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Background Colorectal carcinoma (CRC) is the third most common cancer in the world and also the third leading cause of cancer-related mortality in Taiwan. CRC tumorigenesis is a multistep process, starting from mutations causing loss of function of tumor suppressor genes, canonically demonstrated in adenomatous polyposis coli pathogenesis. Although many genes or chromosomal alterations have been shown to be involved in this process, there are still unrecognized molecular events within CRC tumorigenesis. Elucidating these mechanisms may help improve the management and treatment. Methods In this study, we aimed to identify copy number alteration of the smallest chromosomal regions that is significantly associated with sporadic CRC tumorigenesis using high-resolution array-based Comparative Genomic Hybridization (aCGH) and quantitative Polymerase chain reaction (qPCR). In addition, microsatellite instability assay and sequencing-based mutation assay were performed to illustrate the initiation event of CRC tumorigenesis. Results A total of 571 CRC patients were recruited and 377 paired CRC tissues from sporadic CRC cases were used to define the smallest regions with chromosome copy number changes. In addition, 198 colorectal polyps from 160 patients were also used to study the role of 20q13.33 gain in CRC tumorigenesis. We found that gain in 20q13.33 is the main chromosomal abnormalities in this patient population and counts 50.9 and 62.8% in CRC and colon polyps, respectively. Furthermore, APC and KRAS gene mutations were profiled simultaneously and co-analyzed with microsatellite instability and 20q13.33 gain in CRC patients. Our study showed that the frequency of 20q13.33 copy number gain was highest among all reported CRC mutations. Conclusion As APC or KRAS mutations are currently identified as the most important targets for CRC therapy, this study proposes that 20q13.33 copy number gain and the associated chromosomal genes function as promising biomarkers for both early stage detection and targeted therapy of sporadic CRCs in the future.

The short isoform of human TIAM2 has been shown to promote proliferation and invasion in various cancer cells. However, the roles of TIAM2S in immune cells in relation to tumor development have not been investigated. To characterize the effects of TIAM2S, we generated TIAM2S-overexpressing mouse lines and found that aged TIAM2S-transgenic (TIAM2S-TG) developed significantly higher occurrence of lymphocytic infiltration and tumorigenesis in various organs, including colon. In addition, TIAM2S-TG is more sensitized to AOM-induced colon tumor development, suggesting a priming effect toward tumorigenesis. In the light of our recent findings that TIAM2S functions as a novel regulator of cellular serotonin level, we found that serotonin, in addition to Cox2, is a unique inflammation marker presented in the colonic lesion sites in the aged TG animals. Furthermore, our results demonstrated that ectopic TIAM2S altered immunity via the expansion of T lymphocytes, this was especially pronounced in CD8+ T cells in combination with CXCL13/BCA-1 pro-inflammatory chemokine in the serum of TIAM2S-TG mice. Consequently, T lymphocytes and B cells were recruited to the lesion sites and stimulated IL-23/IL17A expression to form the tertiary lymphoid organs. Collectively, our research suggests that TIAM2S provokes a pro-inflammatory immune microenvironment permissive to colorectal tumorigenesis through the serotonin-induced immunomodulatory effects.

Background Infratentorial siderosis (iSS) is a progressive degenerative disorder targeting primarily the cerebellum and cranial nerve eighth; therefore, progressive ataxia and its neuro-otological findings are common. Toxicity from hemosiderin involves selectively vulnerable neurons and glia in these posterior fossa structures. Other neurologic findings may be present, though our focus relates to the cochlea-vestibular cerebellar involvement. Radiographic evidence of siderosis may be the result of recurrent, albeit covert bleeding in the subarachnoid space, or the consequence of an overt post-traumatic or aneurysmal subarachnoid hemorrhage (SAH). The radiographic iSS appearance is identical regardless of the SAH cause. A recent study provides compelling evidence to search and correct possible hemorrhage sources in the spinal canal. The removal of residual existing hemosiderin deposits that may potentially cause clinical symptoms remains as a major therapeutic challenge. Methods We reviewed large data sources and identified salient papers that describe the pathogenesis, clinical and neurotologic manifestations, and the radiographic features of iSS. Results The epidemiology of iSS is unknown. In a recent series, clinically evident iSS was associated with recurrent SAH; by contrast, in a follow-up period ranging from weeks up to 11 years after a monophasic episode of SAH, radiographic siderosis was clinically silent. However, the post-aneurysmal or post-trauma SAH sample size in this single study was small and their observation period relatively short; moreover, the burden of intraneuronal hemosiderin is likely greater with recurrent SAH. There are a few reports of late iSS, several decades after traumatic SAH. A recent report found subjective hearing loss in aneurysmal SAH individuals with radiographic siderosis. Only in recent years, it is safe to perform magnetic resonance imaging (MRI) in post-aneurysmal SAH, because of the introduction of titanium, MRI-compatible aneurysm clips. Conclusion iSS can be associated with significant neurotologic and cerebellar morbidity; the recurrent SAH variant is frequently clinically symptomatic, has a shorter latency and greater neurotologic disability. In these cases, a thorough search and management of a covert source of bleeding may stop clinical progression. The frequency and clinical course of radiographic iSS after traumatic and post-aneurysmal SAH is largely unknown. Detection of radiographic iSS after trauma or aneurysm bleeding suggests that the slower clinical course could benefit from an effective intervention if it became available. The use of cochlear implants is a valid alternative with advanced hearing impairment.