Cervical cancer is one of the most frequent cancers in women and is associated with human papillomavirus (HPV) in 70 % of cases. Cervical cancer occurs because of progression of low-differentiated cervical intraepithelial neoplasia through grade 2 and 3 lesions. Along with the protein-coding genes, long noncoding RNAs (lncRNAs) play an important role in the development of malignant cell transformation. Although human papillomavirus is widespread, there is currently no well-characterized transcriptomic signature to predict whether this tumor will develop in the presence of HPV-associated neoplastic changes in the cervical epithelium. Changes in gene activity in tumors reflect the biological diversity of cellular phenotype and physiological functions and can be an important diagnostic marker. We performed comparative transcriptome analysis using open RNA sequencing data to assess differentially expressed genes between normal tissue, neoplastic epithelium, and cervical cancer. Raw data were preprocessed using the Galaxy platform. Batch effect correction, identification of differentially expressed genes, and gene set enrichment analysis (GSEA) were performed using R programming language packages. Subcellular localization of lncRNA was analyzed using Locate-R and iLoc-LncRNA 2.0 web services. 1,572 differentially expressed genes (DEGs) were recorded in the \"cancer vs. control\" comparison, and 1,260 DEGs were recorded in the \"cancer vs. neoplasia\" comparison. Only two genes were observed to be differentially expressed in the \"neoplasia vs. control\" comparison. The search for common genes among the most strongly differentially expressed genes among all comparison groups resulted in the identification of an expression signature consisting of the CCL20, CDKN2A, CTCFL, piR-55219, TRH, SLC27A6 and EPHA5 genes. The transcription level of the CCL20 and CDKN2A genes becomes increased at the stage of neoplastic epithelial changes and stays so in cervical cancer. Validation on an independent microarray dataset showed that the differential expression patterns of the CDKN2A and SLC27A6 genes were conserved in the respective gene expression comparisons between groups.
Рак шейки матки является одним из наиболее частых онкологических заболеваний у женщин и в 70 % случаев связан с вирусом папилломы человека (ВПЧ). Рак шейки матки развивается в результате прогрессии цервикальной интраэпителиальной неоплазии через поражения второй и третьей степени. Помимо белок-кодирующих генов, важную роль в развитии злокачественной трансформации клеток играют длинные некодирующие РНК. Хотя вирус папилломы человека широко распространен, в настоящее время нет хорошо охарактеризованных транскриптомных признаков, позволяющих предсказать злокачественную трансформацию клеток эпителия при наличии связанной с ВПЧ неоплазии эпителия шейки матки. Изменения генной активности в опухолях отражают биологическое разнообразие клеточного фенотипа и физиологических функций и могут быть важным диагностическим маркером. Используя открытые данные секвенирования РНК, мы провели сравнительный анализ транскриптома для оценки дифференциально экспрессируемых генов в образцах нормальной ткани, эпителия с диспластическими изменениями и раком шейки матки. Первичные данные были предварительно обработаны с использованием платформы Galaxy. Коррекция пакетного эффекта, идентификация дифференциально экспрессируемых генов и анализ обогащения набора генов выполнены в пакетах языка программирования R. Субклеточная локализация днРНК была проанализирована с помощью веб-сервисов Locate-R и iLoc-LncRNA 2.0. В сравнении «рак vs. контроль» зарегистрировано 1572 дифференциально экспрессируемых гена, в сравнении «рак vs. неоплазия» – 1260. Только два дифференциально экспрессируемых гена выявлено при сравнении контроля и неоплазии. Поиск общих среди наиболее сильно дифференциально экспрессируемых генов во всех группах сравнения привел к выявлению сигнатуры экспрессии, состоящей из генов CCL20, CDKN2A, CTCFL, piR-55219, TRH, SLC27A6 и EPHA5. Повышенный уровень транскрипции генов CCL20 и CDKN2A возникает на стадии неопластических изменений эпителия и сохраняется при раке шейки матки. Валидация на независимом наборе данных микрочипа показала, что паттерны дифференциальной экспрессии генов CDKN2A и SLC27A6 сохраняются в соответствующих сравнениях экспрессии генов между группами.

OBJECTIVE: To observe the therapeutic effects and underlying mechanism of baicalin against colon cancer.
METHODS: The effects of baicalin on the proliferation and growth of colon cancer cells MC38 and CT26. WT were observed and predicted potential molecular targets of baicalin for colon cancer therapy were studied by network pharmacology. Furthermore, molecular docking and drug affinity responsive target stability (DARTS) analysis were performed to confirm the interaction between potential targets and baicalin. Finally, the mechanisms predicted by in silico analyses were experimentally verified in-vitro and in-vivo.
RESULTS: Baicalin significantly inhibited proliferation, invasion, migration, and induced apoptosis in MC38 and CT26 cells (all P<0.01). Additionally, baicalin caused cell cycle arrest at the S phase, while the G0/G1 phase was detected in the tiny portion of the cells. Subsequent network pharmacology analysis identified 6 therapeutic targets associated with baicalin, which potentially affect various pathways including 39 biological processes and 99 signaling pathways. In addition, molecular docking and DARTS predicted the potential binding of baicalin with cyclin dependent kinase inhibitor 2A (CDKN2A), protein kinase B (AKT), caspase 3, and mitogen-activated protein kinase (MAPK). In vitro, the expressions of CDKN2A, MAPK, and p-AKT were suppressed by baicalin in MC38 and CT26 cells. In vivo, baicalin significantly reduced the tumor size and weight (all P<0.01) in the colon cancer mouse model via inactivating p-AKT, CDKN2A, cyclin dependent kinase 4, cyclin dependent kinase 2, interleukin-1, tumor necrosis factor α, and activating caspase 3 and mouse double minute 2 homolog signaling (all P<0.05).
CONCLUSIONS: Baicalin suppressed the CDKN2A protein level to prevent colon cancer and could be used as a therapeutic target for colon cancer.

OBJECTIVE: Gliomas are highly heterogeneous malignancies originating from diverse cell types within the brain. Although their precise etiology is frequently unknown, risk factors, such as chemical exposure, radiation, and specific uncommon genetic disorders have been identified. Diagnosis typically entails imaging tests, such as magnetic resonance imaging and computed tomography, complemented by a biopsy for confirmation, which may be further validated through genetic testing.
METHODS: Next-generation sequencing technology revealed germline co-deletion deletion of cyclin-dependent kinase inhibitor 2 A and B genes (CDKN2A and CDKN2B) in a patient diagnosed with pleomorphic xanthoastrocytoma based on the tumor\'s molecular characteristics. Following this result, we performed focused genetic analysis with use of multiplex ligation-dependent probe amplification technology for the mother that revealed the same co-deletion. Moreover, due to the father\'s neuroendocrine pancreatic cancer, application of the NGS technology detected a pathogenic variant in the BRCA1-interacting helicase 1 (BRIP1) gene. Comprehensive multi-gene testing conducted within the familial context, marked by a varied spectrum of cancer type, revealed a constellation of genetic predispositions.
CONCLUSIONS: This case study underscores the critical importance of molecular testing for tumor characterization and highlights the pivotal role of genetic testing in facilitating early intervention and screening for at-risk family members. Furthermore, the identification of germline co-deletions in cancer lays the foundation for the development of targeted therapeutic strategies aimed at restoring normal cellular regulation and improving patient management.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a heterogeneous entity comprised of several biologically distinct subtypes. Recently, novel genetic classifications of DLBCL have been resolved based on common mutational patterns indicative of distinct pathways of transformation. However, the complicated and costly nature of the novel classifiers has precluded their inclusion into routine practice. In view of this, the status of the TP53 gene, which is mutated or deleted in 20-30% of the cases, has emerged as an important prognostic factor for DLBCL patients, setting itself apart from other predictors. TP53 genetic lesions are particularly enriched in a genetic subtype of DLBCL that shares genomic features with Richter Syndrome, highlighting the possibility of a subset of DLBCL arising from the transformation of an occult chronic lymphocytic leukemia-like malignancy, such as monoclonal B-cell lymphocytosis. Patients with TP53-mutated DLBCL, including those with Richter Syndrome, have a particularly poor prognosis and display inferior responses to standard chemoimmunotherapy regimens. The data presented in this manuscript argue for the need for improved and more practical risk-stratification models for patients with DLBCL and show the potential for the use of TP53 mutational status for prognostication and, in prospect, treatment stratification in DLBCL.

Introduction Cyclin-dependent kinase inhibitor 2A (CDKN2A) is a suppressor carcinogenic gene that is upregulated across various types of cancer including breast, liver, thyroid, and bile duct cancer due to its crucial role in cell cycle regulation and cell division. Nevertheless, it is mostly investigated at the genetic level, but it is still poorly studied on pan-cancer analysis as a biomarker and this study shows its significant potential diagnostic and prognostic characteristics. However, this study aims to investigate the role of CDKN2A as a diagnostic and prognostic biomarker across various types of cancer focusing primarily on colon adenocarcinoma (COAD). Methods We investigated CDKN2A gene expression in a pan-cancer analysis across different types of cancer to show its diagnostic potential characteristics by using various bioinformatic tools, including Tumor Immune Estimation Resource (TIMER) 2.0, Gene Expression Profiling Interactive Analysis (GEPIA), and University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) database. TIMER was used to profile gene expression across 32 types of cancer composed of 10,000 RNA-seq samples obtained from the Cancer Genome Atlas (TCGA) and to analyze the tumor-infiltrating immune cells. In addition, GEPIA and UALCAN were further used to analyze gene expression, in terms of gene regulation, pathological stages, and clinical parameters, including gender, age, and race. Therefore, we used GEPIA, UALCAN, and Kaplan-Meier plotter particularly across adenocarcinoma to investigate CDKN2A prognosis by studying its high expression association with the patient\'s overall survival rate to show the tumor progression. Then, we looked into the genetic alteration of CDKN2A by using the cBio Cancer Genomics Portal (cBioPortal), including 10 pan-cancer studies. We concluded the analysis with gene validation by using a public cohort in Gene Expression Omnibus (GEO). Results CDKN2A showed a trend of upregulation in most cancers and it was significantly upregulated in five cancers, which were commonly identifiable in three databases, including breast invasive carcinoma (p < 0.001), kidney chromophobe (p < 0.001), kidney renal clear cell carcinoma (p < 0.001), kidney renal papillary cell carcinoma (p < 0.001), and COAD (p < 0.001). The upregulation was significantly different in association with pathogenic stages II and III (pr(>F) = 0.00234) which was identifiable significantly in COAD more than in other cancers. The gene showed a high upregulation in association with poor prognosis of patient survival in three cancers, including COAD (log-rank p = 0.011), mesothelioma (log-rank p = 5.9e-07), and liver hepatocellular carcinoma (log-rank p = 0.0045). Therefore, COAD was the only comprehensively analyzed tumor to show a diagnostic and prognostic potential characteristic during high upregulation of CDKN2A. Furthermore, CDKN2A displayed a rare mutation in the form of deep deletion (9%) and revealed an upregulation associated with CD4+ T cells (p = 0.0108), macrophage (p = 0.0073), and neutrophils (p = 0.0272) as immune cells infiltrating COAD.  Conclusion Our study demonstrates the pan-cancer relevance of CDKN2A and revealed a novelty in showing CDKN2A underscores its potential as a diagnostic prognostic biomarker in COAD since CDKN2A is mostly studied at a genetic level across COAD.

Cuproptosis is a type of cell death characterized by excessive copper-lipid reactions in the tricarboxylic acid cycle, resulting in protein toxicity stress and cell death. Although known as a cuproptosis inhibitor through CRISPR-Cas9 screening, the role of cyclin-dependent kinase inhibitor 2A (CDKN2A) in cuproptosis resistance and its connection to tumor development remains unclear.
In this study, we combined single-cell sequencing, spatial transcriptomics, pathological image analysis, TCGA multi-omics analysis and in vitro experimental validation to comprehensively investigate CDKN2A distribution, expression, epigenetic modification, regulation and genomic features in colorectal cancer cells. We further explored the associations between CDKN2A and cellular pathway, immune infiltration and spatial signal communication.
Our findings showed an increasing trend in cuproptosis in the trajectory of tumor progression, accompanied by an upward trend of CDKN2A. CDKN2A underwent transcriptional activation by MEF2D and via the SNHG7/miR-133b axis, upregulating glycolysis, copper metabolism and copper ion efflux. CDKN2A likely drives epithelial-mesenchymal transition (EMT) and progression by activating Wnt signaling. CDKN2A is associated with high genomic instability and sensitivity to radiation and chemotherapy. Tumor regions expressing CDKN2A exhibit distinctive SPP1+ tumor-associated macrophage (TAM) infiltration and MMP7 enrichment, along with unique signaling crosstalk with adjacent areas.
CDKN2A mediates cuproptosis resistance through regulating glycolysis and copper homeostasis, accompanied by a malignant phenotype and pro-tumor niche. Radiation and chemotherapy are expected to potentially serve as therapeutic approaches for cuproptosis-resistant colorectal cancer with high CDKN2A expression.

暂无摘要。

UNASSIGNED: A 55-year-old male patient developed a mass in the left inguinal area with left lower limb swelling and first visited a local hospital 3 months earlier because of unrelieved pain. An MRI scan suggested left suprapubic branch and left acetabular bone destruction, abnormal soft tissue signals within the iliopsoas muscle of the anterior edge of the left iliac bone, and enlarged lymph nodes in the left iliac fossa and left inguinal region. The patient subsequently underwent left pelvic lesion open biopsy and inguinal lymph node resection biopsy. According to pathological reports, the left inguinal mass was considered to be a malignant tumor of cutaneous accessory origin (pilomatrix carcinoma) with extensive vitreous changes. The suprapupubis branch mass was considered to be a bone metastatic pilomatrix carcinoma. Immunohistochemistry (IHC) revealed a PDL1 combined positive score (CPS) of 8. DNA next-generation sequencing (NGS) showed CDKN2A L65Rfs*53 mutation. The patient received three cycles of gemcitabine and nedaplatin. However, the lesion progressed.
UNASSIGNED: Chemotherapy is not effective for treating pilomatrix carcinoma. PDL1 antibodies and CDK4/6 inhibitors might be treatment options for pilomatrix carcinoma.

The precise cause of HS/DCS is still unknown. The relatively low incidence in humans urges for an animal model with a high incidence to accelerate knowledge about genetics and optimal treatment of HS/DCS. Namely, until now, the therapies targeting genetic variants are still more experimental and sparsely used, while consensus is missing. In addition, the literature about variants and possible mutation-targeted therapies in humans and dogs consists mainly of case reports scattered throughout the literature. Therefore, an overview is provided of all currently known genetic variants in humans and dogs with HS/DCS and its subtypes, their possible mutation-targeted therapies, their efficacy, and a contemplation about the future. Several genetic variants have already been discovered in HS/DCS, of which many are shared between canine and human HS/DCS, but unique variants exist as well. Unfortunately, none of these already found variants seem to be specifically causal for HS/DCS, and the puzzle of its landscape of genetic variation is far from complete. The use of mutation-targeted therapies, including MAPK-/MEK-inhibitors and the future use of PTPN11-, CDK4/6- and PD-1-inhibitors, seems to be promising for these specific variants, but clearly, clinical trials are needed to determine optimal inhibitors and standardised protocols for all variants. It can be concluded that molecular analysis for variants and subsequent mutation-targeted therapy are an essential addition to cancer diagnostics and therapy. A joint effort of humans and dogs in research is urgently needed and will undoubtedly increase knowledge and survival of this devastating disease in dogs and humans.