Pathology, research and practice最新文献

Background: Cervical cancer (CC) is one of the most deadly cancers in women, its current treatments still result in poor outcomes and developing the novel targets and therapeutic strategies are urgently needed. Qiu's Cervical Prescription (QCP) is one of the traditional Chinese medicines used in the treatment of cervical cancer in China. Although its curative effect is remarkable, the internal mechanism of its treatment is still poorly understood. Recent studies have shown that LncRNA ATB might be used as a new proliferation marker for cancer diagnosis and prognosis. This study aimed to investigate the possible mechanism of action of QCP in the treatment of cervical cancer.

Methods: The functional assays of migration and invasion in vitro using transwell assays and wound healing assays was performed to confirm the pro-carcinogenic effect of LncRNA ATB, and the changes of migration and invasion of HeLa cells were observed after treatment with QCP containing drug serum. The changes in tumor volume, general condition of transplanted tumor-bearing mice and expression of LncRNA ATB pathway-related proteins were detected by qPCR, Western blotting and HE staining after treatment with the QCP.

Results: We induced LncRNA ATB knockdown and overexpression in cervical cancer cell lines and detected the biological behavior changes in vitro. Furthermore, we established murine models using stable LncRNA ATB-shRNA HeLa cells or overexpression LncRNA ATB cells or normal Hela cells with QCP to evaluate how suppression of LncRNA ATB affects tumor growth.

Conclusion: We showed that potential mechanism of QCP in the treatment of cervical cancer may be through inhibition of the LncRNA ATB/miR-126/TGFβ1 signaling axis. In conclusion, QCP may be a promising approach for the treatment of CC.

Hirschsprung's (HSCR) disease, also known as aganglionic megacolon, or congenital intestinal aganglionosis affects roughly 1 out of every 5000 newborns. It is a birth defect characterized by the partial or complete loss of ganglion cells in the myenteric and submucosal plexus of the distal intestine which leads to ineffective peristalsis, constipation, and obstruction. Clinical assessment and radiological observations might imply HSCR disease, but definitive diagnosis requires biopsy interpretation and confirmation of ganglion cell loss. The difficulty in identifying immature ganglion cells added to the variability in interpreting immunohistochemical markers of ganglion cells warrants the search for new markers. Our recent research identified Beta-1,3-N-acetylglucosaminyltransferase (B3GNT6) as a potential candidate, as it consistently stains the cytoplasm of ganglion cells. To evaluate its utility, we conducted a preliminary assessment of B3GNT6 expression in nineteen gastrointestinal tissue samples and observed cytoplasmic staining in ganglion cells across all samples. This consistent staining pattern suggests B3GNT6 could serve as a reliable marker for diagnosing Hirschsprung's disease. This article serves as a preliminary evaluation of B3GNT6 as a ganglion cell immunohistochemical marker, highlighting its potential significance while acknowledging the need for further validation in larger, more diverse cohorts.

Several molecular strategies based on targeted gene delivery systems have been developed in recent years; however, the CRISPR-Cas9 technology introduced a new era of targeted gene editing, precisely modifying oncogenes, tumor suppressor genes, and other regulatory genes involved in carcinogenesis. However, efficiently and safely delivering CRISPR-Cas9 to cancer cells across the cell membrane and the nucleus is still challenging. Using viral vectors and nanoparticles presents issues of immunogenicity, off-target effects, and low targeting affinity. Naturally, extracellular vesicles called exosomes have garnered the most attention as delivery vehicles in oncology-related CRISPR-Cas9 calls due to their biocompatibility, loading capacity, and inherent targeting features. The following review discusses the current progress in using exosomes to deliver CRISPR-Cas9 components, the approaches to load the CRISPR components into exosomes, and the modification of exosomes to increase stability and tumor-targeted delivery. We discuss the latest strategies in targeting recently accomplished in the exosome field, including modifying the surface of exosomes to enhance their internalization by cancer cells, as well as the measures taken to overcome the impacts of TME on delivery efficiency. Focusing on in vitro and in vivo experimentation, this review shows that exosome-mediated CRISPR-Cas9 can potentially treat cancer types, including pancreatic, lymphoma, and leukemia, for given gene targets. This paper compares exosome-mediated delivery and conventional vectors regarding safety, immune response, and targeting ability. Last but not least, we present the major drawbacks and potential development of the seemingly promising field of exosome engineering in gene editing, with references to CRISPR technologies and applications that may help make the target exosomes therapeutic in oncology.

Background: Adenocarcinoma of the esophagus and stomach demands a deeper molecular understanding to advance treatment strategies and improve patient outcomes. Here, we profiled the genome and transcriptome landscape of these cancers, explored molecular characteristics that are undetectable by other sequencing platforms, and analyzed their potential clinical ramifications.

Methods: Our study employed state-of-the-art integrative analyses of whole genome and transcriptome sequencing on 51 matched tumor and germline samples from 46 patients. Mutations and rearrangements in clinically relevant cancer genes were investigated and correlated with OncoKB, a knowledge-based precision oncology database, to identify treatment implications. Genome-wide signatures and manually curated molecular profiles were also determined.

Results: The analyses revealed 90 targetable oncogenic mutations and fusions in 63 % of the patients, including novel NTRK, NRG1, ALK, and MET fusions, and structural variants in cancer genes like RAD51B. Also, molecular signatures associated with mismatch repair and homologous recombination deficiency were elucidated. Notably, we identified CDK12-type genomic instability associated with CDK12 fusions.

Conclusions: Our findings support the potential of whole genome and transcriptome sequencing analyses as a comprehensive approach to identify treatment targets in adenocarcinoma of the stomach and the esophagus, and their application in precision oncology.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the digestive tract. Despite multiple therapeutic advances, patients with advanced disease frequently develop resistance to tyrosine kinase inhibitors (TKIs), and therefore represent a therapeutic challenge. We employed whole genome sequencing (WGS) on three metastatic GISTs refractory to various TKIs and explored a publicly available cohort of 499 GISTs. This study sheds light on the clinical importance of alterations in cell cycle genes such as cyclin-dependent kinase 2 A (CDKN2A), and cyclin-dependent kinase 2B (CDKN2B), their frequent alteration in metastatic GISTs and their potential role in tumor progression of this neoplasm. Likewise, new structural variations were identified in cyclin-dependent kinase 12 (CDK12). Whole genome profiling of metastatic GIST provides new insights to advance precision care of the disease, focusing on new therapeutic possibilities, especially for emerging targets such as CDK12.

REV7 is a multifunctional protein involved in the DNA damage response, cell cycle regulation, gene expression, or primordial germ cell maintenance. REV7 expression in tumor cells is associated with clinical aggressive features and chemoresistance in several human malignancies, however, the clinicopathological significance of REV7 in lung adenocarcinoma (LUAD) has not been studied yet. In this study, we investigated the significance of REV7 expression in LUAD using clinical materials and cell lines. REV7 expression in 142 invasive LUADs were determined using immunohistochemistry, and the relationship between REV7 expression and clinicopathological features was analyzed. High levels of REV7 expression in tumor tissues were positively associated with progressive tumor behavior as assessed by Ki-67 labeling indexes (p < 0.001), maximum standardized uptake values on positron emission tomography (p = 0.005), pathological stage (p = 0.031), N factor (p = 0.048), recurrence (p = 0.038), and disease-specific death (p = 0.020). The REV7-high-expression group showed poorer relapse-free survival (RFS) (p = 0.025) and overall survival (OS) (p = 0.019) compared to the REV7-low-expression group, and REV7 was a significant prognostic factor for RFS and OS. CRISPR/Cas9-mediated REV7-knockout and siRNA-mediated REV7 knockdown were carried out using the LUAD cell lines A549 and H1975, respectively, and it was demonstrated that REV7 inactivation led to slower cell growth, attenuated activation of AKT signaling, and enhanced chemosensitivity compared with control cells. These results suggest that REV7 is a potential predictive biomarker for poor prognosis in invasive LUAD and a possible molecular target for LUAD management.

Prolonged cold ischemia time (CIT) and neoadjuvant chemotherapy (NACT) can each independently impact the expression of breast cancer-related biomarkers, but their combined effects are not well studied. Herein, we assessed whether prolonged CIT has a higher modulatory effect on post-NACT biomarker expression in breast cancer specimens than in otherwise similar but non-NACT specimens. Our study cohort included 334 biopsy/resection breast cancer specimen pairs in which immunohistochemistry (IHC for estrogen receptor [ER], progesterone receptor [PR], HER2) and HER2 FISH had been performed on both specimens. These included 209 pairs with a post-NACT resection (NACT[+]), and 125 pairs unassociated with NACT (NACT[-]). Each group was subclassified into prolonged CIT (>1 hr; CITp) and non-prolonged CIT (≤1 hr, CITnp). NACT[+]/CITp (n = 125) and NACT[-]/CITp (n = 84) subgroups showed no statistically significant differences regarding the frequency of biopsy-to-resection change in the final result [i.e. positive versus negative] for any of the 4 biomarkers. Similarly, the NACT[+]/CITp and NACT[+]/CITnp subgroups showed no significant differences regarding the percentage of cases with any biopsy-to-resection change in final result for ER, HER2 (IHC) and HER2 (FISH). For PR, a biopsy-to-resection change in status was more commonly observed in CITnp (44.1 %) as compared to the CITp (19.2 %) subgroup (p = 0.02). In summary, we found no conclusive evidence that prolonged CIT has a more significant modulatory effect on biomarker expression in post-NACT breast cancer resection specimens than their otherwise comparable (i.e. NACT[-], CITp) counterparts regarding the final test result, which suggests that post-NACT specimens do not require more stringent CIT-related handling requirements than NACT[-] specimens.

Aim: Endometrial cancer (EC) is one of the three most common gynecological malignancies. Thus, it is estimated that the mortality rates due to this disease will increase. Our aim is to study the immune microenvironment in all ECs together with Hematoxylin Eosin (H&E), immunohistochemical (IHC) and Biochemical parameters (NLR) and to evaluate their contribution to prognosis by comparing them with each other.

Materials and methods: A total of 340 EC patients were included in the study. PDL-1 immunohistochemical stain was applied to blocks prepared from representative tumor tissues by Tissue Microarray method. Tumor- infiltrating lymphocytes and neutrophils were also scored with Hematoxylin Eosin stain. The NLR values calculated from peripheral blood. The effects of all parameters on survival, recurrence/metastasis were statistically evaluated.

Results: Regarding TIL Scores, patients with higher TIL scores were found to have longer disease-free survival and total survival. In patients with high TIN scores, disease-free survival and overall survival were shorter. (p < 0.001) The overall survival of patients with PDL-1 negative was found to be longer. (p: 0.07). In terms of the effect on OS, an NLR cut-off value of 2.72 was determined (specificity 38.89 %, sensitivity 82.57 %, AUC 0.65). OS was 77.11 months ( ± 0.04, 95 % CI: 71.8-81.9) in the patients with NLR value slower than 2.72 and 76.5 months ( ± 1.3, 95 % CI: 36.3-63.7) in those with NLR ≥ 2.72 (p: 0.001).

Conclusion: In this study, all patients of EC with high TIL scores, low TIN scores, and with PD-L1 negativity exhibited significantly longer survival times. TIN appears to be a highly valuable parameter in terms of both OS and PFS, particularly compared to TIL and PD-L1. This research represent a pioneering study for future studies involving larger samples in the context of being able to use different parameters in predicting prognosis and treatment in patients with EC.

Gastrointestinal (GI) cancers, such as gastric cancer, hepatocellular carcinoma, colorectal cancer, and esophageal cancer, pose a significant medical and economic burden globally, accounting for the majority of new cancer cases and deaths each year. A lack of knowledge about the molecular mechanisms of GI cancers is reflected in the low efficacy of treatment for individuals with late stage and recurring illness. Understanding the molecular pathways that promote the growth of GI cancers may open doors for their therapy. Numerous long non-coding RNAs (lncRNAs) that are produced differently in normal and malignant tissues have been discovered by genome-wide techniques. The role of lncRNAs in the diagnosis, proliferation, metastasis, and drug resistance of different GI cancers has been investigated in recent research. LncRNAs may affect transcription, epigenetic modifications, protein/RNA stability, translation, and post-translational modifications via their interactions with DNA, RNAs, and proteins. Also, by functioning as competing endogenous RNAs (ceRNAs), they control the synthesis of certain microRNAs (miRNAs), which in turn modify the downstream target molecules of these miRNAs. Based on recent studies, lncRNAs in particular, CRNDE and HOTAIR, sponge different miRNAs and their downstream genes, which in turn regulate GI cancers development, including cell proliferation, invasion, migration, and chemoresistance. In this comprehensive review, we present an overview of the biological roles of CRNDE and HOTAIR and their associated mechanisms, miRNAs/mRNA pathways, in various GI cancers, encompassing colorectal cancer, hepatocellular carcinoma, esophageal cancer, and gastric cancer.

Various aggressive lymphomas entities have been associated with immunodeficiency. To provide further evidence that also MYC-negative high-grade B-cell (formerly Burkitt-like) lymphoma with 11q aberrations comprises an immunodeficiency-related subtype, we here conducted a comprehensive pathological and genetic workup of a 25-year-old patient with this type of lymphoma and simultaneous papillary renal cell carcinoma. The patient developed both malignancies following extensive childhood immunosuppression and a kidney transplant. Germline and somatic genetic analyses included interphase cytogenetics, imbalance mapping, and exome sequencing. We identified potential germline-predisposition to inborn errors of immunity, kidney disease, and cancer, along with a germline region of homozygosity in 20q. Each tumor showed imbalances and single nucleotide variants typical for the respective diagnosis, with shared gains in the name-giving region in 11q, gain of the MYC gene in 8q24 and trisomy 12. While we can show that the imbalances in 8q and 11q arise from different mechanisms in both tumors, trisomy 12 involved gain of the same parental chromosome. Our findings corroborate the existence of a subtype of immunodeficiency-related high-grade B-cell lymphomas with 11q aberrations, provide further insights into its molecular pathogenesis, and reveal potential pitfalls in the molecular diagnosis of simultaneous tumors based on the technology applied.