Germline tp53 testing in breast cancers: Why, when and how?

Germline TP53 variants represent a main genetic cause of breast cancers before 31 years of age. Development of cancer multi-gene panels has resulted in an exponential increase of germline TP53 testing in breast cancer patients. Interpretation of TP53 variants, which are mostly missense, is complex and requires excluding clonal haematopoiesis and circulating tumour DNA. In breast cancer patients harbouring germline disease-causing TP53 variants, radiotherapy contributing to the development of subsequent tumours should be, if possible, avoided and, within families, annual follow-up including whole-body MRI should be offered to carriers. We consider that, in breast cancer patients, germline TP53 testing should be performed before treatment and offered systematically only to patients with: (i) invasive breast carcinoma or ductal carcinoma in situ (DCIS) before 31; or (ii) bilateral or multifocal or HER2+ invasive breast carcinoma/DCIS or phyllode tumour before 36; or (iii) invasive breast carcinoma before 46 and another TP53 core tumour (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumour, adrenocortical carcinoma); or (iv) invasive breast carcinoma before 46 and one first-or second-degree relative with a TP53 core tumour before 56. In contrast, women presenting with breast cancer after 46, without suggestive personal or familial history, should not be tested for TP53.D.G.E. and E.R.W. are supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007)

Microdeletion del(22)(q12.2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Pierre-Robin sequence (PRS) is defined by micro- and/or retrognathia, glossoptosis and cleft soft palate, either caused by deformational defect or part of a malformation syndrome. Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome caused by mutations in the <it>NF2 </it>gene on chromosome 22q12.2. NF2 is characterized by bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas and ependymomas, and juvenile cataracts. To date, NF2 and PRS have not been described together in the same patient.</p> <p>Case presentation</p> <p>We report a female with PRS (micrognathia, cleft palate), microcephaly, ocular hypertelorism, mental retardation and bilateral hearing loss, who at age 15 was also diagnosed with severe NF2 (bilateral cerebellopontine schwannomas and multiple extramedullary/intradural spine tumors). This is the first published report of an individual with both diagnosed PRS and NF2. High resolution karyotype revealed 46, XX, del(22)(q12.1q12.3), FISH confirmed a deletion encompassing <it>NF2</it>, and chromosomal microarray identified a 3,693 kb deletion encompassing multiple genes including <it>NF2 </it>and <it>MN1 </it>(meningioma 1).</p> <p>Five additional patients with craniofacial dysmorphism and deletion in chromosome 22-adjacent-to or containing <it>NF2 </it>were identified in PubMed and the DECIPHER clinical chromosomal database. Their shared chromosomal deletion encompassed <it>MN1</it>, <it>PITPNB </it>and <it>TTC28</it>. <it>MN1</it>, initially cloned from a patient with meningioma, is an oncogene in murine hematopoiesis and participates as a fusion gene (<it>TEL</it>/<it>MN1</it>) in human myeloid leukemias. Interestingly, <it>Mn1</it>-haploinsufficient mice have abnormal skull development and secondary cleft palate. Additionally, <it>Mn1 </it>regulates maturation and function of calvarial osteoblasts and is an upstream regulator of <it>Tbx22</it>, a gene associated with murine and human cleft palate. This suggests that deletion of <it>MN1 </it>in the six patients we describe may be causally linked to their cleft palates and/or craniofacial abnormalities.</p> <p>Conclusions</p> <p>Thus, our report describes a <it>NF2</it>-adjacent chromosome 22q12.2 deletion syndrome and is the first to report association of <it>MN1 </it>deletion with abnormal craniofacial development and/or cleft palate in humans.</p

Rotate-and-Press: A Non-Visual Alternative to Point-and-Click

Most computer applications manifest visually rich and dense graphical user interfaces (GUIs) that are primarily tailored for an easy-and-efficient sighted interaction using a combination of two default input modalities, namely the keyboard and the mouse/touchpad. However, blind screen-reader users predominantly rely only on keyboard, and therefore struggle to interact with these applications, since it is both arduous and tedious to perform the visual \u27point-and-click\u27 tasks such as accessing the various application commands/features using just keyboard shortcuts supported by screen readers. In this paper, we investigate the suitability of a \u27rotate-and-press\u27 input modality as an effective non-visual substitute for the visual mouse to easily interact with computer applications, with specific focus on word processing applications serving as the representative case study. In this regard, we designed and developed bTunes, an add-on for Microsoft Word that customizes an off-the-shelf Dial input device such that it serves as a surrogate mouse for blind screen-reader users to quickly access various application commands and features using a set of simple rotate and press gestures supported by the Dial. Therefore, with bTunes, blind users too can now enjoy the benefits of two input modalities, as their sighted counterparts. A user study with 15 blind participants revealed that bTunes significantly reduced both the time and number of user actions for doing representative tasks in a word processing application, by as much as 65.1% and 36.09% respectively. The participants also stated that they did not face any issues switching between keyboard and Dial, and furthermore gave a high usability rating (84.66 avg. SUS score) for bTunes

Hydroxy double salts loaded with bioactive ions: Synthesis, intercalation mechanisms, and functional performance

The intercalation of the anions of diclofenac (Dic), naproxen (Nap), and valproic acid (Val) into three hydroxy double salts (HDSs) has been explored in this work. Experiments were performed with [Co1.2Zn3.8(OH)8](NO3)2·2H2O (CoZn-NO3), [Ni2Zn3(OH)8](NO3)2·2H2O (NiZn-NO3) and [Zn5(OH)8](NO3)2·2H2O (Zn-NO3). It proved possible to intercalate diclofenac and naproxen into all three HDSs. In contrast, Val could be intercalated into CoZn-NO3 but when it was reacted with Zn-NO3 the HDS structure was destroyed, and the product comprised ZnO. Successful intercalation was verified by X-ray diffraction, IR spectroscopy, and elemental microanalysis. Molecular dynamics simulations showed the Dic and Nap ions to arrange themselves in an “X” shape in the interlayer space, forming a bilayer. Val was found to adopt a position with its aliphatic groups parallel to the HDS layer, again in a bilayer. In situ time resolved X-ray diffraction experiments revealed that intercalation of Dic and Nap into CoZn-NO3 and Zn-NO3 is mechanistically complex, with a number of intermediate phases observed. In contrast, the intercalation of all three guests into NiZn-NO3 and of Val into CoZn-NO3 are simple one step reactions proceeding directly from the starting material to the product. The HDS-drug composites were found to have sustained release profiles

Vestibular schwannoma: role of conservative management

Objective: To assess the outcome of conservative management of vestibular schwannoma.Study design: Observational study. Setting: Tertiary referral centre.Patients: Four hundred and thirty-six patients with vestibular schwannoma (490 tumours), including 327 sporadic tumours and 163 tumours in 109 patients with neurofibromatosis type two.Main outcome measures: The relationship of tumour growth to tumour size at presentation, and to certain demographic features.Results: The initial tumour size was significantly larger in the neurofibromatosis type two group (11 mm) than in the sporadic vestibular schwannoma group (5.1 mm). In both groups, 68 per cent of tumours did not grow during follow up (mean 3.6 years; range one to 14 years). The mean growth rate was 1.1 mm/year (range 0-15 mm/year) for sporadic tumours and 1.7 mm/year (range 0-18 mm/year) for neurofibromatosis type two tumours. The tumour growth rate correlated positively with tumour size in the sporadic tumour group, and correlated negatively with age in the neurofibromatosis type two group.Conclusion: Two-thirds of vestibular schwannomas did not grow. Radiological surveillance is an acceptable approach in carefully selected patients. Once a sporadic vestibular schwannoma reaches 2 cm in intracranial diameter, it is likely to continue growing. We do not recommend conservative management for sporadic tumours with an intracranial diameter of 1.5 cm or more. Vestibular schwannoma management is more complex in patients with neurofibromatosis type two

Things change: Women’s and men’s marital disruption dynamics in Italy during a time of social transformations, 1970-2003

We study women’s and men’s marital disruption in Italy between 1970 and 2003. By applying an event-history analysis to the 2003 Italian variant of the Generations and Gender Survey we found that the spread of marital disruption started among middle-highly educated women. Then in recent years it appears that less educated women have also been able to dissolve their unhappy unions. Overall we can see the beginning of a reversed educational gradient from positive to negative. In contrast the trend in men’s marital disruption risk appears as a change over time common to all educational groups, although with persisting educational differentials.determinants, educational differences, event history analysis, gender difference, Italy, marital disruption