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This article in the journal Histopathology examines the recognition of poroid tumors with NUTM1 rearrangements. Poromas are adnexal tumors that can be eccrine or apocrine, and they have different histologic variants. The study aims to identify morphological clues that can distinguish between YAP1:MAML2 and YAP1:NUTM1 fused poroid tumors. The study analyzes clinical, microscopic, and genetic features of the tumors and finds no significant differences in age, sex, or anatomical location between the two groups. The study confirms previous findings of high frequencies of YAP1:NUTM1 fusions in poroid hidradenoma and provides insights into the microscopic features of poroid tumors with different genetic rearrangements. [Extracted from the article]

1 TABLE SSTR2A expression scores in trichogerminomas, follicular and no follicular differentiation tumours. Trichogerminoma (TG) is a rare follicular neoplasm characterized by immature morphology and "cell ball" formation.[1] This entity should be distinguished from other follicular neoplasms composed of germinative cells notably trichoblastoma and basal cell carcinoma. To conclude, we reported intense and expression of SSTR2A in more 50% of tumour cells in TG, which might therefore be used as an additional immunohistochemical marker for the diagnosis of this neoplasm. [Extracted from the article]

Merkel cell carcinoma from renal transplant recipients are mostly MCPyV-negative and are frequently associated with squamous cell carcinomas or precursors Briefly, patients were mostly male (M/F: 10/5), with a median age at MCC diagnosis of 63 years (range 52-84) and a median delay of 11.5 years (range 1-24 years) between transplantation and MCC diagnosis. In line with the hypothesis that MCPyV-negative tumours may derive from SCC, six patients with MCPyV-negative tumours had a prior history of SCC. [Extracted from the article]

Aims: Recently, YAP1 fusion genes have been demonstrated in eccrine poroma and porocarcinoma, and the diagnostic use of YAP1 immunohistochemistry has been highlighted in this setting. In other organs, loss of YAP1 expression can reflect YAP1 rearrangement or transcriptional repression, notably through RB1 inactivation. In this context, our objective was to re‐evaluate the performance of YAP1 immunohistochemistry for the diagnosis of poroma and porocarcinoma. Methods and results: The expression of the C‐terminal part of the YAP1 protein was evaluated by immunohistochemistry in 543 cutaneous epithelial tumours, including 27 poromas, 14 porocarcinomas and 502 other cutaneous tumours. Tumours that showed a lack of expression of YAP1 were further investigated for Rb by immunohistochemistry and for fusion transcripts by real‐time PCR (YAP1::MAML2 and YAP1::NUTM1). The absence of YAP1 expression was observed in 24 cases of poroma (89%), 10 porocarcinoma (72%), 162 Merkel cell carcinoma (98%), 14 squamous cell carcinoma (SCC) (15%), one trichoblastoma and one sebaceoma. Fusions of YAP1 were detected in only 16 cases of poroma (n = 66%), 10 porocarcinoma (71%) all lacking YAP1 expression, and in one sebaceoma. The loss of Rb expression was detected in all cases except one of YAP1‐deficient SCC (n = 14), such tumours showing significant morphological overlap with porocarcinoma. In‐vitro experiments in HaCat cells showed that RB1 knockdown resulted in repression of YAP1 protein expression. Conclusion: In addition to gene fusion, we report that transcriptional repression of YAP1 can be observed in skin tumours with RB1 inactivation, including MCC and a subset of SCC. [ABSTRACT FROM AUTHOR]

The sarcomatoid component harbored additional amplifications of the chromosomes 1q, 6q, 9q, 13q, 20, 21, and 22. gl Microscopically, both combined cases showed an MCC component with tumour cells arranged in sheets, with a high nucleocytoplasmic ratio and condensed chromatin associated with in situ (case #1) or invasive conventional SCC (case #2). Merkel cell carcinoma (MCC) is a rare cancer with a 5-year overall survival rate estimated at 40%.[1] About 80% of cases are related to the genomic integration of Merkel cell Polyomavirus (MCPyV).[2] In comparison, the prominent UV signature is a hallmark of MCPyV-negative cases.[1] Interestingly, the cell of origin remains a matter of debate for both MCPyV-negative and MCPyV-positive cases.[[1], [3]] In 5%-10% of cases, MCC is associated with another component, mainly squamous cell carcinoma (SCC). Merkel cell polyomavirus-negative -Merkel cell carcinoma originating from in situ squamous cell carcinoma: a keratinocytic tumor with neuroendocrine differentiation. [Extracted from the article]

We report 21 cases of trichogerminoma harbouring previously undescribed FOXK1::GRHL1/2 or GPS2::GRHL1/2/3 in‐frame fusion transcripts. Microscopic examination of a preliminary set of five cases revealed well‐delimitated tumours located in the dermis with frequent extension to the subcutaneous tissue. Tumours presented a massive and nodular architecture and consisted of a proliferation of basaloid cells. A biphasic pattern sometime resulting in tumour cell nests ('cell balls') was present. Immunohistochemistry demonstrated the expression of cytokeratins (CKs) 15, 17, and PHLDA1. In addition, numerous CK20‐positive Merkel cells were detected. RNA sequencing (RNA‐seq) revealed a FOXK1::GRHL1 chimeric transcript in three cases and a FOXK1::GRHL2 fusion in two cases. In a second series for validation (n = 88), FOXK1::GRHL1/2 fusion transcripts were detected by RT‐qPCR or FISH in an additional 12 trichogerminomas and not in any other follicular tumour entities or basal cell carcinoma cases (n = 66). Additional RNA‐seq analysis in trichogerminoma cases without detected FOXK1::GRHL1/2 rearrangements revealed GPS2::GRHL1 fusion transcripts in two cases, GPS2::GRHL2 in one case, and GPS2::GRHL3 fusion transcript in one case. Therefore, our study strongly suggests that GRHL1/2/3 gene rearrangements might represent the oncogenic driver in trichogerminoma, a subset of follicular tumours characterized by immature features and numerous Merkel cells. © 2022 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Abstract Background Robot-mediated therapies offer entirely new approaches to neurorehabilitation. In this paper we present the results obtained from trialling the GENTLE/S neurorehabilitation system assessed using the upper limb section of the Fugl-Meyer (FM) outcome measure. Methods We demonstrate the design of our clinical trial and its results analysed using a novel statistical approach based on a multivariate analytical model. This paper provides the rational for using multivariate models in robot-mediated clinical trials and draws conclusions from the clinical data gathered during the GENTLE/S study. Results The FM outcome measures recorded during the baseline (8 sessions), robot-mediated therapy (9 sessions) and sling-suspension (9 sessions) was analysed using a multiple regression model. The results indicate positive but modest recovery trends favouring both interventions used in GENTLE/S clinical trial. The modest recovery shown occurred at a time late after stroke when changes are not clinically anticipated. Conclusion This study has applied a new method for analysing clinical data obtained from rehabilitation robotics studies. While the data obtained during the clinical trial is of multivariate nature, having multipoint and progressive nature, the multiple regression model used showed great potential for drawing conclusions from this study. An important conclusion to draw from this paper is that this study has shown that the intervention and control phase both caused changes over a period of 9 sessions in comparison to the baseline. This might indicate that use of new challenging and motivational therapies can influence the outcome of therapies at a point when clinical changes are not expected. Further work is required to investigate the effects arising from early intervention, longer exposure and intensity of the therapies. Finally, more function-oriented robot-mediated therapies or sling-suspension therapies are needed to clarify the effects resulting from each intervention for stroke recovery.

Aim: Hepatocellular carcinoma (HCC) is a common outcome of chronic hepatitis C virus (HCV) infection and constitutes the main burden of this disease. The molecular mechanisms underlying the development of HCC are multiple and might involve certain microRNA (miR). As discordant results have been reported concerning the detection of expression of miR‐152 and miR‐122 in HCC, our aim was to measure the levels of both miRs in serum and liver samples. Methods: We analyzed miR‐152 and miR‐122 expression by reverse transcription–quantitative polymerase chain reaction in a serum cohort from 14 HCV‐infected patients who developed HCC, 20 HCV+ patients without HCC, and 19 control patients. We also studied miR‐152 and miR‐122 in an independent tissue cohort from 11 normal livers, and from paired HCC and non‐tumor adjacent livers of 11 HCV‐infected patients and 12 non‐infected patients. Results: In serum samples, higher levels of miR‐122 were found in non‐HCC HCV+ compared to HCC HCV+ and control groups, whereas miR‐152 was detectable in a lower range in HCC HCV+ compared to non‐HCC HCV+ and control groups. We found higher signals for miR‐122 and miR‐152 in non‐tumor liver and HCC tissues compared to control tissues. Hepatocellular carcinoma etiology had no detectable influence on miR‐122 expression, whereas miR‐152 was increased in HCV+ tissue samples. Conclusions: Detection of low values of circulating miR‐152 is a potentially interesting marker of hepatocarcinogenesis in HCV+ patients, in contrast to miR‐122, which varies according to hepatocyte damage. [ABSTRACT FROM AUTHOR]

Dear Editor, Approximately 50% of cutaneous melanomas carry mutations in the I BRAF i gene, most frequently located at exon 15, codon 600, and resulting in constitutive BRAF-mediated activation of the mitogen-activated protein kinase (MAPK) pathway.1 BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) have been approved for the treatment of metastatic melanomas with activating BRAF p.V600E or p.V600K mutations which account for 90% of BRAF-mutated melanomas.1,2 Although efficacy of BRAFi/MEKi have been reported with other activating mutations located at codon 600 (V600R, V600D),2,3 their relevance in the setting of "orphan" non-p.V600E/K/R/D mutations of uncertain significance has seldom been reported.2 We report the efficacy of BRAFi/MEKi in a metastatic melanoma with a mutation combining the deletion of the valine (V) at position 600, the deletion of the lysine (K) at position 601, and insertion of a glutamic acid (E). Efficacy and tolerance of BRAF and MEK inhibitors on metastatic melanoma carrying the orphan pV600 K601 delinsE mutation of the BRAF gene High Resolution Melting for rapid screening on the primary melanoma was consistent with a mutation of the I BRAF i gene in exon 15, but pyrosequencing did not detect mutations in codon 600. [Extracted from the article]

Background NaV1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients' death. In breast cancer cells, NaV1.5 activity promotes the proteolytic degradation of the extracellular matrix and enhances cell invasiveness. Findings In this study, we showed that the extinction of NaV1.5 expression in human breast cancer cells almost completely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated that ranolazine (50 µM) inhibited NaV1.5 currents in breast cancer cells and reduced NaV1.5-related cancer cell invasiveness in vitro. In vivo, the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by NaV1.5- expressing human breast cancer cells. Conclusions Taken together, our results demonstrate the importance of NaV1.5 in the metastatic colonisation of organs by breast cancer cells and indicate that small molecules interfering with NaV activity, such as ranolazine, may represent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments. [ABSTRACT FROM AUTHOR]

This paper provides some additional evidence in support of the hypothesis that robot therapies are clinically beneficial in neurorehabilitation. Although only four subjects were included in the study, the design of the intervention and the measures were done so as to minimize bias. The results are presented as single case studies, and can only be interpreted as such due to the study size. The intensity of intervention was 16 h and the therapy philosophy (based on Carr and Shepherd) was that coordinated movements are preferable to joint based therapies, and that coordinating distal movements (in this case grasps) helps not only to recover function in these areas, but has greater value since the results are immediately transferable to daily skills such as reach and grasp movements. [ABSTRACT FROM AUTHOR]

Purpose: To investigate factors associated with post-traumatic growth (PTG) 13 years after severe traumatic brain injury (TBI) and to see if PTG had remained consistent between 11 and 13 years after injury. Method: TBI survivors (n = 21), were interviewed and completed face-to face administration of questionnaires measuring PTG and factors potentially associated with PTG. The design was a longitudinal follow-up study. Results: Factors significantly associated with PTG included: having a sense of personal meaning (purpose and coherence), high life satisfaction now, social support, high-activity levels, a high number of life events, having paid work, new stable relationships after injury, milder disability, and having religious faith. Having a high level of 'purpose' was the best predictor of PTG. There was no change in PTG between 11 and 13 years after injury suggesting PTG is a relatively stable phenomenon once established after the early years. Conclusion: Clinicians should be aware of PTG and how it is associated with factors such as 'meaning' and 'purpose' as well as demographic factors such as, social support, activity such as work, new and stable relationships, milder disability and a shift towards spiritual values. Clinicians can focus advice, resource and effort on supporting these developments. [ABSTRACT FROM AUTHOR]

Objective: To determine the efficacy of Sativex (USAN: nabiximols) in the alleviation of spasticity in people with multiple sclerosis. Methods: The results from three randomized, placebo-controlled, double-blind parallel group studies were combined for analysis. Patients: 666 patients with multiple sclerosis and spasticity. Measures: A 0-100mm Visual Analogue Scale (VAS, transformed to a 0-10 scale) or a 0-10 Numerical Rating Scale (0-10 NRS) was used to measure spasticity. Patients achieving a ⩾30% improvement from baseline in their spasticity score were defined as 'responders'. Global impression of change (GIC) at the end of treatment was also recorded. Results: The patient populations were similar. The adjusted mean change of the numerical rating scale from baseline in the treated group was -1.30 compared with -0.97 for placebo. Using a linear model, the treatment difference was -0.32 (95% CI -0.61, -0.04, p=0.026). A statistically significant greater proportion of treated patients were responders (odds ratio (OR)=1.62, 95% CI 1.15, 2.28; p=0.0073) and treated patients also reported greater improvement: odds ratio 1.67 (95% CI 1.05, 2.65; p=0.030). High numbers of subjects experienced at least one adverse event, but most were mild to moderate in severity and all drug-related serious adverse events resolved. Conclusion: The meta-analysis demonstrates that nabiximols is well tolerated and reduces spasticity. [ABSTRACT FROM AUTHOR]

Primary objective: To investigate the time course of any positive psychological changes after traumatic brain injury (TBI) by comparing questionnaire responses in two groups of TBI survivors, early, 1–3 years post-injury and late, 10–12 years post-injury. Research design: A cross-sectional, between-group design. Method and Procedure: TBI survivors were selected from the Reading Head Injury out-patient records by date of registration, early survivors from 2002–2004 and late survivors from 1993–1996 and sent a battery of postal questionnaires. These included The Post-traumatic Growth Inventory, The Life Satisfaction Checklist and The Hospital Anxiety and Depression Scale. Individuals were also given the opportunity to answer questions about their perception of their condition and to provide free text responses to reflect best and worst advice received, to describe positive and negative changes in themselves and to identify their most useful coping strategies. Results: 61 ‘early’ and 65 ‘late’ people were contacted with study details and 52 consented to the study, receiving questionnaires which provided 23 ‘early’ and 25 ‘late’ responses. There was a significantly greater degree of post-traumatic growth, as measured on ‘The Post-traumatic Growth Inventory’, reported by the later group (*p = 0.000), but no other significant differences between the groups in terms of all the other variables. Both groups reported greater life satisfaction pre-injury. Conclusion: Measures of Post-traumatic Growth (Relating to Others, Personal Strength, New Possibilities, Appreciation of Life and Spirituality) appear to increase over time after head injury. This is a positive message that clinicians should note and reinforce and could help to shape future adjustment. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs), which belong to the nuclear hormone receptor superfamily, have recently been described as potent key regulators of epidermal development. As 1,25-dihydroxyvitamin D[sub 3], retinoic acid and triiodothyronine are known to exert effects on skin and hair follicle growth through similar receptors, we decided to investigate both the expression pattern of the PPARα, -δ and -γ subtypes and their role in human hair follicles. Using reverse transcriptase-polymerase chain reaction and immunohistochemistry, we established that PPAR α, -δ and -γ were expressed in both dermal and epithelial human hair follicle cells. Additionally, we evaluated the dose effect of clofibrate, a PPARα ligand, on the survival of human hair follicles in culture. A beneficial effect was observed within a narrow range of concentrations. [ABSTRACT FROM AUTHOR]

A series of 40 patients accepted for prosthetic rehabilitation after lower limb amputations for peripheral vascular disease were reviewed nine to 27 months later. Two have since died, one has not been traced, and 37 have been assessed. Fourteen were successful full-time limb users ('walkers'), 10 were partial users ('partial walkers') and 13 were wheelchair-dependent ('none walkers' or 'wheelchair users'). Of the walkers, 85% completed a 10-metre walk in under 30 seconds (mean 20s), whereas 90% of the partial walkers took over 30 seconds (mean 79s). The Barthel Activities of Daily Living (ADL) Index, a measure of independence in self-care, correlated closely with outcome status and walking speed. Other items that correlated well with outcome included grip strength, assessed using a simple hand-held dynanometer, and cardiovascular fitness, the measure being time taken for the pulse to return to resting baselme after exercise. This was less than two minutes in 85% of the walkers (mean 94s) and two minutes or more in 100% of the partial walkers (mean 240s). Age did not indicate whether prosthetic training would be successful, but in those who were walking it correlated closely with speed. The partial walkers had lower kitchen and domestic activity scores, which were due to lack of environmental modification for wheelchair use, it being assessed that their walking status conferred ability to do tasks whilst standing. These patients can easily be identified by measuring their walking speed and Barthel ADL Index. [ABSTRACT FROM PUBLISHER]

Presents issues related to medicine. Link between duodenal ulcer, gastric acid and Helicobacter pylori; Oral complications of cancer; Importance of health check ups during middle age.

The effectiveness of a short test of everyday memory in discriminating memory ability of independently living and of partially dependent elderly people has been investigated. Results indicate that overall test performance is significantly different in the two groups but that not all individual items discriminate equally well. The test as a whole correlates well with a standard cognitive screening test but it also contains items for abilities not measured in the general test, notably visuo-spatial memory. In addition, it appears to provide a more sensitive measure of memory function when general cognitive decline is minimal. [ABSTRACT FROM PUBLISHER]

Amyotrophic lateral sclerosis is a neurodegenerative disease of largely unknown cause, predominantly affecting upper and lower motor neurons. A recent study in Italy suggested an increased incidence of ALS among professional Italian soccer players. We report a cluster of three amateur league soccer players who were friends from the same part of southern England, and developed ALS simultaneously. This might suggest that keen amateur soccer players are also at risk. [ABSTRACT FROM AUTHOR]

The article presents a discussion on menopause, multiple sclerosis, and hormone replacement therapy. Multiple sclerosis is a chronic, inflammatory, demyelinating condition of the central nervous system (CNS). It also cites the link between rapid bone loss and menopause in women. It also discusses the risk of deep vein thrombosis (DVT) in multiple sclerosis.

Conciliating biosafety with efficient gene transfer remains a constant concern in the development of retroviral vectors. Semliki Forest virus (SFV) replicons allow important retroviral vector production with interesting features. It is noteworthy that retroviruses have the ability to package Ψ+ and, to some extent, Ψ- cellular RNAs. Therefore, it was important to study the retroviral transfer of highly abundant SFV genomes expressing retroviral proteins. Here, we show that full-length SFV-vector replicons, with or without Ψ, are efficiently packaged into retrovirus particles. Mechanistically, our data suggest that SFV packaging is the sum of its retroviral nucleocapsid-dependent recruitment together with a passive hijacking of membrane-anchored SFV replicon. A direct consequence of this phenomenon is the formation of particles harboring autonomous replicative abilities and contaminating vector preparations. Importantly, we confirm that retroviral SFV mobilization is not an exclusive feature of murine gamma retroviruses, since it is also observed using lentivectors. [ABSTRACT FROM AUTHOR]

The development of efficient and safe production procedures are an essential goal conditioning viral vectors usefulness. For retroviral vectors production, two groups have suggested that Semliki forest virus (SFV) derived systems might generate interestingly elevated yields. The system relies on the transfection of three complementary SFV replicons. It is noteworthy that Muriaux and collaborator have shown that RNA is an important component for retroviral particles and that some SFV RNA could be packaged into retroviral particles. Furthermore, Lebedeva et al. and Rolls et al. have shown the arising of autonomous replication replicon from SFV vectors expressing various viral glyco-proteins envelopes. Thus, these data suggested that retroviral vectors might be vehicles for all sorts of SFV derived replicons.We designed a study aimed at thoroughly examining the packaging of full length SFV replicon into retroviral vectors. For this purpose we constructed two GFP expressing SFV replicons. One contained a prototypic Ψ sequence from MLV, while the other was missing this sequence. As SFV replicons normally give rise to genomic as well as subgenomic RNAs, we also modified their structure to prevent the formation of the later. This allowed us to set simple mobilization assays with straightforward read out based on the counting of GFP positive cells. In a first series of experiments we separately followed the mobilization of the modified SFV-GFP vectors in three conditions: using standard retroviral producing cells (PhoenixA cells); using the Li and Garoff Semliki based retroviral producing system and, lastly, in a tri-transfection lentiviral vector production. We observed mobilization events with all three conditions, albeit at different efficiencies. Using a secondary mobilization assay, we next showed that, in the Li and Garoff system, the MLV particles not only contained the GFP Semliki vector but also the Gagpol and the Env full length SFV replicons. Furthermore, a western blot analysis suggested that the retroviral particles might also contained uncleaved replicase.Finally we have shown that, in producing cells, both the retroviral proteins and the Semliki replicase were colocalised.All together, our data clearly demonstrate that retroviral particles have the ability to package genomic and subgenomic SFV RNAs, containing or not a retroviral Ψ. Therefore, these observations strongly advocate against the use of the Semliki system for clinical grade retroviral or lentiviral vector production.Molecular Therapy (2006) 13, S183–S183; doi: 10.1016/j.ymthe.2006.08.542 [ABSTRACT FROM AUTHOR]

The classic model of tumor suppression implies that malignant transformation requires full "two-hit" inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a "continuum" model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity. Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of conditions. Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash polycythemia, whereas heterozygous carriers are free of disease. Individuals with classic, heterozygous VHL mutations have VHL disease and are at high risk of multiple tumors (e.g., CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma). We report here an atypical family bearing two VHL gene mutations in cis (R200W and R161Q), together with phenotypic analysis, structural modeling, functional, and transcriptomic studies of these mutants in comparison with classical mutants involved in the different VHL phenotypes. We demonstrate that the complex pattern of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways. Thus, by studying naturally occurring familial mutations, our work validates in humans the "continuum" model of tumor suppression. [ABSTRACT FROM AUTHOR]