Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target

Atypical teratoid rhabdoid tumor (AT/RT) is among the most fatal of all pediatric brain tumors. Aside from loss of function mutations in the SMARCB1 (BAF47/INI1/SNF5) chromatin remodeling gene, little is known of other molecular drivers of AT/RT. LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers. We identified high-levels of LIN28A and LIN28B in AT/RT primary tumors and cell lines, with corresponding low levels of the LIN28-regulated microRNAs of the let-7 family. Knockdown of LIN28A by lentiviral shRNA in the AT/RT cell lines CHLA-06-ATRT and BT37 inhibited growth, cell proliferation and colony formation and induced apoptosis. Suppression of LIN28A in orthotopic xenograft models led to a more than doubling of median survival compared to empty vector controls (48 vs 115 days). LIN28A knockdown led to increased expression of let-7b and let-7g microRNAs and a down-regulation of KRAS mRNA. AT/RT primary tumors expressed increased mitogen activated protein (MAP) kinase pathway activity, and the MEK inhibitor selumetinib (AZD6244) decreased AT/RT growth and increased apoptosis. These data implicate LIN28/RAS/MAP kinase as key drivers of AT/RT tumorigenesis and indicate that targeting this pathway may be a therapeutic option in this aggressive pediatric malignancy.     

Sentencing risk: history of incarceration and HIV/STD transmission risk behaviours among Black men who have sex with men in Massachusetts

This study investigated the role of incarceration in HIV/STD risk among 197 Black men who have sex with men in Massachusetts, USA. More than half (51%) reported a history of incarceration (28% 相似文献   

Claudin-6 is a nonspecific marker for malignant rhabdoid and other pediatric tumors

Claudins are tight junction proteins with claudin-6 (CLDN6) expression mostly restricted to embryonic and fetal life. Previously reported gene expression microarray analysis showed an increased level of CLDN6 in atypical teratoid rhabdoid tumors (AT/RT) compared with other central nervous system (CNS) tumors and sarcomas. However, there exist conflicting data on expression of CLDN6 as assessed by immunohistochemistry in CNS tumors. We established membranous staining as a specific and reproducible method for evaluating CLDN6 expression based on fetal and adolescent controls. We then evaluated a large group (257) of pediatric tumors using tissue microarrays, including: 47 malignant rhabdoid tumors (MRTs), (31 AT/RTs and 16 non-CNS MRTs); 67 small, round, blue cell tumors (10 Wilms tumors, 10 embryonal rhabdomyosarcomas, 10 neuroblastomas (NBs), 10 synovial sarcomas (SSs), 9 hepatoblastomas (HBs), 9 alveolar rhabdomyosarcomas, and 9 Ewings sarcomas); and 143 CNS tumors (24 medulloblastomas, 21 pilocytic astrocytomas, 14 astrocytomas grade II/III, 13 gangliogliomas, 12 glioblastomas, 12 ependymal tumors, 11 choroid plexus tumors, 10 meningiomas, 8 dysembryoplastic neuroepithelial tumors, 8 oligodendrogliomas, 4 craniopharyngiomas, 2 germinomas, 2 primitive neuroectodermal tumors (PNET), and 2 central neurocytomas). CLDN6 expression was seen in 12 of 31 (39%) AT/RTs, 7 of 16 (44%) non-CNS MRTs, 5 of 10 (50%) Wilms tumors, 1 of 9 (11%) HBs, 2 of 2 (100%) germinomas, 1 of 2 (50%) CNS PNETs, 1 of 24 (4%) medulloblastomas, and 1 of 10 (10%) meningiomas. Ten of 11 (91%) choroid plexus tumors showed apical staining but no concentric membranous staining. Although CLDN6 is expressed in both AT/RTs and MRTs, it is not a specific biomarker as it is expressed in a variety of other pediatric CNS and soft tissue tumors.     

Alterations in mineral composition observed in osteoarthritic joints of cynomolgus monkeys

Osteoarthritis (OA) is a prevalent joint disease that affects more than 40 million Americans and is characterized by degeneration of the articular cartilage and thickening of the underlying subchondral bone. Although subchondral bone thickening has been implicated in articular cartilage degeneration, very little is known about the composition of subchondral bone in OA. In the present study, infrared microspectroscopy (IRMS) was used to determine the chemical composition of the calcified cartilage-subchondral bone plate in a monkey model of OA. Specifically, the levels of mineralization (mineral/protein ratio), carbonate accumulation (carbonate/protein ratio), crystallinity, and collagen structure were determined as a function of animal age and OA severity. OA severity was assessed using a grading scheme that included scores or measurements for several histomorphometric parameters including articular cartilage fibrillation or clefting, subchondral bone thickness, and numbers of tidemarks and chondrocyte clones. Individual scores and measurements were summarized using principal components (factor) analysis. Results demonstrated that the level of mineralization and carbonate content increased as a function of animal age. In addition, bone mineralization level increased as subchondral bone thickness increased. Dramatic increases in the mineralization level and carbonate accumulation were also observed as a function of the number of tidemarks. The presence of multiple tidemarks indicates the occurrence of one or more additional phases of cartilage calcification, suggesting that the observed compositional changes are due to cartilage mineralization. Our results support a reactivation of endochondral ossification that occurs with age, which is more pronounced in OA. No relationships were observed between mineral crystallinity and collagen cross-linking as a function of age or OA severity. In summary, compositional analysis of the mineralized plate beneath the articular cartilage in OA is characterized by thickened, overmineralized calcified cartilage or subchondral bone, which likely puts added mechanical stress on the joint, contributing to the progression of OA.     

Subclinical endophthalmitis following a rooster attack

Ocular injury resulting from rooster attacks is rarely reported in the literature. Sadly, the target of these attacks is most often children younger than 3 years old, whose naiveté of the aggressive, territorial behavior of birds can place them at risk. Acute sequelae of these attacks can result in a lifetime of visual impairment. The possibility of a subacute or occult infection is an unusual occurrence that must always be considered. In an effort to prevent future attacks and ocular casualties, we present a case of a 12-month-old boy who suffered an open globe following a rooster attack. The open globe was emergently repaired. One week later, a white cataract was noticed on examination in the absence of systemic or ocular signs of inflammation. Traumatic endophthalmitis and lenticular abscess were suspected during examination under anesthesia. Vitrectomy, lensectomy, and injection of intravitreal antibiotics were performed. Culture of lenticular and vitreous aspirates grew alpha-streptococcus. Alpha-streptococcal endophthalmitis can result from ocular injuries caused by rooster pecking. The infection may present insidiously and without typical ocular or systemic symptoms or signs. Management is challenging and may require surgery.     

Nodular Lymphoid Hyperplasia and Colo-Rectal Carcinoma

Two cases of colo-rectal carcinoma with prominent nodular lymphoid hyperplasia in adjacent bowel are presented. The normal incidence and associated conditions are discussed.