by harmonizing therapeutic prosthetics with the surrounding masticatory system than simply increasing the number of teeth to prevent or delay cognitive impairment in elderly individuals.

Qualitative focus group interview study of communication between patients, dentists and physicians for efficient osteonecrosis of the jaw practices.

OBJECTIVES: To investigate problems and the current status of existing methods of communication between patients, dentists and physicians for the prevention and treatment of medication-related osteonecrosis of the jaw (MRONJ). DESIGN: A focus group interview study with a descriptive design using qualitative content analysis of transcripts. SETTING: Secondary care in Korea. PARTICIPANTS: 3 patient groups and 4 health professional groups in a total of 32 participants including patients with osteoporosis or bone metastasis, dentists and physicians. RESULTS: This study revealed that patients lacked medical knowledge of osteoporosis drugs, whereas dentists and physicians lacked each other's expertise. All patients reported undergoing dental treatments during the osteoporosis drug treatment, but dentists and physicians had different MRONJ experiences depending on their work setting in primary or secondary care. Patients expressed dissatisfaction with the current system of communication with health professionals via letter as they found this to be a slow process. Dentists and physicians reported the need for effective communication because they felt defensive when sending and receiving medical consults. CONCLUSIONS: Despite the low incidence of MRONJ among patients with osteoporosis, it is difficult to treat; thus, it is necessary to inform dentists, physicians and patients about the importance of MRONJ prevention. To this end, close communication among all involved stakeholders about osteoporosis drugs is required.

Access opening guide produced using a 3D printer (AOG-3DP) as an effective tool in difficult cases for dental students.

OBJECTIVES: The aim of this study was to determine the effectiveness of using an access opening guide in teaching ideal access opening shape and preventing excessive tooth loss, with a focus on predoctoral dental students. METHODS: Ninety teeth that were mounted in a box just below the level of the cementoenamel junction using tray resin were randomly divided into two study groups. An access opening guide produced using a 3D printer (AOG-3DP) was designed using cone-beam computed tomography (CBCT). The AOG-3DP was applied in the test groups, while no aid was used in the control group. Access preparations in both groups performed by predoctoral dental students were scanned using CBCT to detect overpreparation. The preparation time and access cavity volume were evaluated. RESULTS: The mean times required for achieving access opening were 327.2 and 97.4 s in the control and AOG-3DP groups, respectively, for premolars, and 547.4 and 104.5 s for molars. The mean volumes for premolars and molars differed from the ideal cavities by 38.1 and 72.2 mm3 , respectively, in the control group, and by -2.0 and -8.7 mm3 the AOG-3DP group. CONCLUSIONS: Using the AOG-3DP significantly reduced the access opening time for premolars and molars. However, there is a limitation in that CBCT DICOM images must be converted to stereolithographic .stl files in order to be printed via 3D technology. This requires additional preclinical treatment time for imaging and subsequent printing. It could be considered that this can be a useful method in difficult cases.

Factors affecting root migration after coronectomy of the mandibular third molar.

ABSTRACT: Nerve injury especially inferior alveolar nerve (IAN) is the one of the complications that occur when the mandibular third molar (M3) is extracted and in case of high risk patients, coronectomy might be an alternative to tooth extraction. The purpose of this retrospective study was to analyze root migration and its influencing factors at 6 months after coronectomy in both 2- and 3-dimensions using periapical view and cone-beam computed tomography (CBCT). We analyzed 33 cases of root remnant after coronectomy and measured the amount of migration in CBCT. The following factors that could possibly affect root migration were also analyzed: age, gender, number of M3 roots, shape of M3s, Pell, and Gregory classification, mesiodistal (MD) angulation, buccolingual (BL) angulation, contact point with the second molar, root curvature, and complete removal of the coronal portion. Migration of greater than 2 mm was found in 64% of the roots in the 2-dimensional (2D) analysis, and the average root migration was 4.11 mm in the 3-dimensional (3D) analysis. The factors affecting migration were the root morphology, complete removal of the coronal portion, impaction depth, and MD angulation in the 2D analysis, and MD and BL angulation in the 3D analysis. Ensuring sufficient space for root migration especially considering angulation, depth and complete removal of the coronal portion might be important factors after coronectomy of the M3. Root remnant after coronectomy of M3 may migrate in young patients who has sufficient empty coronal space and this may reduce the nerve damage by the separation of IAN and M3.

Body donation trends in Yonsei University: a statistical analysis of donor records.

Body donation trends in Korea have changed significantly over the last 3 decades. Establishing a body donation system will promote donations to universities for academic purposes. Yonsei University College of Medicine started its own body donation system in 1992, including documenting donors' records. However, there has been no reported attempt to analyze the trend of these records, which could provide noteworthy information that can be interpreted for medical advances. This study performed a statistical analysis of the donors' records between 1992 and 2019 to analyze the sociological and anthropological changes. Donor personal information such as sex, age, religion, and place and cause of death were extracted from the Yonsei University College of Medicine database. Our statistical analysis revealed significant correlations between donors' records and the changes in the number of geriatric hospitals, religious beliefs, number of donations, and donor age.

Importance of oral health and dental treatment in organ transplant recipients.

OBJECTIVES: The purpose of the present study was to investigate which peri-transplant dental treatments were deemed necessary, and to determine retrospectively how often these treatments were actually performed, in patients who had received organ transplants. MATERIALS AND METHODS: Medical records of the Department of Advanced General Dentistry at Yonsei University Dental Hospital were searched to identify liver or kidney transplant recipients who attended from 1st March 2014 to 31st December 2017. A total of 418 patients were identified, and their medical charts were reviewed. Sex, underlying systemic disease, oral hygiene status, dental treatment deemed necessary, dental treatment actually performed and durations of follow-up were tabulated. RESULTS: More than half (53.8%) of the liver transplant recipients had poor oral hygiene, and poor oral hygiene was statistically significantly more prevalent in the liver transplant group than in the kidney transplant group (40.3%). In liver recipients in whom scaling was deemed to be required pre-transplant, the rate of it actually being performed pre-transplant was high (83.2%). By contrast, the rates of tooth extraction and prosthetic treatment actually being performed pre-transplant were low (12.8% and 0%, respectively). In kidney recipients, the rates of scaling, tooth extraction and prosthetic treatment actually performed pre-transplant, when deemed to be required, were 93.5%, 10.0% and 0.0%, respectively. CONCLUSIONS: We recommend that patients scheduled to receive an organ transplant be referred to a dental clinic as soon as possible beforehand, to remove any potential sources of oral infection. Educating physicians, as well as their patients, about the importance of early dental screening and pre-transplant dental treatment is essential.

Importance of Photography Education to Improve Image Quality for Accurate Remote Diagnoses in Dental Trauma Patients: Observational Study.

BACKGROUND: High-quality photos are critical for the remote diagnosis of dental trauma and thus are beneficial to the prognosis. The quality of the images obtained using a cell phone depends on the level of dental and photography knowledge of the person who is taking the photos. OBJECTIVE: This study aimed to determine the efficacy of photography education in improving images used for the remote diagnosis of dental trauma. METHODS: The subjects comprised 30 laypeople and 30 dentists who were randomly assigned to 15 subgroups with 2 subjects in each. Each subject was asked to take photos of their own anterior teeth and those of their partner on the assumption that an accident occurred using both an iPhone 4s and iPhone 6. Education about how to take an appropriate photo of the anterior teeth for teleconsultation purposes was then provided, after which photos were taken again. Photos were assessed by a dentist for their usefulness in diagnosis. RESULTS: This study analyzed 965 photos: 441 taken by laypeople and 524 taken by dentists. Photos taken after providing education had significantly higher scores for all assessment items than those taken before education (P<.05). The scores were also significantly higher for photos taken using the rear camera than those taken using the front camera (P<.02). The iPhone 6 did not have overwhelming advantages. The photos taken by dentists had significantly higher scores than those taken by laypeople for most of the evaluated items. CONCLUSIONS: Both laypeople and dentists might find photography education useful for when they are taking photos to be used in teleconsultations. The type of cell phone does not significantly affect the usefulness of such photos.

FOXO1 Suppression is a Determinant of Acquired Lapatinib-Resistance in HER2-Positive Gastric Cancer Cells Through MET Upregulation.

PURPOSE: Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells. MATERIALS AND METHODS: Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription-polymerase chain reaction were performed. RESULTS: SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin. CONCLUSION: FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.

FOXO1 reduces tumorsphere formation capacity and has crosstalk with LGR5 signaling in gastric cancer cells.

Gastric cancer (GC) is a major of cause of cancer-related death and is characterized by its heterogeneity and molecular complexity. FOXO1 is a transcription factor that plays a key role in GC growth and metastasis. However, the implication of FOXO1 in GC cell stemness has been elusive. This study, for the first time, demonstrates that FOXO1 regulates GC cell stemness in association with LGR5. FOXO1 expression was significantly lower in GC tumorsphere cells than in adherent GC cells. FOXO1 silencing and overexpression promoted and inhibited the tumorsphere formation capacity of GC cells, respectively. Additionally, there was an inverse correlation between FOXO1 and GC stem cell marker LGR5 in human GC specimens. Further in vitro and in vivo experiments showed that negative crosstalk between these two molecules exists and that LGR5 silencing reversed the FOXO1 shRNA-induced tumorsphere formation even without FOXO1 restoration. Taken together, our results suggest that FOXO1 inhibits the self-renewal capacity of GC cells through interaction with LGR5. Thus, FOXO1/LGR5 signaling pathway may provide a novel targeted therapy for GC.

HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer.

AIM: To investigated the relationships between HER2, c-Jun N-terminal kinase (JNK) and protein kinase B (AKT) with respect to metastatic potential of HER2-positive gastric cancer (GC) cells. METHODS: Immunohistochemistry was performed on tissue array slides containing 423 human GC specimens. Using HER2-positve GC cell lines SNU-216 and NCI-N87, HER2 expression was silenced by RNA interference, and the activations of JNK and AKT were suppressed by SP600125 and LY294002, respectively. Transwell assay, Western blot, semi-quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining were used in cell culture experiments. RESULTS: In GC specimens, HER2, JNK, and AKT activations were positively correlated with each other. In vitro analysis revealed a positive regulatory feedback loop between HER2 and JNK in GC cell lines and the role of JNK as a downstream effector of AKT in the HER2/AKT signaling pathway. JNK inhibition suppressed migratory capacity through reversing EMT and dual inhibition of JNK and AKT induced a more profound effect on cancer cell motility. CONCLUSION: HER2, JNK and AKT in human GC specimens are positively associated with each other. JNK and AKT, downstream effectors of HER2, co-operatively contribute to the metastatic potential of HER2-positive GC cells. Thus, targeting of these two molecules in combination with HER2 downregulation may be a good approach to combat HER2-positive GC.

Hypoxic inactivation of glycogen synthase kinase-3ß promotes gastric tumor growth and angiogenesis by facilitating hypoxia-inducible factor-1 signaling.

Since the molecular mechanism of hypoxic adaptation in cancer cells is cell-type specific, we investigated whether glycogen synthase kinase-3ß (GSK-3ß) activation is involved in hypoxia-induced gastric tumor promotion. Stable gastric cancer cell lines (SNU-638, SNU-484, MKN1, and MKN45) were cultured under hypoxic conditions. Cells overexpressing wild-type GSK-3ß (WT-GSK-3ß) or kinase-dead mutant of GSK-3ß (KD-GSK-3ß) were generated and used for cell culture and animal studies. In cell culture experiments, hypoxia decreased GSK-3ß activation in gastric cancer cells. Cell viability and the expressions of HIF-1α protein and VEGF mRNA in gastric cancer cells were higher in KD-GSK-3ß transfectants than in WT-GSK-3ß transfectants under hypoxic conditions, but not under normoxic conditions. Gastric cancer xenografts showed that tumor growth, microvessel area, HIF-1α activation, and VEGF expression were higher in KD-GSK-3ß tumors than in WT-GSK-3ß tumors in vivo. In addition, the expression of hypoxia-induced HIF-1α protein was regulated by GSK-3ß at the translational level. Our data suggest that GSK-3ß is involved in hypoxic adaptation of gastric cancer cells as an inhibitory upstream regulator of the HIF-1α/VEGF signaling pathway.

c-Jun N-terminal kinase activation has a prognostic implication and is negatively associated with FOXO1 activation in gastric cancer.

BACKGROUND: Since the biological function of c-Jun N-terminal kinase (JNK) in gastric cancer remains unclear, we investigated the clinical significance of JNK activation and its association with FOXO1 activation. METHODS: Immunohistochemical tissue array analysis of 483 human gastric cancer specimens was performed, and the results of the immunostaining were quantified. The correlation between JNK activation (nuclear staining for pJNK) and clinicopathological features, the proliferation index, prognosis or FOXO1 inactivation (cytoplasmic staining for pFOXO1) was analyzed. The SNU-638 gastric cancer cell line was used for in vitro analysis. RESULTS: Nuclear staining of pJNK was found in 38 % of the gastric carcinomas and was higher in the early stages of pTNM (P < 0.001). pJNK staining negatively correlated with lymphatic invasion (P = 0.034) and positively correlated with intestinal type by Lauren's classification (P = 0.037), Ki-67-labeling index (P < 0.001), cyclin D1 (P = 0.045), cyclin E (P < 0.001) and pFOXO1 (P < 0.001). JNK activation correlated with a longer patients survival (P =0.008) and patients with a JNK-active and FOXO1-inactive tumor had a higher survival rate than the remainder of the population (P = 0.004). In vitro analysis showed that JNK inhibition by SP600125 in SNU-638 cells decreased cyclin D1 protein expression and increased FOXO1 activation. Further, JNK inhibition markedly suppressed colony formation, which was partially restored by FOXO1 shRNA expression. CONCLUSIONS: Our results indicate that JNK activation may serve as a valuable prognostic factor in gastric cancer, and that it is implicated in gastric tumorigenesis, at least in part, through FOXO1 inhibition.

Forkhead Transcription Factor FOXO1 Inhibits Angiogenesis in Gastric Cancer in Relation to SIRT1.

PURPOSE: We previously reported that forkhead transcription factors of the O class 1 (FOXO1) expression in gastric cancer (GC) was associated with angiogenesis-related molecules. However, there is little experimental evidence for the direct role of FOXO1 in GC. In the present study, we investigated the effect of FOXO1 on the tumorigenesis and angiogenesis in GC and its relationship with SIRT1. MATERIALS AND METHODS: Stable GC cell lines (SNU-638 and SNU-601) infected with a lentivirus containing FOXO1 shRNA were established for animal studies as well as cell culture experiments. We used xenograft tumors in nude mice to evaluate the effect of FOXO1 silencing on tumor growth and angiogenesis. In addition, we examined the association between FOXO1 and SIRT1 by immunohistochemical tissue array analysis of 471 human GC specimens and Western blot analysis of xenografted tumor tissues. RESULTS: In cell culture, FOXO1 silencing enhanced hypoxia inducible factor-1α (HIF-1α) expression and GC cell growth under hypoxic conditions, but not under normoxic conditions. The xenograft study showed that FOXO1 downregulation enhanced tumor growth, microvessel areas, HIF-1α activation and vascular endothelial growth factor (VEGF) expression. In addition, inactivated FOXO1 expression was associated with SIRT1 expression in human GC tissues and xenograft tumor tissues. CONCLUSION: Our results indicate that FOXO1 inhibits GC growth and angiogenesis under hypoxic conditions via inactivation of the HIF-1α-VEGF pathway, possibly in association with SIRT1. Thus, development of treatment modalities aiming at this pathway might be useful for treating GC.

Signal transducers and activators of transcription 3-induced metastatic potential in gastric cancer cells is enhanced by glycogen synthase kinase-3ß.

The transcription factor signal transducers and activators of transcription 3 (STAT3) can promote cancer metastasis, but its underlying regulatory mechanisms in gastric cancer cell invasiveness still remain obscure. We investigated the relationship between STAT3 and glycogen synthase kinase-3ß (GSK-3ß) and its significance in metastatic potential in gastric cancer cells. Immunohistochemical tissue array analysis of 267 human gastric carcinoma specimens showed that the expressions of active forms of STAT3 (pSTAT3) and GSK-3ß (pGSK-3ß) were found in 68 (25%) and 124 (46%) of 267 gastric cancer cases, respectively, showing a positive correlation (p < 0.001). Cell culture experiments using gastric cancer cell lines SNU-638 and SNU-668 revealed that STAT3 suppression did not affect pGSK-3ß expression, whereas GSK-3ß inhibition reduced pSTAT3 expression. With respect to metastatic potential in gastric cancer cells, both STAT3 suppression and GSK-3ß inhibition decreased cell migration, invasion, and mesenchymal marker (Snail, Vimentin, and MMP9) expression. Moreover, the inhibitory effects of STAT3 and GSK-3ß on cell migration were synergistic. These results demonstrated that STAT3 and GSK-3ß are positively associated and synergistically contribute to metastatic potential in gastric cancer cells. Thus, dual use of STAT3 and GSK-3ß inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.