Next generation sequencing of prostate cancer from a patient identifies a deficiency of methylthioadenosine phosphorylase, an exploitable tumor target

Castrate-resistant prostate cancer (CRPC) and neuroendocrine carcinoma of the prostate are invariably fatal diseases for which only palliative therapies exist. As part of a prostate tumor sequencing program, a patient tumor was analyzed using Illumina genome sequencing and a matched renal capsule tumor xenograft was generated. Both tumor and xenograft had a homozygous 9p21 deletion spanning the MTAP, CDKN2, and ARF genes. It is rare for this deletion to occur in primary prostate tumors, yet approximately 10% express decreased levels of methylthioadenosine phosphorylase (MTAP) mRNA. Decreased MTAP expression is a prognosticator for poor outcome. Moreover, it seems that this deletion is more common in CRPC than in primary prostate cancer. We show for the first time that treatment with methylthioadenosine and high dose 6-thioguanine causes marked inhibition of a patient-derived neuroendocrine xenograft growth while protecting the host from 6-thioguanine toxicity. This therapeutic approach can be applied to other MTAP-deficient human cancers as deletion or hypermethylation of the MTAP gene occurs in a broad spectrum of tumors at high frequency. The combination of genome sequencing and patient-derived xenografts can identify candidate therapeutic agents and evaluate them for personalized oncology.     

Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development

Pancreatic cancer is a disease with an extremely poor prognosis. Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a proapoptotic stress-induced p53 target gene. In this article, we show by immunohistochemical analysis that TP53INP1 expression is dramatically reduced in pancreatic ductal adenocarcinoma (PDAC) and this decrease occurs early during pancreatic cancer development. TP53INP1 reexpression in the pancreatic cancer-derived cell line MiaPaCa2 strongly reduced its capacity to form s.c., i.p., and intrapancreatic tumors in nude mice. This anti-tumoral capacity is, at least in part, due to the induction of caspase 3-mediated apoptosis. In addition, TP53INP1(-/-) mouse embryonic fibroblasts (MEFs) transformed with a retrovirus expressing E1A/ras(V12) oncoproteins developed bigger tumors than TP53INP1(+/+) transformed MEFs or TP53INP1(-/-) transformed MEFs with restored TP53INP1 expression. Finally, TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in PDAC cells. TP53INP1 is a previously unknown miR-155 target presenting anti-tumoral activity.     

Orthopedic effects of splint high-pull headgear—A cephalometric appraisal

ObjectiveThe purpose of this study was to investigate the orthopedic effect of maxillary splint high-pull head gear appliance on maxillary complex.DesignRetrospective study.SettingsPatients under treatment in the Department of Orthodontics, Azad University, during one year period from November 2003 to March 2004.SubjectsLateral cephalometric radiograph of 26 patients (11 boys and 15 girls, with a mean age of 11.3 years) treated with splint high-pull headgear appliance was compared with a similar control group of 26 individuals (11 boys and 15 girls with a mean age of 12.6 years).Main outcome measuresThe result of the present study showed that the treated group more closely approximated Class I cephalometric values after treatment, whereas the control group with a Class II skeletal pattern did not necessarily become “less Class II” due to growth.ResultsPoint A was held efficiently in the treated group (S–A = 0.4 mm) whereas in the control group it had relocated downward and forward 2.00 mm along sella–point A (S–A) line. Also, the relocation of the point A in the horizontal (X-axis) and vertical (Y-axis) planes confirmed these findings. No rotational changes of palatal plane were recorded in the treated group. Mandibular skeletal changes were similar to the control group. Maxillary dentition was relocated more posteriorly.ConclusionsIt was concluded that the maxillary splint with high-pull headgear in the present study held the maxilla in position without any rotational changes of the palatal plane. Therefore, a normal skeletal relationship was achieved in the treated group through a combination of maxillary basal bone and dentoalveolar growth inhibition and a normal expression of mandibular growth.     

Proteinase-activated receptor-2 expression in basal and squamous cell carcinomas compared with normal skin

Proteinase-activated receptor-2 (PAR-2) is a transmembrane G-protein expressed in many normal tissues and overexpressed in several cancer cell lines. It contributes to metastasis, promotes epidermal growth factor receptor proliferation, angiogenesis and tumor progression in many carcinomas. The purpose of this study was to investigate the expression of PAR-2 in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in comparison with that of normal skin.
Immunohistochemical (IHC) expression of PAR-2 was examined using paraffin-embedded sections from 30 BCCs, 30 SCCs and also 30 normal sun-exposed skin specimens. PAR-2 was expressed in all specimens of SCC and normal skin. In marked contrast, all BCC specimens had negative IHC staining. Given the important role of PAR-2 in angiogenesis and metastasis, our finding can explain the far less aggressive behavior of BCC as compared with SCC.     

HIV related stigma associated with social support,alcohol use disorders,depression, anxiety,and suicidal ideation among people living with HIV: a systematic review and meta-analysis

Supportive supervision has been shown to improve worker resilience and wellbeing, which are particularly important in the context of humanitarian emergency settings. Despite its noted importance however, supervision remains an under-prioritised area in mental health and psychosocial support (MHPSS). The present study used a Delphi consensus-building methodology to examine levels of agreement among a diverse sample of MHPSS stakeholders (n = 48) on key ideas and concepts relating to supervision in humanitarian settings. The majority of statements presented showed a high degree of consensus, with some receiving almost universal agreement, such as the importance of using active listening skills in the supervisory context and the need for supervisors to have access to their own supervisory support. However, disagreement on several points remained. For example, participants disagreed about whether the qualities required to be an effective supervisor can be taught, or whether they are more innate and should be screened for when recruiting supervisors. Gender differences in responses were also analysed, with potential associations between gender and level of agreement emerging in relation to statements about power dynamics, remote supervision, and intervention quality enhancement. The findings of the present study are discussed in terms of their implications for a forthcoming set of guidelines for supervision of MHPSS in humanitarian settings: The Integrated Model for Supervision (IMS).     

Chorionic Bump in First-trimester Sonography

Objectives

The present research was motivated by providing new insight into early pregnancies with a chorionic bump diagnosis in first-trimester sonography and its impact on live birth rate.