Loss of cyclin A2 in murine colonic epithelial cells disrupts colon homeostasis by triggering DNA damage and dysplasia and high cyclin A2 expression is a good-prognosis factor in patients with colorectal cancer

To clarify the function of cyclin A2 in colon homeostasis and colorectal cancer (CRC) we generated mice deficient for cyclin A2 in colonic epithelial cells (CEC). Colons of those mice displayed architectural changes in the mucosa, and signs of inflammation as well as an increased proliferation of CEC associated with the appearance of low- and high-grade dysplasia. The main initial events triggering those alterations in cyclin A2 deficient CEC appear to be abnormal mitoses and DNA damage. Cyclin A2 deletion in CEC promoted the development of dysplasia and adenocarcinomas in the murine colitis-associated cancer model. We next explored the status of cyclin A2 expression in clinical CRC samples at the mRNA and protein level and found higher expression in tumors of stage I and II patients compared to those of stage III and IV. A meta-analysis of 11 transcriptome datasets comprising 2,239 primary CRC tumors displayed differentCCNA2(the mRNA coding for cyclin A2) expression levels among the CRC tumor subtypes with highest in CMS1 and lowest in CMS4. Moreover, high expression ofCCNA2was found to be a good prognosis factor independently from other prognostic factors for the CMS1, CMS3 and CMS4 subtypes.

Mucinous Carcinoma, Gastric Type of The Cervix

Introduction: Mucinous carcinoma, gastric type is an uncommon variant of cervical adenocarcinoma. This variant is different with most of cervical cancers due to gastric differentiation and unrelated with HPV infection. Well differentiated form of mucinous carcinoma, gastric type sometimes is called minimal deviation adenocarcinoma or adenoma malignum. The incidence is found in almost all groups of age (25- 72 years old) with mean 42 years old. Objective: To present a new and uncommon variant case in Indonesia primarily in Medan. Case description: We reported a case of 47-year- old woman, Mrs. M, who was clinically diagnosed with suspected carcinoma of cervix. A whitish, poorly demarcated mass in cervix was found in hysterectomy specimens. Microscopic examination showed that the cervix was lined by atypical and pleomorphic columnar cells, partially forming papillary pattern. The glands were proliferated with variable sized, some of which dilated and filled with mucin, and also the glands formed back to back appearance. In some foci were found disorganized glands. Glandular epithelium lining consisted of atypical and pleomorphic columnar cells with coarse chromatin and partially prominent nucleoli. Abnormal mitoses were easily found. In some foci, tumor cells also formed solid pattern. Discussion and Conclusion: According to these histological features, a diagnosis of mucinous carcinoma, gastric type of cervix was made (ICD-0 8482/3). Despite well differentiated form of mucinous carcinoma, gastric type, this variant has aggressive behavior and worse prognosis than other cervical carcinoma variants (usual type endocervical adenocarcinoma). Mucinous carcinoma, gastric type is an uncommon variant of cervical adenocarcinoma. This type is different from most of cervical cancers due to gastric differentiation and unrelated with HPV infection. Well differentiated form of mucinous carcinoma, gastric type sometimes is called minimal deviation adenocarcinoma or adenoma malignum. The incidence was found in almost all groups of age (25-72 years old). The average age was around 42 years old. This study objective is to present a new and uncommon variant case in Indonesia primarily in Medan. This study reported a case of 47-year- old woman, Mrs. M, who was clinically diagnosed with suspected carcinoma of cervix. A whitish, poorly demarcated mass in cervix was found in hysterectomy specimens. Microscopic examination revealed that the cervix was lined by atypical and pleomorphic columnar cells, partially forming papillary pattern. The glands were proliferated with variable sized, some of which dilated and covered with mucin, and also the glands formed back to back appearance. Disorganized glands were found in some foci. Glandular epithelium lining consisted of atypical and pleomorphic columnar cells with coarse chromatin and partially prominent nucleoli. Abnormal mitoses were easily found. In some foci, tumor cells also formed solid pattern. According to these histological features, a diagnosis of mucinous carcinoma, gastric type of cervix was made (ICD-0 8482/3). Despite well differentiated form of mucinous carcinoma, gastric type, this variant had aggressive behavior and worse prognosis than other cervical carcinoma variants (usual type endocervical adenocarcinoma).

Variability of cytogenetic disturbances in Lonicera caerulea (blue honeysuckle) population in an active fault zone

Background. In active fault zones, geophysical and geochemical anomalies may have a genotoxic effect on plants growing there, as one of the factors of evolutionary transformation of plant populations. Materials and methods. We applied a cytogenetic analysis to evaluate the genotoxic effect on a Lonicera caerulea L. (blue honeysuckle) natural population in one of the active fault zones in the Altai Mountains. Results. We derived principal cytogenetic indices (i.e., mitotic, prophase, metaphase, anaphase, and telophase indices as well as proportion and range of abnormal mitoses) for meristematic cells of Lonicera caerulea seedlings. The increase in the mitotic activity of meristematic cells from the sites in the local fault zone is connected with the occurrence of the prophase-metaphase block to prevent consequences of an increased cell death (as a result of abnormal mitoses in these phases) and to compensate their losses by a greater number of divisions. We observed the increase in the proportion of abnormal mitoses in samples from almost all the test sites, compared with the control site. This demonstrates the increase in the genotoxic effect of geophysical and geochemical anomalies in these sites. The range of abnormal mitoses of samples from all the test sites shows the increase in the proportion of abnormalities in metaphase, compared to the control site where they can be equally found in metaphase, anaphase, and telophase. Conclusion. The results demonstrate changes of mitotic activity, frequency of occurrence and the spectrum of mitotic anomalies in the root meristem of blue honeysuckle, which grows in conditions with contrast geophysical characteristics.

Pleomorphic Invasive Ductal Carcinoma of the Breast in a Patient with Huntington’s Disease

A pleomorphic invasive ductal carcinoma developed in a patient with Huntington’s disease. The tumour showed marked nuclear pleomorphism and contained large number of bizarre tumour giant cells and abundant abnormal mitoses. Tumour cells showed nuclear vesicles and inclusions similar to those described in nuclei of neural cells in patients with Huntington’s disease. The case suggests that, in some patients, tumour morphology may reflect specific individual features.

In vivo transformation of mouse conventional CD8α+ dendritic cells leads to progressive multisystem histiocytosis

Division and proliferation of dendritic cells (DCs) have been proposed to contribute to homeostasis and to prolonged antigen presentation. Whether abnormal proliferation of dendritic cells causes Langerhans cell histiocytosis (LCH) is a highly debated topic. Transgenic expression of simian virus 40 (SV40) T antigens in mature DCs allowed their transformation in vivo while maintaining their phenotype, function, and maturation capacity. The transformed cells were differentiated splenic CD8 alpha–positive conventional dendritic cells with increased Langerin expression. Their selective transformation was correlated with higher steady-state cycling compared with CD8 alpha–negative DCs in wild-type and transgenic mice. Mice developed a DC disease involving the spleen, liver, bone marrow, thymus, and mesenteric lymph node. Surprisingly, lesions displayed key immunohistologic features of Langerhans cell histiocytosis, including expression of Langerin and absence of the abnormal mitoses observed in Langerhans cell sarcomas. Our results demonstrate that a transgenic mouse model with striking similarities to aggressive forms of multisystem histiocytosis, such as the Letterer-Siwe syndrome, can be obtained by transformation of conventional DCs. These findings suggest that conventional DCs may cause some human multisystem LCH. They can reveal shared molecular pathways for human histiocytosis between humans and mice.

Mutations inDrosophila myblead to centrosome amplification and genomic instability

We have previously established that the single myb gene in Drosophila melanogaster, Dm myb, which is related to the proto-oncogene Myb, is required for the G2/M transition of the cell cycle and for suppression of endoreduplication in pupal wing cells. We now report that studies of the abdominal phenotype in loss-of-function Dm myb mutants reveal additional roles for Dm myb in the cell cycle, specifically in mitosis. Abdominal epidermal cells that are mutant for Dm myb proliferate more slowly than wild-type controls throughout pupation, with particularly sluggish progression through the early stages of mitosis. Abnormal mitoses associated with multiple functional centrosomes, unequal chromosome segregation, formation of micronuclei, and/or failure to complete cell division are common in the later cell cycles of mutant cells. Resulting nuclei are often aneuploid and/or polyploid. Similar defects have also been observed in loss-of-function mutations of the tumor suppressor genes p53, Brca1 and Brca2. These data demonstrate that in abdominal epidermal cells, Dm myb is required to sustain the appropriate rate of proliferation, to suppress formation of supernumerary centrosomes, and to maintain genomic integrity.

Primary Malignant Melanoma of the Larynx

Primary malignant melanoma of the larynx is a rare clinical entity. Only 53 cases have been reported in the medical literature to date. This report describes a case of primary malignant melanoma arising in the larynx and diagnosed by histologic examination of an excisional biopsy specimen. The patient was a 53-year-old man with a history of smoking and hoarseness. There was no clinical evidence of other primary malignant melanocytic lesions. Microscopically, the tumor consisted of polygonal-epithelioid cells admixed with more elongated, spindle-shaped cells. The majority of the cells demonstrated dark brown cytoplasmic and nuclear melanin. Marked pleomorphism and abnormal mitoses were also identified. Despite significant ulceration and disruption of the epithelium, in situ malignant melanocytes were recognized within the remaining portion of the epithelium. Immunohistochemical studies were positive for S100, HMB-45, and vimentin, while cytokeratin and iron stains were negative. Based on the clinical and histologic findings, a diagnosis of primary malignant melanoma of the larynx was established.

XCS-1, a maternally expressed gene product involved in regulating mitosis in Xenopus

The regulation of the cell cycle during early development is an important and complex biological process. We have cloned a cDNA, XCS-1, that may play an important role in regulating mitosis during early embryogenesis in Xenopus laevis. XCS-1 is a maternally expressed gene product that is the Xenopus homologue of the human cleavage signal protein (CS-1). XCS-1 transcripts were detected in oocytes with the titer decreasing just prior to the MBT. During development the XCS-1 protein was detected on the membrane and in the nucleus of blastomeres. It was also detected on the mitotic spindle in mitotic cells and on the centrosomes in interphase cells. Overexpression of myc-XCS-1 in Xenopus embryos resulted in abnormal mitoses with increased numbers of centrosomes, multipolar spindles, and abnormal distribution of chromosomes. Also, we observed incomplete cytokinesis resulting in multiple nuclei residing in the same cytoplasm with the daughter nuclei in different phases of the cell cycle. The phenotype depended on the presence of the N terminus of XCS-1 (aa 1–73) and a consensus NIMA kinase phosphorylation site (aa159-167). Mutations in this site affected the ability of the overexpressed XCS-1 protein to produce the phenotype. These results suggest that XCS-1 is a maternal factor playing an important role in the regulation of the cell cycle during early embryogenesis and that its function depends on its state of phosphorylation.