SIRT1 Mediates the Antagonism of Wnt/ß-Catenin Pathway by Vitamin D in Colon Carcinoma Cells.

Cancer initiation and progression result from genetic and epigenetic alterations caused by interactions between environmental and endogenous factors leading to aberrant cell signalling. Colorectal cancers (CRC) are linked to abnormal activation of the Wnt/ß-catenin pathway, whose key feature is the nuclear accumulation of acetylated ß-catenin in colon epithelial cells. Nuclear ß-catenin acts as a transcriptional co-activator, targeting genes involved in cell proliferation and invasion. 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3 or calcitriol), the active form of vitamin D, antagonizes Wnt/ß-catenin over-activation by engaging its high affinity receptor, VDR. Here we unveil that 1,25(OH)2D3-bound VDR activates Silent Information Regulator of Transcription, sirtuin 1 (SIRT1), leading to ß-catenin deacetylation and nuclear exclusion, downregulation of its pro-tumourigenic target genes and inhibition of human colon carcinoma cell proliferation. Notably, orthogonal SIRT1 activation mimics nuclear exclusion of ß-catenin while SIRT1 inhibition blocks the effects of 1,25(OH)2D3. Thus, SIRT1 emerges as a crucial mediator in the protective action of vitamin D against CRC. The mutual negative feedback loop unveiled here between Wnt and SIRT1 represents an important surrogate target in CRC. Since nuclear localisation of ß-catenin is a critical driver of CRC that requires its acetylation, we provide a mechanistic foundation for the epidemiological evidence linking vitamin D deficiency and increased CRC risk and mortality.

[Times and conditions of storage of samples in anatomic pathology. Recommendations of the Spanish Society of Anatomic Pathology (SEAP) part 1: samples for diagnosis]. / Tiempos y condiciones de almacenamiento de las muestras en anatomía patológica. Recomendaciones de la Sociedad Española de Anatomía Patológica parte 1: muestras destinadas al diagnóstico.

INTRODUCTION: The correct storage of specimens in the Pathology service is of vital importance for patient safety. However, there are no clear recommendations as regarding how long samples should be stored for a minimum period. MATERIAL AND METHODS: A working group of the Spanish Society of Anatomic Pathology has reviewed a series of recommendations established in the literature and after two rounds of consultations and a discussion and voting phase has established a series of storage time proposals. RESULTS: Each of the proposals is presented with the data found in the literature and sometimes offers definitions and exceptions to the proposal. CONCLUSION: These recommendations, which are minimums, establish a period of at least 10 years for paraffin embedded blocks (including cell blocks), histological preparations, general cytology, pathologic cervico-vaginal cytology and electron microscopy blocks; at least 3 years for cervico-vaginal cytology, 5 years for extracted nucleic acids, at least 4 weeks for tissue in formalin and from the time of diagnosis for liquid cytology material and fluids.

In-Depth Proteomic Analysis of Paraffin-Embedded Tissue Samples from Colorectal Cancer Patients Revealed TXNDC17 and SLC8A1 as Key Proteins Associated with the Disease.

A deeper understanding of colorectal cancer (CRC) biology would help to identify specific early diagnostic markers. Here, we conducted quantitative proteomics on FFPE healthy, adenoma, and adenocarcinoma tissue samples from six stage I sporadic CRC patients to identify dysregulated proteins during early CRC development. Two independent quantitative 10-plex TMT experiments were separately performed. After protein extraction, trypsin digestion, and labeling, proteins were identified and quantified by using a Q Exactive mass spectrometer. A total of 2681 proteins were identified and quantified after data analysis and bioinformatics with MaxQuant and the R program. Among them, 284 and 280 proteins showed significant upregulation and downregulation (expression ratio ≥1.5 or ≤0.67, p-value ≤0.05), respectively, in adenoma and/or adenocarcinoma compared to healthy tissue. Ten dysregulated proteins were selected to study their role in CRC by WB, IHC, TMA, and ELISA using tissue and plasma samples from CRC patients, individuals with premalignant colorectal lesions (adenomas), and healthy individuals. In vitro loss-of-function cell-based assays and in vivo experiments using three CRC cell lines with different metastatic properties assessed the important roles of SLC8A1 and TXNDC17 in CRC and liver metastasis. Additionally, SLC8A1 and TXNDC17 protein levels in plasma possessed the diagnostic ability of early CRC stages.

Use of Chemoimmunotherapy for Locally Advanced Deficient Mismatch Repair (dMMR) Gastric Adenocarcinoma With Curative Intent: A Case Report.

The standard of care for patients with operable gastric adenocarcinoma is perioperative chemotherapy and surgical resection. The deficient mismatch repair (dMMR)/microsatellite instability (MSI-H) phenotype is a major predictive biomarker for immune checkpoint inhibitors (ICIs) efficacy in advanced disease. Several phase II and III trials suggest a promising future role of immunotherapy with or without chemotherapy in the neoadjuvant/adjuvant setting, especially in MSI-H localized gastric adenocarcinomas. We present a 38-year-old man diagnosed in March 2022 with poorly differentiated gastric adenocarcinoma clinical stage III (cT4 N0 M0) with deficiency of MLH1 and PMS2, combined positive score (CPS) of 100 and negative HER2 immunohistochemistry, had poor tumor response to preoperative 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT). It was considered unresectable because of the involvement of the colon, mesocolon, duodenum, pancreas, and retroperitoneum. Then, first-line systemic treatment with 5-FU, leucovorin, and oxaliplatin (FOLFOX)-nivolumab was initiated in August 2022, with a significant radiologic tumor reduction after six cycles, allowing a curative surgery in March 2023 with complete pathologic tumor response, followed by capecitabine and nivolumab for one year, maintaining radiological remission in the last follow-up in April 2024. With this case report, we conclude that it is likely that chemoimmunotherapy or immunotherapy alone may be alternative neoadjuvant treatment choices for MSI-H locally advanced gastric cancer patients.

Prognostic Influence of Galectin-1 in Gastric Adenocarcinoma.

Galectin-1 (Gal-1), a member of the human lectin family, has garnered attention for its association with aggressive behavior in human tumors, prompting research into the development of targeted drugs. This study aims to assess the staining pattern and prognostic significance of Gal-1 immunohistochemical expression in a homogeneous cohort of Western patients with gastric cancer (GC). A total of 149 cases were included and tissue microarrays were constructed. Stromal Gal-1 expression was observed to some extent in most tumors, displaying a cytoplasmic pattern. Cases with stromal Gal-1 overexpression showed significantly more necrosis, lymphovascular invasion, advanced pTNM stages, recurrences, and cancer-related deaths. Epithelial Gal-1 expression was present in 63.8% of the cases, primarily exhibiting a cytoplasmic pattern, and its overexpression was significantly associated with lymphovascular invasion, peritumoral lymphocytic infiltration, and tumor-related death. Kaplan/Meier curves for cancer-specific survival (CSS) revealed a significantly worse prognosis for patients with tumors exhibiting stromal or epithelial Gal-1 overexpression. Furthermore, stromal Gal-1 expression stratified stage III patients into distinct prognostic subgroups. In a multivariable analysis, increased stromal Gal-1 expression emerged as an independent prognostic factor for CSS. These findings underscore the prognostic relevance of Gal-1 and suggest its potential as a target for drug development in Western patients with GC.

Hereditary Gastrointestinal Tumor Syndromes: When Risk Comes with Your Genes.

Despite recent campaigns for screening and the latest advances in cancer therapy and molecular biology, gastrointestinal (GI) neoplasms remain among the most frequent and lethal human tumors. Most GI neoplasms are sporadic, but there are some well-known familial syndromes associated with a significant risk of developing both benign and malignant GI tumors. Although some of these entities were described more than a century ago based on clinical grounds, the increasing molecular information obtained with high-throughput techniques has shed light on the pathogenesis of several of them. The vast amount of information gained from next-generation sequencing has led to the identification of some high-risk genetic variants, although others remain to be discovered. The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants. Herein, we aim to summarize the most relevant hereditary cancer syndromes involving the stomach and colon, with an emphasis on new molecular findings, novel entities, and recent changes in the management of these patients.

Cannabidiol decreases histological intestinal injury in a neonatal experimental model of necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is a severe inflammatory bowel disease in neonates. Our group has developed an experimental model of NEC, with an effectiveness of 73%. Cannabidiol (CBD) is an innovative treatment for neonatal cerebral hypoxic-ischemic pathologies due to its neuroprotective effect, as a potent anti-inflammatory and reducing oxidative stress substance. Our aim was to evaluate the effect of CBD on intestinal lesions in an experimental model of NEC. RESULTS: Mortality and intestinal histological damage was significantly lower in the CBD group compared to the rest (p<0.05), establishing CBD as a protective factor against the development of NEC (OR=0.0255; 95% CI=0.0015-0.4460). At IHQ level (TUNEL technique), a lower cell death rate was also observed in the CBD group compared to the VEH group (p<0.05). CONCLUSIONS: In our experimental model, intraperitoneal CBD acts as a protective factor against NEC, resulting in less histological damage and a lower rate of intestinal cell death.

Molecular Classifications in Gastric Cancer: A Call for Interdisciplinary Collaboration.

Gastric cancer (GC) is a heterogeneous disease, often diagnosed at advanced stages, with a 5-year survival rate of approximately 20%. Despite notable technological advancements in cancer research over the past decades, their impact on GC management and outcomes has been limited. Numerous molecular alterations have been identified in GC, leading to various molecular classifications, such as those developed by The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG). Other authors have proposed alternative perspectives, including immune, proteomic, or epigenetic-based classifications. However, molecular stratification has not yet transitioned into clinical practice for GC, and little attention has been paid to alternative molecular classifications. In this review, we explore diverse molecular classifications in GC from a practical point of view, emphasizing their relationships with clinicopathological factors, prognosis, and therapeutic approaches. We have focused on classifications beyond those of TCGA and the ACRG, which have been less extensively reviewed previously. Additionally, we discuss the challenges that must be overcome to ensure their impact on patient treatment and prognosis. This review aims to serve as a practical framework to understand the molecular landscape of GC, facilitate the development of consensus molecular categories, and guide the design of innovative molecular studies in the field.

Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest.

In pancreatic ductal adenocarcinoma (PDAC), metabolic rewiring and resistance to standard therapy are closely associated. PDAC cells show enormous requirements for glucose-derived citrate, the first rate-limiting metabolite in the synthesis of new lipids. Both the expression and activity of citrate synthase (CS) are extraordinarily upregulated in PDAC. However, no previous relationship between gemcitabine response and citrate metabolism has been documented in pancreatic cancer. Here, we report for the first time that pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose-derived citrate levels. Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression. Lowered citrate availability was found to be directly associated with diminished proliferation and, remarkably, enhanced gemcitabine response. Moreover, the deregulated citrate-derived lipogenic pathway correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism. Modulation of citric acid metabolism in highly chemoresistant pancreatic adenocarcinoma, through molecules such as vitamin C, could be considered as a future clinical option to improve patient response to standard chemotherapy regimens.

Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells.

BACKGROUND: Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA's role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer. METHODS: We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features. RESULTS: The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype. CONCLUSIONS: AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.

A complex of cadherin 17 with desmocollin 1 and p120-catenin regulates colorectal cancer migration and invasion according to the cell phenotype.

BACKGROUND: Cadherin-17 (CDH17), a marker of differentiation in intestinal cells, binds and activates α2ß1 integrin to promote cell adhesion and proliferation in colorectal cancer (CRC) metastasis. Furthermore, CDH17 associates with p120- and ß-catenin in a manner yet to be fully elucidated. In this report, we explored the molecular mediators involved in this association, their contribution to CRC dissemination and potential therapeutic implications. METHODS: Proteomic and confocal analyses were employed to identify and validate CDH17 interactors. Functional characterization involved the study of proliferation, migration, and invasion in cell lines representative of various phenotypes. Immunohistochemistry was conducted on CRC tissue microarrays (TMA). In vivo animal experiments were carried out for metastatic studies. RESULTS: We found that desmocollin-1 (DSC1), a desmosomal cadherin, interacts with CDH17 via its extracellular domain. DSC1 depletion led to increased or decreased invasion in CRC cells displaying epithelial or mesenchymal phenotype, respectively, in a process mediated by the association with p120-catenin. Down-regulation of DSC1 resulted in an increased expression of p120-catenin isoform 1 in epithelial cells or a shift in cellular location in mesenchymal cells. Opposite results were observed after forced expression of CDH17. DSC1 is highly expressed in budding cells at the leading edge of the tumor and associates with poor prognosis in the stem-like, mesenchymal CRC subtypes, while correlates with a more favorable prognosis in the less-aggressive subtypes. In vivo experiments demonstrated that DSC1 silencing reduced tumor growth, liver homing, and metastasis in CRC mesenchymal cells. Furthermore, a synthetic peptide derived from CDH17, containing the NLV motif, effectively inhibited invasion and liver homing in vivo, opening up new possibilities for the development of novel therapies focused on desmosomal cadherins. CONCLUSIONS: These findings shed light on the multifaceted roles of CDH17, DSC1, and p120-catenin in CRC metastasis, offering insights into potential therapeutic interventions for targeting desmosomal cadherins in poorly-differentiated carcinomas.

Gastric metaplasia as a precursor of nonconventional dysplasia in inflammatory bowel disease.

Gastric metaplasia in colonic mucosa with inflammatory bowel disease (IBD) develops as an adaptation mechanism. The association between gastric metaplasia and nonconventional and/or conventional dysplasia as precursors of colitis-associated colorectal cancer is unknown. To address this question, we retrospectively reviewed a series of 33 IBD colectomies to identify gastric metaplasia in 76 precursor lesions. We obtained 61 nonconventional and 15 conventional dysplasias. Among nonconventional dysplasia, 31 (50.8 %) were low-grade (LGD), 4 (6.5 %) were high-grade (HGD), 9 (14.8 %) had both LGD and HGD, and 17 (27.9 %) had no dysplasia (ND), while 14 (93 %) conventional dysplasias had LGD, and 1 (7 %) had LGD and HGD. Gastric metaplasia was assessed by concomitant immunoexpression of MUC5AC and loss of CDX2 staining. Expression of a p53-mut pattern was considered as a surrogate for gene mutation, and complete loss of MLH1 staining as presence of MLH1 hypermethylation. In nonconventional dysplasia, MUC5AC immunoexpression decreased as the degree of dysplasia increased, being 78 % in LGD and 39 % in HGD (p = 0.006). CDX2 was lost in epithelial glands with high expression of MUC5AC (p < 0.001). The p53-mut pattern was observed in 77 % HGD, 45 % LGD, and in 6 % with ND (p < 0.001). Neither nonconventional nor conventional dysplasia showed complete loss of MLH1 staining. Gastric metaplasia was also present in mucosa adjacent to nonconventional dysplasia with chronic changes or active inflammation. Our results show that gastric metaplasia appears in IBD-inflamed colon mucosa, it is the substrate of most nonconventional dysplasia and occurs prior to p53 alterations.

Prognostic role of the log odds of positive lymph nodes in Western patients with resected gastric cancer: A comparison with the 8th edition of the TNM staging system.

OBJECTIVES: Several alternative lymph node staging systems have recently been described for gastric cancer. The log odds of positive lymph nodes (LODDS) system may be superior to the pN stage (American Joint Committee on Cancer) and lymph node ratio systems in predicting outcomes for patients with gastric cancers, as indicated by some researchers. Most studies, however, have been conducted in Asian countries, and conflicting results have been reported by other investigators. METHODS: We conducted a retrospective study of all 377 cases of gastric cancer resected at a tertiary hospital in Spain between 2000 and 2019. Clinicopathologic features were collected, LODDS were calculated and categorized into 5 groups (S1-S5), and statistical analysis was performed. RESULTS: The cases included (n = 315) were classified as S1 (25.6%), S2 (18.4%), S3 (21.3%), S4 (20.3%), and S5 (14.4%). The LODDS classification was significantly associated with tumor size, Laurén subtype, presence of signet ring cells, tumor grade, perineural infiltration, lymphovascular invasion, growth pattern, pT, tumor recurrence, and death. Kaplan-Meier analysis based on the LODDS classification demonstrated improved patient stratification compared with the pN stage for both overall survival (OS) and disease-free survival (DFS). Area under the curve values for recurrence and death were superior for the LODDS classification, and this classification was independently related to OS and DFS. In addition, the LODDS classification successfully divided patients without lymph node metastases (pN0) into subgroups with distinct prognoses. CONCLUSIONS: For our cohort, the LODDS system showed better prognostic performance than pN stage; it was an independent predictor of OS and DFS, and it provided valuable prognostic information in cases without lymph node metastases. Its prognostic accuracy, however, decreased in cases with fewer than 16 lymph nodes resected.

Functional Proteomics Characterization of the Role of SPRYD7 in Colorectal Cancer Progression and Metastasis.

SPRY domain-containing protein 7 (SPRYD7) is a barely known protein identified via spatial proteomics as being upregulated in highly metastatic-to-liver KM12SM colorectal cancer (CRC) cells in comparison to its isogenic poorly metastatic KM12C CRC cells. Here, we aimed to analyze SPRYD7's role in CRC via functional proteomics. Through immunohistochemistry, the overexpression of SPRYD7 was observed to be associated with the poor survival of CRC patients and with an aggressive and metastatic phenotype. Stable SPRYD7 overexpression was performed in KM12C and SW480 poorly metastatic CRC cells and in their isogenic highly metastatic-to-liver-KM12SM-and-to-lymph-nodes SW620 CRC cells, respectively. Upon upregulation of SPRYD7, in vitro and in vivo functional assays confirmed a key role of SPRYD7 in the invasion and migration of CRC cells and in liver homing and tumor growth. Additionally, transient siRNA SPRYD7 silencing allowed us to confirm in vitro functional results. Furthermore, SPRYD7 was observed as an inductor of angiogenesis. In addition, the dysregulated SPRYD7-associated proteome and SPRYD7 interactors were elucidated via 10-plex TMT quantitative proteins, immunoproteomics, and bioinformatics. After WB validation, the biological pathways associated with the stable overexpression of SPRYD7 were visualized. In conclusion, it was demonstrated here that SPRYD7 is a novel protein associated with CRC progression and metastasis. Thus, SPRYD7 and its interactors might be of relevance in identifying novel therapeutic targets for advanced CRC.

DLL3 Is a Prognostic and Potentially Predictive Biomarker for Immunotherapy Linked to PD/PD-L Axis and NOTCH1 in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm with very poor patient survival outcomes despite available treatments. There is an urgent need for new potential treatment options and novel biomarkers for these patients. Delta-like canonical Notch ligand 3 (DLL3) interacts with the Notch receptor and causes inhibition of Notch signaling, which confers a survival advantage to PDAC cells. Thus, DLL3 expression could affect cell survival, and its inhibition could increase a patient's survival. To test this hypothesis, a survival analysis was conducted using the progression-free and overall survival from two independent datasets of PDAC patients, with one using mRNA z-score levels and the other using the Hscore protein expression level; both were carried out using a log-rank test and plotted using Kaplan-Meier curves. DLL3 at the mRNA expression level showed an association between high mRNA expression and both a longer progression-free survival (PFS) and overall survival (OS) of patients. Then, we designed a retrospective study with resected PDAC samples. Our primary objective with this dataset was to assess the relationship between PFS and OS and DLL3 protein expression. The secondary assessment was to provide a rationale for the use of anti-DLL3-based treatments in combination with immunotherapy that is supported by the link between DLL3 and other factors that are involved in immune checkpoints. The survival analyses revealed a protective effect of high DLL3 protein expression levels in both PFS and OS. Interestingly, high DLL3 protein expression levels were significantly correlated with PD-L1/2 and negatively correlated with NOTCH1. Therefore, DLL3 could be considered a biomarker for better prognosis in resectable PDAC patients as well as a therapeutic biomarker for immunotherapy response. These facts set a rationale for testing anti-DLL3-based treatments either alone or combined with immunotherapy or other NOTCH1 inhibitors.

Diagnostic clues for hyalinizing trabecular tumor on fine needle aspiration cytology.

Objectives: The hyalinizing trabecular tumor (HTT) is a rare benign neoplasm of the thyroid gland. This neoplasm has overlapping cytological features with Papillary Thyroid Carcinoma, Medullary Carcinoma and Follicular Neoplasm with Nuclear Features of Papillary Carcinoma. This can lead to misdiagnosis of malignancy in fine needle aspiration (FNA) cytology specimens with unnecessary total thyroidectomy. The aim of this study is to determine if there are some cytological features that could help us to suspect HTT on FNA specimens and avoid radical surgery. Material and Methods: With this purpose we have collected 6 cases diagnosed of HTT in Hospital Clínico San Carlos of Madrid (Spain) in the last 10 years and reviewed the cytological specimens. Result: We conclude that the presence of hyaline material in FNA specimens of HTT is a constant feature being a diagnostic clue. We must be cautious not to confuse it with dense colloid or amyloid material, the latter seen in Medullary Carcinoma. Papillary architecture and fibrovascular cores are not present in a HTT. Special stains as ki-67, calcitonin and Congo Red staining could help us in achieving the correct diagnosis. Conclusion: We feel the cytopathologists must be aware of the distinguishing features of this lesion, mainly the typical hyaline material to achieve a proper diagnosis and be able to reduce unnecessary aggressive management of these patients.

Impact of Age at Diagnosis on Clinicopathological Features, Prognosis, and Management of Gastric Cancer: A Retrospective Single-Center Experience from Spain.

The impact of age on various aspects of gastric cancer (GC) remains controversial. Clarifying this issue can improve our understanding of the disease, refine risk stratification models, and aid in personalized therapeutic approaches. This study aimed to evaluate the influence of age at diagnosis on the clinicopathological features, prognosis, and management of a specific cohort of Spanish patients with resected GC. The study encompassed 315 patients treated at a single tertiary hospital in Spain, divided into two age-based subgroups: ≤65 years and >65 years. The mean and median ages at diagnosis were 72 and 76 years. Most tumors were diagnosed at pT3 stage (49.2%), and 59.6% of patients had lymph node metastases. 21.3% of cases were diagnosed with GC at age ≤ 65 years. Younger patients showed a significantly higher prevalence of flat, diffuse, high-grade tumors, signet-ring cells, perineural infiltration, D2 lymphadenectomies, and adjuvant therapy. They also exhibited a higher rate of recurrences, but had a significantly longer follow-up. Kaplan-Meier curves indicated no significant prognostic differences based on age. Finally, age did not independently predict overall survival or disease-free survival. Our results suggest that younger patients may require more aggressive treatment due to adverse clinicopathologic features, but the lack of prognostic differences among age groups in our cohort indicates the need for further investigation into the complex interplay between age, clinicopathologic factors, and long-term outcomes in GC.

Vitamin D induces SIRT1 activation through K610 deacetylation in colon cancer.

Posttranslational modifications of epigenetic modifiers provide a flexible and timely mechanism for rapid adaptations to the dynamic environment of cancer cells. SIRT1 is an NAD+-dependent epigenetic modifier whose activity is classically associated with healthy aging and longevity, but its function in cancer is not well understood. Here, we reveal that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol), the active metabolite of vitamin D (VD), promotes SIRT1 activation through auto-deacetylation in human colon carcinoma cells, and identify lysine 610 as an essential driver of SIRT1 activity. Remarkably, our data show that the post-translational control of SIRT1 activity mediates the antiproliferative action of 1,25(OH)2D3. This effect is reproduced by the SIRT1 activator SRT1720, suggesting that SIRT1 activators may offer new therapeutic possibilities for colon cancer patients who are VD deficient or unresponsive. Moreover, this might be extrapolated to inflammation and other VD deficiency-associated and highly prevalent diseases in which SIRT1 plays a prominent role.

Anal cytology: Diagnosis of intestinal spirochaetosis.

OBJECTIVE: A case of intestinal spirochaetosis diagnosed in anal cytology is presented. METHODS: An anal liquid-based cytology was performed and stained with Papanicolau and Warthin-Starry stains. RESULTS: An apical filamentous "fringe" was identified in columnar cells groups. CONCLUSION: Anal cytology is a potential tool for intestinal spirochaetosis diagnosis.