Chaperonopathies and Chaperonotherapy. Hsp60 as Therapeutic Target in Cancer: Potential Benefits and Risks.

In this minireview we focus on Hsp60 as a target for anticancer therapy. We discuss the new concepts of chaperonopathies and chaperonotherapy and present information on Hsp60 localization in the cell membrane of human tumor cells. We describe novel mechanisms for Hsp60 reaching the extracellular environment that involve membrane-associated stages, as well as data on anti-Hsp60 antibodies found in human sera, both in normal subjects and patients affected by autoimmune diseases. Finally, we discuss possible therapeutic applications of anti-Hsp60 antibodies in cancer treatment, evaluating also side effects on non-tumor cells. In conclusion, the way for investigating Hsp60-targeted anti-tumor therapy is open, at least for those tumors that express Hsp60 on its surface and/or secrete it outside the cell, as is the search for the molecular mechanisms involved in Hsp60 translocation from cytosol to cell membrane: elucidation of this mechanism will greatly facilitate the optimization of chaperonotherapy centered on Hsp60 with anti-tumor efficacy and minimal side effects

CD1A-positive cells and HSP60 (HSPD1) levels in keratoacanthoma and squamous cell carcinoma

CD1a is involved in presentation to the immune system of lipid antigen derived from tumor cells with subsequent T cell activation. Hsp60 is a molecular chaperone implicated in carcinogenesis by, for instance, modulating the immune reaction against the tumor. We have previously postulated a synergism between CD1a and Hsp60 as a key factor in the activation of an effective antitumor immune response in squamous epithelia. Keratoacantomas (KAs) are benign tumors that however can transform into squamous cell carcinomas (SCCs), but the reasons for this malignization are unknown. In a previous study, we found that CD1a-positive cells are significantly more numerous in KA than in SCC. In this study, we analyzed a series of KAs and SCCs by immunohistochemistry for CD1a and Hsp60. Our results show that the levels of both are significantly lower in KA than in SCC and support the hypothesis that KA may evolve towards SCC if there is a failure of the local modulation of the antitumor immune response. The data also show that immunohistochemistry for CD1a and Hsp60 can be of help in differential diagnosis between KAs and well-differentiated forms of SCC

Impaired cognitive plasticity and goal-directed control in adolescent obsessive-compulsive disorder.

BACKGROUND: Youths with obsessive-compulsive disorder (OCD) experience severe distress and impaired functioning at school and at home. Critical cognitive domains for daily functioning and academic success are learning, memory, cognitive flexibility and goal-directed behavioural control. Performance in these important domains among teenagers with OCD was therefore investigated in this study. METHODS: A total of 36 youths with OCD and 36 healthy comparison subjects completed two memory tasks: Pattern Recognition Memory (PRM) and Paired Associates Learning (PAL); as well as the Intra-Extra Dimensional Set Shift (IED) task to quantitatively gauge learning as well as cognitive flexibility. A subset of 30 participants of each group also completed a Differential-Outcome Effect (DOE) task followed by a Slips-of-Action Task, designed to assess the balance of goal-directed and habitual behavioural control. RESULTS: Adolescent OCD patients showed a significant learning and memory impairment. Compared with healthy comparison subjects, they made more errors on PRM and PAL and in the first stages of IED involving discrimination and reversal learning. Patients were also slower to learn about contingencies in the DOE task and were less sensitive to outcome devaluation, suggesting an impairment in goal-directed control. CONCLUSIONS: This study advances the characterization of juvenile OCD. Patients demonstrated impairments in all learning and memory tasks. We also provide the first experimental evidence of impaired goal-directed control and lack of cognitive plasticity early in the development of OCD. The extent to which the impairments in these cognitive domains impact academic performance and symptom development warrants further investigation.This work was funded by a Wellcome Trust Grant (grant number 089589/Z/09/Z) awarded to TW Robbins, BJ Everitt, AC Roberts, JW Dalley, and BJ Sahakian, and a Wellcome Trust Senior Investigator Award (104631/Z/14/Z) to TW Robbins. The research was conducted in the Behavioural and Clinical Neuroscience Institute, which is supported by a joint award from the Medical Research Council and Wellcome Trust (G00001354). J Gottwald was supported by a BCNI MRC PhD studentship and St John’s College, Cambridge

Quantitative patterns of Hsps in tubular adenoma compared with normal and tumor tissues reveal the value of Hsp10 and Hsp60 in early diagnosis of large bowel cancer

Large bowel carcinogenesis involves accumulation of genetic alterations leading to transformation of normal mucosa into dysplasia and, lastly, adenocarcinoma. It is pertinent to elucidate the molecular changes occurring in the pre-neoplastic lesions to facilitate early diagnosis and treatment. Heat shock proteins (Hsps), many of which are molecular chaperones, are implicated in carcinogenesis, and their variations with tumor progression encourage their study as biomarkers. There are many reports on Hsps and cancer but none to our knowledge on their systematic quantification in pre-neoplastic lesions of the large bowel. We performed immunohistochemical determinations of Hsp10, Hsp60, Hsp70, and Hsp90 in biopsies of large bowel tubular adenomas with moderate grade of dysplasia and compared to normal mucosa and adenocarcinoma with a moderate grade of differentiation (G2). A significant elevation of Hsp10 and Hsp60 only, i.e., in the absence of elevation of Hsp70 or Hsp90, in both epithelium and lamina propria was found in tubular adenoma by comparison with normal mucosa. In contrast, adenocarcinoma was characterized by the highest levels of Hsp10 and Hsp60 in epithelium and lamina propria, accompanied by the highest levels of Hsp70 only in epithelium and of Hsp90 only in lamina propria, by comparison with normal and tubular adenoma counterparts. Hsp10 and Hsp60 are promising biomarkers for early diagnosis of tubular adenoma and for its differentiation from more advanced malignant lesions. Hsp10 and Hsp60 may be implicated in carcinogenesis from its very early steps and, thus, are potentially convenient targets for therapy

Heat-shock protein 60 kDa and atherogenic dyslipidemia in patients with untreated mild periodontitis: a pilot study.

Identification of predictors of cardiovascular risk can help in the prevention of pathologic episodes and the management of patients at all stages of illness. Here, we investigated the relationships between serum levels of Hsp60 and dyslipidemia in patients with periodontitis by performing a cross-sectional study of 22 patients with mild periodontitis without any prior treatment for it (i.e., drug naïve) and 22 healthy controls, matched for age and body mass index (BMI). All subjects were evaluated for periodontal status, gingival inflammation, and oral hygiene. Levels of circulating Hsp60, C-reactive protein (CRP), and plasma lipids were measured, and small, dense low-density lipoproteins (LDL) were indirectly assessed by determining the triglycerides/high-density lipoproteins (HDL) cholesterol ratio. We also assessed by immunohistochemistry Hsp60 levels in oral mucosa of patients and controls. No difference was found in CRP levels or plasma lipids between the two groups, but subjects with periodontitis showed, in comparison to controls, higher levels of small, dense LDL (p  = 0.0355) and circulating Hsp60 concentrations (p < 0.0001). However, levels of mucosal Hsp60 did not change significantly between groups. Correlation analysis revealed that circulating Hsp60 inversely correlated with HDL-cholesterol (r  = -0.589, p  = 0.0039), and positively with triglycerides (r  = +0.877, p < 0.0001), and small, dense LDL (r  = +0.925, p < 0.0001). Serum Hsp60 significantly correlated with the degree of periodontal disease (r  = +0.403, p  = 0.0434). In brief, untreated patients with mild periodontitis had increased small, dense LDL and serum Hsp60 concentrations, in comparison to age- and BMI-matched controls and both parameters showed a strong positive correlation. Our data indicate that atherogenic dyslipidemia and elevated circulating Hsp60 tend to be linked and associated to periodontal pathology. Thus, the road is open to investigate the potential value of elevated levels of circulating Hsp60 as predictor of risk for cardiovascular disease when associated to dyslipidemia in periodontitis patients

Upon oxidative stress, the antiapoptotic Hsp60/procaspase-3 complex persists in mucoepidermoid carcinoma cells.

Hsp60, a mitochondrial chaperonin highly conserved during evolution, has been found elevated in the cytosol of cancer cells, both in vivo and in vitro, but its role in determining apoptosis during oxidative stress (OS) has not yet been fully elucidated. The aim of the present work was to study the effects of OS on Hsp60 levels and its interactions with procaspase- 3 (p-C3) and p53 in tumor cells. NCI-H292 (mucoepidermoid carcinoma) cells were exposed to various concentrations of hydrogen peroxide (H2O2) for 24 hours. Cell viability was determined by Trypan blue and MTT assays. DNA damage was assessed by the Comet assay, and apoptosis was measured by the AnnexinV cytofluorimetric test. Exposure to increasing concentrations of H2O2 resulted in a reduction of cell viability, DNA damage, and early apoptotic phenomena. Hsp60, p-C3, p53, and p21 were assessed by Western blotting and immunocytochemistry before and after OS. Hsp60 and p-C3 were present before and after OS induction. Immunoprecipitation experiments showed an Hsp60/p-C3 complex before OS that persisted after it, while an Hsp60/p53 complex was not detected in either condition. The presence of wild type (wt) p53 was confirmed by RT-PCR, and p21 detection suggested p53 activation after OS. We postulate that, although OS may induce early apoptosis in NCI-H292 cells, Hsp60 exerts an anti-apoptotic effect in these cells and, by extension, it may do so in other cancer cell

Morphological and Functional Aspects of Human Skeletal Muscle

Skeletal muscle has multiple functions and is a key component of the locomotor system. It consists of carbohydrates and amino acids for different tissues such as skin, heart and brain. It contributes to the maintenance of blood glucose levels during periods of starvation. Skeletal muscle health is particularly important for the prevention of various diseases. This review discusses various aspects of skeletal muscle tissue including its development, structure, function and morphology, including the guidelines for histology methods. We have also discussed, sarcopenia, age-related muscle diseases and exercise. We hope this review will benefit readers of a clinical and non-clinical background

The Free State Housing Campaign: supporting people-led demands for social justice and accountable governance

In South Africa, community advice offices (CAOs) have historically played an important role as intermediaries for community issues and in efforts to increase accountability. CAOs are non-profit organisations that offer free legal and human rights information, advice and services to local communities, particularly poor and marginalised groups. Since the end of apartheid, their role has changed and their funding has been cut, with some turning to state service provision, potentially compromising their social justice role. Yet CAOs remain a well-known and trusted body for local people to raise issues through. This practice paper focuses on the experience of the Free State Housing Campaign, run by a group of 22 CAOs across the province, which aimed to improve people’s access to housing. The campaign came about through a Making All Voices Count scouting process, which convened the 22 CAOs. The CAOs received an innovation grant to design and launch a housing campaign to tackle their most pressing problems. The campaign adopted a participatory action research approach as a fundamental way of working and achieving its goals. The campaign also received an embedded practitioner research and learning grant from Making All Voices Count, to enable a process of evaluation, reflection and learning, rather than simply focusing on achieving the stated campaign objectives. The key themes in this paper include: participatory action research as a way to strengthen voice and build activism; the challenge and potential of community-led activism in the current neoliberal context; building women’s leadership in a patriarchal context; lessons for donor agencies about supporting grass-roots campaigns towards accountability and good governance.DFIDUSAIDSidaOmidyar Networ

Susceptibility of patients with airways disease to SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic. People with airways disease are at higher risk of respiratory infection, and viruses can trigger respiratory exacerbations. Patients with airways disease may therefore be more susceptible to SARS-CoV-2 infection, development of covid-19, or be at higher risk of adverse outcomes. Here we review susceptibility, based on current epidemiological studies, and explore biological mechanisms. Evidence from multiple large observational studies has shown chronic obstructive pulmonary disease (COPD) is a significant risk factor for covid-19 related mortality. Whether people with asthma are more susceptible to infection or severe outcomes has been much debated but appears to be related to their asthma phenotype and severity. To what extent these differences are biological or influenced by public health non-pharmacological interventions is difficult to quantify. Biological mechanisms that may influence susceptibility and adverse outcomes in airways disease include the increased expression of protein receptors enabling viral cell entry, dysfunctional epithelial airway immunity, type-2 inflammation and the use of inhaled corticosteroids. A better understanding of the susceptibility and mechanisms is essential for developing preventative and therapeutic strategies. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Interventions to reduce the effects of air pollution and of extreme heat on maternal, newborn, and child health outcomes: a mapping of the literature

Background There is an increasing awareness of the ongoing and projected impacts of air pollution and of extreme heat on maternal, newborn, and child health (MNCH) outcomes, showing significant short and long-term health problems. There is a dearth of information available for policy makers on interventions that have been implemented to reduce the impact on MNCH, impeding the integration of action into health planning. This paper presents an inventory of interventions aimed at reducing the effects of these two climate hazards on MNCH. Methods We conducted a scoping review of articles published in three databases and grey literature to identify and map interventions implemented to address the impact of air pollution and/or extreme heat on MNCH. Items were included if published between January 2016 and November 2022, regardless of language, and as this is an inventory, regardless of if the intervention was evaluated. Over 32 700 journal items were reviewed for inclusion and a sample of grey literature from web-based searches. Results A final inventory of 76 items were included. Interventions identified were primarily based in the Global North (n = 51), with the largest proportion in the USA (n = 17), while 32 items were based in the Global South. Fifty-seven items focused on air pollution, 18 on extreme heat, and one on both. Interventions were categorised in four adapted socioecological components: (i) individual and household interventions (n = 30), (ii) community and service interventions (n = 18), (iii) structural interventions and urban landscape interventions (n = 15), (iv) policy interventions (n = 16). Most items were focused on child health outcomes (n = 65); 61 items were evaluated. Conclusions This scoping review maps interventions implemented and proposes a categorisation of these to initiate reflections and dialogue on what has been done and how to start building an evidence base. The review also highlights gaps in interventions and the knowledge base, with most interventions implemented to address air pollution, in the Global North and most addressing child health need. As country programmes seek to address the impact of climate change on MNCH, additional efforts are needed to better understand what has been done, document lessons learned, agree on common outcome measurements and feasible study designs for evaluation to start building the evidence base