Corporate Governance in Large UK Family Firms

This report presents an updated database of family firms ranked among the largest 1,000 companies registered in the United Kingdom (UK) (as measured by turnover) and it examines their corporate governance arrangements. The project has led to the development of a large database covering key information about large UK family firms’ ownership, corporate governance and important dimensions of strategy and performance. Using these data, the report provides an overview of the population of large UK family firms and several analyses

The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC

Lurasidone in adolescents and adults with schizophrenia: from clinical trials to real-world clinical practice

Introduction: Lurasidone is an atypical antipsychotic agent approved in the European Union for the treatment of schizophrenia in adults and adolescents (13-17 years). Clinical trials have shown a generally favorable balance between efficacy and tolerability. Areas covered: This paper provides a review and commentary regarding the use of lurasidone in adults and adolescents with schizophrenia. The available information about efficacy, tolerability, dosing, and switching is analyzed, highlighting the strategies that may be most useful in real-world clinical practice. Virtual case studies, designed based on the authors' clinical experience with real-world patients, are provided. Expert opinion: Lurasidone is efficacious in adolescents and adults in a wide range of symptoms of schizophrenia. Choosing the right dose for each patient and combining lurasidone with other medications is key to treatment success. Lurasidone has proven effective both in adolescents and adults in treating the acute phase of schizophrenia and reducing the risk of relapse. It has shown a relatively favorable tolerability profile, with minimal effects on metabolic parameters and prolactin levels

The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma

Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms

The association between insight and depressive symptoms in schizophrenia: Undirected and Bayesian network analyses

Background. Greater levels of insight may be linked with depressive symptoms among patients with schizophrenia, however, it would be useful to characterize this association at symptom-level, in order to inform research on interventions. Methods. Data on depressive symptoms (Calgary Depression Scale for Schizophrenia) and insight (G12 item from the Positive and Negative Syndrome Scale) were obtained from 921 community-dwelling, clinically-stable individuals with a DSM-IV diagnosis of schizophrenia, recruited in a nationwide multicenter study. Network analysis was used to explore the most relevant connections between insight and depressive symptoms, including potential confounders in the model (neurocognitive and social-cognitive functioning, positive, negative and disorganization symptoms, extrapyramidal symptoms, hostility, internalized stigma, and perceived discrimination). Bayesian network analysis was used to estimate a directed acyclic graph (DAG) while investigating the most likely direction of the putative causal association between insight and depression. Results. After adjusting for confounders, better levels of insight were associated with greater self-depreciation, pathological guilt, morning depression and suicidal ideation. No difference in global network structure was detected for socioeconomic status, service engagement or illness severity. The DAG confirmed the presence of an association between greater insight and self-depreciation, suggesting the more probable causal direction was from insight to depressive symptoms. Conclusions. In schizophrenia, better levels of insight may cause self-depreciation and, possibly, other depressive symptoms. Person-centered and narrative psychotherapeutic approaches may be particularly fit to improve patient insight without dampening self-esteem

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Neuroendocrine aspects of cutaneous melanoma: focus on somatostatin receptors (SSTRs) expression and role of the pan-SSTR-agonist Pasireotide on cell proliferation

Cutaneous malignant melanoma (CMM) is an aggressive malignancy whose incidence and mortality has increased worldwide. CMM is the most common cause of death from skin cancer. Wide surgical excision of early stage melanoma remains the main curative treatment. Unresectable advanced melanoma presents an aggressive behavior, tendency to rapidly metastasize and an intrinsic resistance to chemotherapy. The only targeted therapy approved for melanoma is vemurafenib, a small molecule targeting BRAF particularly when affected by common mutations in the nucleotides encoding for the aminoacid V600. These evidences suggest that novel therapeutic options for advanced CMM are still required. Melanocytes derive from neural crest cells and melanoma cells can express somatostatin receptors (SSTRs) suggesting that at least a subgroup of melanomas could have a neuroendocrine differentiation. The role of somatostatin (SST) pathway in CMM has been scantly investigated. The aim of this project was to evaluate SSTRs expression and to define the effects of SST analogs in relation to SSTR protein expression in in vitro models of CMM, exploring the role of SST pathway as a potential therapeutic target in human CMM. With this propose four cutaneous melanoma cell lines: A375, HMCB, COLO38 and M14 were used as in vitro models of CMM. The expression of SSTRs was evaluated by retro transcriptase quantitative polymerase chain reaction (RT-qPCR) and immunocitochemisty (ICC) in all four cell lines. The in vitro effects of daily administration of SST analogs pasireotide and octreotide and the BRAF inhibitor vemurafenib on cell viability, proliferation and cell cycle were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay, DNA assay and fluorescence-activated cell sorting (FACS), respectively. Additionally the in vitro effects of daily administration of pasireotide in combination with vemurafenib, on cell viability, proliferation and cell cycle were investigated in two of the four cell lines (A375 and M14) that resulted sensitive to the effects of pasireotide. All tested melanoma cell lines express SSTR mRNA and proteins. At mRNA level, SSTR2 was the most expressed receptor followed by SSTR1, SSTR3 and SSTR5. The protein expression of SSTR1 was strong in A375, COLO38, M14 and moderate for HMCB; protein expression of SSTR2 was mild for A375 and COLO38, moderate for COLO38 and strong for M14; protein expression of SSTR5 was strong for A375 and M14, moderate for HMCB and mild for COLO38. The expression of SSTRs by ICC showed a predominant cytoplasmic localization in all melanoma cell lines used. Moreover, a perinucear staining for SSTR2 in COLO38 cells and for SSTR5 in HMCB and COLO38 cells was observed. Pasireotide significantly inhibited in a dose dependent-manner viability in A375 and M14 melanoma cell lines (maximal effects observed at dose of 10-7M: 41% p0.001 vs control). The antiproliferative effects of pasireotide were observed only in cell lines presenting a strong SSTR5 protein expression (A375 and M14), suggesting that this pattern of SSTR protein expression could be predictive of response to this drug in CMM. Preliminary results of the FACS analysis suggest that the antiploferative effects of pasireotide in A375 and M14 could at least in part depend by an inhibition of cell cycle. Preliminary results of western blotting experiments, exploring the subcellular localization of SSTR2 and 5 in basal condition and after pasireotide or octreotide, suggest that the different trafficking of SSTR2 and 5 might explain the stronger antiproliferative effects observed with pasireotide compared to octreotide in these two melanoma cell lines. In conclusion this study firstly described the protein expression of SSTRs and suggested that the antiproliferative effects of pasireotide in human cutaneous melanoma cell lines could be related to a particular pattern of SSTR protein expression. This study has a potential translational value since the expression of SSTRs might indicate the potential use of SST analogs, radio-labeled SST analogs, SST analogs conjugate with chemotherapic agents and SSTR scintigraphy in the management of a subset of patients with CMM. This study encourages further studies to better define the role of SST pathway in diagnosis, prognosis and as potential target for treatment in human CMM

The effects of the EU Non-Financial Reporting Directive on corporate social responsibility

Using a large sample of EU non-financial firms over the period 2008–2018, this study examines the effect of the 2014 EU Non-Financial Reporting Directive on corporate social responsibility (CSR) and finds that the Directive has led to an increase in CSR transparency and performance. Further, it shows that the association between the Directive and CSR transparency is stronger for smaller firms, firms highly followed by analysts and firms headquartered in countries with strong legal systems. The adoption of CSR reporting after the Directive’s enactment, small firm size and investments in research and development strengthen the positive effects of the Directive on CSR performance. However, the mandating of CSR reporting assurance by some EU member states seems not to have any significant impact. Lastly, our study shows that after the Directive’s enactment, firms adopting CSR reporting experienced lower systematic risk and cost of equity. Our study contributes to the debate about whether and how non-financial disclosure should be regulated and shows the positive effects of the ‘comply or explain’ approach. It also provides insights for the EU in relation to the recently approved proposal to extend CSR reporting regulation to listed small and medium-sized enterprises and mandate CSR reporting assurance

The Wates Corporate Governance Principles for Large Private Companies:Review of reporting against the Wates Principles

This report is an outcome of research commissioned by the FRC to provide an over-time comparison with, and to build upon, our previous assessment of corporate governance statements by large private companies. The previous assessment looked at companies’ 2019/20 statements; this update is based on 2021/22 statements and adds a ‘user perspective’ surveying what information users value most and for what purposes, and how such information is delivered. As with the previous assessment, the aim is to consider how companies respond to the requirement to produce a corporate governance statement and how the quality of those statements can be improved.  This years’ research found that of the 1,815 companies in scope of the Regulations, 547 companies chose to adopt the Wates Principles. Of those that followed the Wates Principles, we found slight improvements in most of the disclosure scores for each Principle. For example, more companies reported on how their purpose aligned with their business practices and on the connection between their strategy and purpose/culture. Other specific disclosures included more information about the Chair, how the board understands the company’s business needs and stakeholder interests, and rationale for its remuneration structure. While improvements were made in some areas, our findings highlight the need for companies to reduce their use of boilerplate disclosures and foster a disclosure approach which explicitly links a company’s purpose, strategy, culture, and values to its board’s activities and the context in which it operates. Going forward it is recommended the companies provide context-relevant and time- specific disclosures