Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective

Many heat shock proteins (HSPs) are essential to survival as a consequence of their role as molecular chaperones, and play a critical role in maintaining cellular proteostasis by integrating the fundamental processes of protein folding and degradation. HSPs are arguably among the most prominent classes of proteins that have been broadly linked to many human disorders, with changes in their expression profile and/or intracellular/extracellular location now being described as contributing to the pathogenesis of a number of different diseases. Although the concept was initially controversial, it is now widely accepted that HSPs have additional biological functions over and above their role in proteostasis (so-called ‘protein moonlighting’). Most importantly, these new insights are enlightening our understanding of biological processes in health and disease, and revealing novel and exciting therapeutic opportunities. This theme issue draws on therapeutic insights from established research on HSPs in cancer and other non-communicable disorders, with an emphasis on how the intracellular function of HSPs contrasts with their extracellular properties and function, and interrogates their potential diagnostic and therapeutic value to the prevention, management and treatment of chronic diseases

A functional dissociation of the left frontal regions that contribute to single word production tasks

Controversy surrounds the interpretation of higher activation for pseudoword compared to word reading in the left precentral gyrus and pars opercularis. Specifically, does activation in these regions reflect: (1) the demands on sublexical assembly of articulatory codes, or (2) retrieval effort because the combinations of articulatory codes are unfamiliar? Using fMRI, in 84 neurologically intact participants, we addressed this issue by comparing reading and repetition of words (W) and pseudowords (P) to naming objects (O) from pictures or sounds. As objects do not provide sublexical articulatory cues, we hypothesis that retrieval effort will be greater for object naming than word repetition/reading (which benefits from both lexical and sublexical cues); while the demands on sublexical assembly will be higher for pseudoword production than object naming. We found that activation was: (i) highest for pseudoword reading [P>O&W in the visual modality] in the anterior part of the ventral precentral gyrus bordering the precentral sulcus (vPCg/vPCs), consistent with the sublexical assembly of articulatory codes; but (ii) as high for object naming as pseudoword production [P&O>W] in dorsal precentral gyrus (dPCg) and the left inferior frontal junction (IFJ), consistent with retrieval demands and cognitive control. In addition, we dissociate the response properties of vPCg/vPCs, dPCg and IFJ from other left frontal lobe regions that are activated during single word speech production. Specifically, in both auditory and visual modalities: a central part of vPCg (head and face area) was more activated for verbal than nonverbal stimuli [P&W>O]; and the pars orbitalis and inferior frontal sulcus were most activated during object naming [O>W&P]. Our findings help to resolve a previous discrepancy in the literature, dissociate three functionally distinct parts of the precentral gyrus, and refine our knowledge of the functional anatomy of speech production in the left frontal lobe

Dissociating the functions of three left posterior superior temporal regions that contribute to speech perception and production

Prior studies have shown that the left posterior superior temporal sulcus (pSTS) and left temporo-parietal junction (TPJ) both contribute to phonological short-term memory, speech perception and speech production. Here, by conducting a within-subjects multi-factorial fMRI study, we dissociate the response profiles of these regions and a third region - the anterior ascending terminal branch of the left superior temporal sulcus (atSTS), which lies dorsal to pSTS and ventral to TPJ. First, we show that each region was more activated by (i) 1-back matching on visually presented verbal stimuli (words or pseudowords) compared to 1-back matching on visually presented non-verbal stimuli (pictures of objects or non-objects), and (ii) overt speech production than 1-back matching, across 8 types of stimuli (visually presented words, pseudowords, objects and non-objects and aurally presented words, pseudowords, object sounds and meaningless hums). The response properties of the three regions dissociated within the auditory modality. In left TPJ, activation was higher for auditory stimuli that were non-verbal (sounds of objects or meaningless hums) compared to verbal (words and pseudowords), irrespective of task (speech production or 1-back matching). In left pSTS, activation was higher for non-semantic stimuli (pseudowords and hums) than semantic stimuli (words and object sounds) on the dorsal pSTS surface (dpSTS), irrespective of task. In left atSTS, activation was not sensitive to either semantic or verbal content. The contrasting response properties of left TPJ, dpSTS and atSTS was cross-validated in an independent sample of 59 participants, using region-by-condition interactions. We also show that each region participates in non-overlapping networks of frontal, parietal and cerebellar regions. Our results challenge previous claims about functional specialisation in the left posterior superior temporal lobe and motivate future studies to determine the timing and directionality of information flow in the brain networks involved in speech perception and production

Lesions that do or do not impair digit span: a study of 816 stroke survivors

Prior studies have reported inconsistency in the lesion sites associated with verbal short-term memory impairments. Here we asked: How many different lesion sites can account for selective impairments in verbal short-term memory that persist over time, and how consistently do these lesion sites impair verbal short-term memory? We assessed verbal short-term memory impairments using a forward digit span task from the Comprehensive Aphasia Test. First, we identified the incidence of digit span impairments in a sample of 816 stroke survivors (541 males/275 females; age at stroke onset 56 ± 13 years; time post-stroke 4.4 ± 5.2 years). Second, we studied the lesion sites in a subgroup of these patients (n = 39) with left hemisphere damage and selective digit span impairment-defined as impaired digit span with unimpaired spoken picture naming and spoken word comprehension (tests of speech production and speech perception, respectively). Third, we examined how often these lesion sites were observed in patients who either had no digit span impairments or digit span impairments that co-occurred with difficulties in speech perception and/or production tasks. Digit span impairments were observed in 222/816 patients. Almost all (199/222 = 90%) had left hemisphere damage to five small regions in basal ganglia and/or temporo-parietal areas. Even complete damage to one or more of these five regions was not consistently associated with persistent digit span impairment. However, when the same regions were spared, only 5% (23/455) presented with digit span impairments. These data suggest that verbal short-term memory impairments are most consistently associated with damage to left temporo-parietal and basal ganglia structures. Sparing of these regions very rarely results in persistently poor verbal short-term memory. These findings have clinical implications for predicting recovery of verbal short-term memory after stroke

SUCI02 inhibits the erbB-2 tyrosine kinase receptor signaling pathway and arrests the cell cycle in G 1 phase in breast cancer cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73321/1/j.1349-7006.2006.00143.x.pd

The Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial

OBJECTIVES: To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection. TRIAL DESIGN: ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management. PARTICIPANTS: Participants will be recruited from >80 hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently. INTERVENTION AND COMPARATOR: Participants will be randomised 1:1:1:1 to: Group 1: standard of care; Group 2: lopinavir (400mg) / ritonavir (100mg) twice daily for 10 days in tablet form; Group 3: hydroxychloroquine (800mg) 4x200mg administered 12 hours apart on Day 1, followed by 400mg twice a day for 6 days; Group 4: lopinavir /ritonavir plus hydroxychloroquine. MAIN OUTCOMES: Proportion of participants alive and not having required intensive respiratory support (invasive or non-invasive ventilation) at 15 days after enrolment. A range of clinical and virological secondary outcomes will also be evaluated. RANDOMISATION: The randomisation schedule will be generated by an independent statistician. Randomisation will be stratified by site and will be in permuted blocks of variable block size. The randomised sequence allocation will only be accessible to the data management group, and site investigators will have individual participant allocation provided through a web-based trial enrolment platform. BLINDING (MASKING): This is an open-label study, with researchers assessing the laboratory outcomes blinded to treatment allocation. No unblinding procedures relating to potential adverse effects are therefore required. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): We assumed that 5% of participants receiving standard of care would meet the primary outcome, aimed to evaluate whether interventions could lead to a relative risk of 0.5, assuming no interaction between intervention arms. This corresponds to a required sample size of 610 per arm, with a 5% two-sided significance level (alpha) and 80% power. The total sample size therefore is planned to be 2440. TRIAL STATUS: ASCOT protocol version 3, May 5, 2020. Recruitment opened April 4, 2020 and is ongoing, with planned completion of enrolment July 31, 2021. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12620000445976 ). Prospectively registered April 6, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol

Damage to Broca's area does not contribute to long-term speech production outcome after stroke

Broca’s area in the posterior half of the left inferior frontal gyrus has long been thought to be critical for speech production. The current view is that long-term speech production outcome in patients with Broca’s area damage is best explained by the combination of damage to Broca’s area and neighbouring regions including the underlying white matter, which was also damaged in Paul Broca’s two historic cases. Here, we dissociate the effect of damage to Broca’s area from the effect of damage to surrounding areas by studying long-term speech production outcome in 134 stroke survivors with relatively circumscribed left frontal lobe lesions that spared posterior speech production areas in lateral inferior parietal and superior temporal association cortices. Collectively, these patients had varying degrees of damage to one or more of nine atlas-based grey or white matter regions: Brodmann areas 44 and 45 (together known as Broca’s area), ventral premotor cortex, primary motor cortex, insula, putamen, the anterior segment of the arcuate fasciculus, uncinate fasciculus and frontal aslant tract. Spoken picture description scores from the Comprehensive Aphasia Test were used as the outcome measure. Multiple regression analyses allowed us to tease apart the contribution of other variables influencing speech production abilities such as total lesion volume and time post-stroke. We found that, in our sample of patients with left frontal damage, long-term speech production impairments (lasting beyond 3 months post-stroke) were solely predicted by the degree of damage to white matter, directly above the insula, in the vicinity of the anterior part of the arcuate fasciculus, with no contribution from the degree of damage to Broca’s area (as confirmed with Bayesian statistics). The effect of white matter damage cannot be explained by a disconnection of Broca’s area, because speech production scores were worse after damage to the anterior arcuate fasciculus with relative sparing of Broca’s area than after damage to Broca’s area with relative sparing of the anterior arcuate fasciculus. Our findings provide evidence for three novel conclusions: (i) Broca’s area damage does not contribute to long-term speech production outcome after left frontal lobe strokes; (ii) persistent speech production impairments after damage to the anterior arcuate fasciculus cannot be explained by a disconnection of Broca’s area; and (iii) the prior association between persistent speech production impairments and Broca’s area damage can be explained by co-occurring white matter damage, above the insula, in the vicinity of the anterior part of the arcuate fasciculus

Better long-term speech outcomes in stroke survivors who received early clinical speech and language therapy: What's driving recovery?

Establishing whether speech and language therapy after stroke has beneficial effects on speaking ability is challenging because of the need to control for multiple non-therapy factors known to influence recovery. We investigated how speaking ability at three time points post-stroke differed in patients who received varying amounts of clinical therapy in the first month post-stroke. In contrast to prior studies, we factored out variance from: initial severity of speaking impairment, amount of later therapy, and left and right hemisphere lesion size and site. We found that speaking ability at one month post-stroke was significantly better in patients who received early therapy (n = 79), versus those who did not (n = 64), and the number of hours of early therapy was positively related to recovery at one year post-stroke. We offer two non-mutually exclusive interpretations of these data: (1) patients may benefit from the early provision of self-management strategies; (2) therapy is more likely to be provided to patients who have a better chance of recovery (e.g., poor physical and/or mental health may impact suitability for therapy and chance of recovery). Both interpretations have implications for future studies aiming to predict individual patients' speech outcomes after stroke, and their response to therapy

The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050

The British mesothelioma register contains all deaths from 1968 to 2001 where mesothelioma was mentioned on the death certificate. These data were used to predict the future burden of mesothelioma mortality in Great Britain. Poisson regression analysis was used to model male mesothelioma deaths from 1968 to 2001 as a function of the rise and fall of asbestos exposure during the 20th century, and hence to predict numbers of male deaths in the years 2002–2050. The annual number of mesothelioma deaths in Great Britain has risen increasingly rapidly from 153 deaths in 1968 to 1848 in 2001 and, using our preferred model, is predicted to peak at around 1950 to 2450 deaths per year between 2011 and 2015. Following this peak, the number of deaths is expected to decline rapidly. The eventual death rate will depend on the background level and any residual asbestos exposure. Between 1968 and 2050, there will have been approximately 90 000 deaths from mesothelioma in Great Britain, 65 000 of which will occur after 2001