Exploring the short linear motif-mediated protein-protein interactions of CrkL through ProP-PD.

Adaptor proteins play a pivotal role in cellular signaling mediating a multitude of protein-protein interaction critical for cellular homeostasis. Dysregulation of these interactions has been linked to the onset of various cancer pathologies and exploited by viral pathogens during host cell takeover. CrkL is an adaptor protein composed of an N-terminal SH2 domain followed by two SH3 domains that mediate interactions with diverse partners through the recognition of specific binding motifs. In this study, we employed proteomic peptide-phage display (ProP-PD) to comprehensively explore the short linear motif (SLiM)-based interactions of CrkL. Furthermore, we scrutinized how the binding affinity for selected peptides was influenced in the context of the full-length CrkL versus the isolated N-SH3 domain. Importantly, our results provided insights into SLiM-binding sites within previously reported interactors, as well as revealing novel human and viral ligands, expanding our understanding of the interactions mediated by CrkL and highlighting the significance of SLiM-based interactions in mediating adaptor protein function, with implications for cancer and viral pathologies.

Identifying and prioritising unanswered research questions for people with hyperacusis: James Lind Alliance Hyperacusis Priority Setting Partnership.

OBJECTIVE: To determine research priorities in hyperacusis that key stakeholders agree are the most important. DESIGN/SETTING: A priority setting partnership using two international surveys, and a UK prioritisation workshop, adhering to the six-staged methodology outlined by the James Lind Alliance. PARTICIPANTS: People with lived experience of hyperacusis, parents/carers, family and friends, educational professionals and healthcare professionals who support and/or treat adults and children who experience hyperacusis, including but not limited to surgeons, audiologists, psychologists and hearing therapists. METHODS: The priority setting partnership was conducted from August 2017 to July 2018. An international identification survey asked respondents to submit any questions/uncertainties about hyperacusis. Uncertainties were categorised, refined and rephrased into representative indicative questions using thematic analysis techniques. These questions were verified as 'unanswered' through searches of current evidence. A second international survey asked respondents to vote for their top 10 priority questions. A shortlist of questions that represented votes from all stakeholder groups was prioritised into a top 10 at the final prioritisation workshop (UK). RESULTS: In the identification survey, 312 respondents submitted 2730 uncertainties. Of those uncertainties, 593 were removed as out of scope, and the remaining were refined into 85 indicative questions. None of the indicative questions had already been answered in research. The second survey collected votes from 327 respondents, which resulted in a shortlist of 28 representative questions for the final workshop. Consensus was reached on the top 10 priorities for future research, including identifying causes and underlying mechanisms, effective management and training for healthcare professionals. CONCLUSIONS: These priorities were identified and shaped by people with lived experience, parents/carers and healthcare professionals, and as such are an essential resource for directing future research in hyperacusis. Researchers and funders should focus on addressing these priorities.

Beta-cell markers and autoantigen expression by a human insulinoma cell line: similarities to native beta cells.

In the present study we have evaluated the expression of different beta-cell markers, islet molecules and auto-antigens relevant in diabetes autoimmunity by a human insulinoma cell line (CM) in order to define its similarities with native beta cells and to discover whether it could be considered as a model for studies on immunological aspects of Type 1 diabetes. First, the positivity of the CM cell line for known markers of neuroendocrine derivation was determined by means of immunocytochemical analysis using different anti-islet monoclonal antibodies including A2B5 and 3G5 reacting with islet gangliosides, and HISL19 binding to an islet glycoprotein. Secondly, the expression and characteristics of glutamic acid decarboxylase (GAD) and of GM2-1 ganglioside, both known to be islet autoantigens in diabetes autoimmunity and expressed by human native beta cells, were investigated in the CM cell line. The pattern of ganglioside expression in comparison to that of native beta cells was also evaluated. Thirdly, the binding of diabetic sera to CM cells reacting with islet cytoplasmic antigens (ICA) was studied by immunohistochemistry. The results of this study showed that beta cell markers identified by anti-islet monoclonal antibodies A2B5, 3G5 and HISL-19 are expressed by CM cells; similarly, islet molecules such as GAD and GM2-1 ganglioside are present and possess similar characteristics to those found in native beta cells; the pattern of expression of other gangliosides by CM cells is also identical to human pancreatic islets; beta cell autoantigen(s) reacting with antibodies present in islet cell antibodies (ICA) positive diabetic sera identified by ICA binding are also detectable in this insulinoma cell line. We conclude that CM cells show close similarities to native beta cells with respect to the expression of neuro-endocrine markers, relevant beta cell autoantigens in Type 1 diabetes (GAD, GM2-1, ICA antigen), and other gangliosides. Therefore, this insulinoma cell line may be considered as an ideal model for studies aimed at investigating autoimmune phenomena occurring in Type 1 diabetes.

[Prognostic factors in operated breast carcinoma]. / Fattori prognostici del carcinoma mammario operato.

The traditional prognostic factors (tumour size, lymph node involvement, receptor status) have now been shown to have limits in terms of prognostic definition. These limits may be partially overcome when parameters exist to determine the extent of tumour biological aggression and the patient's degree of immune response. It is important to clarify these links because they may lead to more precise indications regarding the prognosis and choice of therapy, above all in cases of breast cancer operated with no lymph node involvement. Breast carcinoma is often surrounded by inflammatory cells showing host and tumour interaction. The aim of this study was to evaluate the prognostic value of lymphocyte infiltration in operated breast cancer. The degree of lymphocyte infiltration observed in 56 breast cancer patients was compared with other prognostic factors (tumour size, lymph node status, histological variants, necrotic areas and desmoplastic reaction). This preliminary study allowed the authors to examine the degree of peritumoral lymphocyte density as an important predictive index of overall survival in patients with breast cancer and N-.

[Stereotaxic breast microhistology]. / Microistologia mammaria nella stereotassi.

Mammography is currently the most reliable imaging technique to detect clinically occult breast cancer. Stereotaxic-guided aspiration biopsy during mammography allows lesion nature to be diagnosed in many cases. Our experience with 72 microhistologic breast samplings with fine-needle aspiration cytology is reported; 50% of inadequate cytologic samplings were avoided. Adequate cytologic samples were obtained in 88.9% of cases, while microhistologic samples were adequate in 94.4% of cases. Inadequate samples were 11.1% and 5.6%, respectively. Microhistologic biopsies yielded fewer questionable results than fine-needle aspiration cytology, which helped reduce the number of unnecessary biopsies. This method, which is reliable and well tolerated by the patients, can be considered as a valuable alternative procedure to fine-needle aspiration cytology.

Viral infection induces cytokine release by beta islet cells.

Viral infection has been suggested to play a triggering role in the pancreatic beta cell destruction which occurs in insulin-dependent diabetes (IDDM). However, the underlying mechanism of this phenomenon is unknown. In this study a human insulinoma cell line has been infected with measles, mumps and rubella viruses since a temporal association is reported between the clinical onset of IDDM and diseases caused by these viruses. The infection with measles and mumps viruses induced the release of interleukin-1 (IL-1) and interleukin-6 (IL-6) by the cell line as assessed by a bioassay and up-regulated the expression of human leucocyte antigen (HLA) class I and class II antigens as evaluated by cytofluorimetric analysis. Stimulation with rubella virus induced the release of IL-6 only and had no effect on HLA antigen expression. These data show for the first time that IL-1 and IL-6 secretion by an insulinoma cell line may occur after viral infection and suggest that cytokine release and increased expression of HLA molecules by beta cells may act to induce the immune response towards beta cells in IDDM.

[Chronic calcifying pancreatitis in hospitals in the Ivory Coast]. / Pancréatite chronique calcifiante en milieu hospitalier en Côte d'Ivoire.

The authors report on 34 cases of chronic calcifying pancreatitis in Ivory Coast. Chronic calcifying pancreatitis is rare (0.24 P.C. of admitted patients) and appears mainly in man 40 years old, revealed by diabetes (73.5 P.C.). Principal aetiology was alcoholism, 50 P.C. Genuine tropical chronic calcifying pancreatitis exists in small number. It seems its physiopathological mechanism is not only nutritional.