Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities

The Rho/ROCK pathway is involved in numerous pivotal cellular processes that have made it an area of intense study in cancer medicine, however, Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are yet to make an appearance in the clinical cancer setting. Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm. This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents. ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy. As such, repurposing of these agents as adjuncts to standard treatments may significantly improve outcomes for patients with cancer. A deeper understanding of the controlled and dynamic regulation of the key components of the Rho pathway may lead to effective use of the Rho/ROCK inhibitors in the clinical management of cancer

Mitochondrial reactive oxygen species are scavenged by Cockayne syndrome B protein in human fibroblasts without nuclear DNA damage

Cockayne syndrome (CS) is a human DNA repair-deficient disease that involves transcription coupled repair (TCR), in which three gene products, Cockayne syndrome A (CSA), Cockayne syndrome B (CSB), and ultraviolet stimulated scaffold protein A (UVSSA) cooperate in relieving RNA polymerase II arrest at damaged sites to permit repair of the template strand. Mutation of any of these three genes results in cells with increased sensitivity to UV light and defective TCR. Mutations in CSA or CSB are associated with severe neurological disease but mutations in UVSSA are for the most part only associated with increased photosensitivity. This difference raises questions about the relevance of TCR to neurological disease in CS. We find that CSB-mutated cells, but not UVSSA-deficient cells, have increased levels of intramitochondrial reactive oxygen species (ROS), especially when mitochondrial complex I is inhibited by rotenone. Increased ROS would result in oxidative damage to mitochondrial proteins, lipids, and DNA. CSB appears to behave as an electron scavenger in the mitochondria whose absence leads to increased oxidative stress. Mitochondrial ROS, however, did not cause detectable nuclear DNA damage even when base excision repair was blocked by an inhibitor of polyADP ribose polymerase. Neurodegeneration in Cockayne syndrome may therefore be associated with ROS-induced damage in the mitochondria, independent of nuclear TCR. An implication of our present results is that mitochondrial dysfunction involving ROS has a major impact on CS-B pathology, whereas nuclear TCR may have a minimal role

IL-1-induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation

The features that define autoreactive T helper (Th) cell pathogenicity remain obscure. We have previously shown that Th cells require the transcription factor Bhlhe40 to mediate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Here, using Bhlhe40 reporter mice and analyzing both polyclonal and TCR transgenic Th cells, we found that Bhlhe40 expression was heterogeneous after EAE induction, with Bhlhe40-expressing cells displaying marked production of IFN-γ, IL-17A, and granulocyte-macrophage colony-stimulating factor. In adoptive transfer EAE models, Bhlhe40-deficient Th1 and Th17 cells were both nonencephalitogenic. Pertussis toxin (PTX), a classical co-adjuvant for actively induced EAE, promoted IL-1β production by myeloid cells in the draining lymph node and served as a strong stimulus for Bhlhe40 expression in Th cells. Furthermore, PTX co-adjuvanticity was Bhlhe40 dependent. IL-1β induced Bhlhe40 expression in polarized Th17 cells, and Bhlhe40-expressing cells exhibited an encephalitogenic transcriptional signature. In vivo, IL-1R signaling was required for full Bhlhe40 expression by Th cells after immunization. Overall, we demonstrate that Bhlhe40 expression identifies encephalitogenic Th cells and defines a PTX–IL-1–Bhlhe40 pathway active in EAE

Active Surveillance Versus Thyroid Surgery for Differentiated Thyroid Cancer: A Systematic Review.

Background: Active surveillance has been proposed as an appropriate management strategy for low-risk differentiated thyroid cancer (DTC), due to the typically favorable prognosis of this condition. This systematic review examines the benefits and harms of active surveillance vs. immediate surgery for DTC, to inform the updated American Thyroid Association guidelines. Methods: A search on Ovid MEDLINE, Embase, and Cochrane Central was conducted in July 2021 for studies on active surveillance vs. immediate surgery. Studies of surgery vs. no surgery for DTC were assessed separately to evaluate relevance to active surveillance. Quality assessment was performed, and evidence was synthesized narratively. Results: Seven studies (five cohort studies [N = 5432] and two cross-sectional studies [N = 538]) of active surveillance vs. immediate surgery, and seven uncontrolled treatment series of active surveillance (N = 1219) were included. One cross-sectional study was rated fair quality, and the remainder were rated poor quality. In patients with low risk (primarily papillary), small (primarily ≤1 cm) DTC, active surveillance, and immediate surgery were associated with similar, low risk of all-cause or cancer-specific mortality, distant metastasis, and recurrence after surgery. Uncontrolled treatment series reported no cases of mortality in low-risk DTC managed with active surveillance. Among patients managed with active surveillance, rates of tumor growth were low; rates of subsequent surgery varied and primarily occurred due to patient preference rather than tumor progression. Four cohort studies (N = 88,654) found that surgery associated with improved all-cause or thyroid cancer mortality compared with nonsurgical management, but findings were potentially influenced by patient age and tumor risk category and highly susceptible to confounding by indication; eligibility for, and receipt of, active surveillance; and timing of surgery was unclear. Conclusions: In patients with small low-risk (primarily papillary) DTC, active surveillance and immediate surgery may be associated with similar mortality, risk of recurrence, and other outcomes, but methodological limitations preclude strong conclusions. Studies of no surgery vs. surgery are difficult to interpret due to clinical heterogeneity and potential confounding factors and are unsuitable for assessing the utility of active surveillance. Research is needed to clarify the benefits and harms of active surveillance and determine outcomes in nonpapillary DTC, larger (>1 cm) cancers, and older patients

Exploring Affordance and Situated Meaning in Image Captions: A Multimodal Analysis

This paper explores the grounding issue regarding multimodal semantic representation from a computational cognitive-linguistic view. We annotate images from the Flickr30k dataset with five perceptual properties: Affordance, Perceptual Salience, Object Number, Gaze Cueing, and Ecological Niche Association (ENA), and examine their association with textual elements in the image captions. Our findings reveal that images with Gibsonian affordance show a higher frequency of captions containing 'holding-verbs' and 'container-nouns' compared to images displaying telic affordance. Perceptual Salience, Object Number, and ENA are also associated with the choice of linguistic expressions. Our study demonstrates that comprehensive understanding of objects or events requires cognitive attention, semantic nuances in language, and integration across multiple modalities. We highlight the vital importance of situated meaning and affordance grounding in natural language understanding, with the potential to advance human-like interpretation in various scenarios.Comment: 10 pages, 9 figure

Lexical Retrieval Hypothesis in Multimodal Context

Multimodal corpora have become an essential language resource for language science and grounded natural language processing (NLP) systems due to the growing need to understand and interpret human communication across various channels. In this paper, we first present our efforts in building the first Multimodal Corpus for Languages in Taiwan (MultiMoco). Based on the corpus, we conduct a case study investigating the Lexical Retrieval Hypothesis (LRH), specifically examining whether the hand gestures co-occurring with speech constants facilitate lexical retrieval or serve other discourse functions. With detailed annotations on eight parliamentary interpellations in Taiwan Mandarin, we explore the co-occurrence between speech constants and non-verbal features (i.e., head movement, face movement, hand gesture, and function of hand gesture). Our findings suggest that while hand gestures do serve as facilitators for lexical retrieval in some cases, they also serve the purpose of information emphasis. This study highlights the potential of the MultiMoco Corpus to provide an important resource for in-depth analysis and further research in multimodal communication studies

Serum Thyroglobulin Measurement Following Surgery Without Radioactive Iodine for Differentiated Thyroid Cancer: A Systematic Review.

Background: The utility of serum thyroglobulin (Tg) measurement following partial thyroidectomy or total/near-total thyroidectomy without radioactive iodine (RAI) for differentiated thyroid cancer is unclear. This systematic review examines the diagnostic accuracy of serum Tg measurement for persistent, recurrent, and/or metastatic cancer in these situations. Methods: Ovid MEDLINE, Embase, and Cochrane Central were searched in October 2021 for studies on Tg measurement following partial thyroidectomy or total/near-total thyroidectomy without or before RAI. Quality assessment was performed, and evidence was synthesized qualitatively. Results: Thirty-seven studies met inclusion criteria. Four studies (N = 561) evaluated serum Tg measurement following partial thyroidectomy, five studies (N = 751) evaluated Tg measurement following total/near-total thyroidectomy without RAI, and 28 studies (N = 7618) evaluated Tg measurement following total or near-total thyroidectomy before RAI administration. Following partial thyroidectomy, Tg measurement was not accurate for diagnosing recurrence or metastasis, or estimates were imprecise. Following total/near-total thyroidectomy without RAI, evidence was limited due to few studies with very low rates of recurrence or metastasis, but indicated that Tg levels were usually stable and low. For Tg measurements before RAI administration, diagnostic accuracy for metastatic disease or persistence varied, although sensitivity appeared high (but specificity low) at a cutoff of >1 to 2.5 ng/mL. However, applicability to patients who do not undergo RAI is uncertain because patients selected for RAI are likely to represent a higher risk group. The evidence was very low quality for all scenarios. All studies had methodological limitations, and there was variability in the Tg thresholds evaluated, patient populations, outcomes assessed, and other factors. Conclusions: Very limited evidence suggests low utility of Tg measurement for identifying recurrent or metastatic disease following partial thyroidectomy. Following total/near-total thyroidectomy, Tg levels using a cutoff of 1-2.5 ng/mL might identify patients at low risk for persistent or metastatic disease. Additional research is needed to clarify the role of Tg measurement in these settings, determine optimal Tg thresholds, and determine appropriate measurement intervals

Complex I deficiency due to selective loss of Ndufs4 in the mouse heart results in severe hypertrophic cardiomyopathy.

Mitochondrial complex I, the primary entry point for electrons into the mitochondrial respiratory chain, is both critical for aerobic respiration and a major source of reactive oxygen species. In the heart, chronic dysfunction driving cardiomyopathy is frequently associated with decreased complex I activity, from both genetic and environmental causes. To examine the functional relationship between complex I disruption and cardiac dysfunction we used an established mouse model of mild and chronic complex I inhibition through heart-specific Ndufs4 gene ablation. Heart-specific Ndufs4-null mice had a decrease of ∼ 50% in complex I activity within the heart, and developed severe hypertrophic cardiomyopathy as assessed by magnetic resonance imaging. The decrease in complex I activity, and associated cardiac dysfunction, occurred absent an increase in mitochondrial hydrogen peroxide levels in vivo, accumulation of markers of oxidative damage, induction of apoptosis, or tissue fibrosis. Taken together, these results indicate that diminished complex I activity in the heart alone is sufficient to drive hypertrophic cardiomyopathy independently of alterations in levels of mitochondrial hydrogen peroxide or oxidative damage

The Prevalence and Mental Rehabilitation Outcome of Psychiatric Diseases and Quality of Life in Taiwan Survivors after Morakot Typhoon

Background and purposes: Post-disaster mental rehabilitation is not just a short-term intervention, but also need to be mid-term and long-term follow up. Therefore, this project is going to explore the prevalence and mental rehabilitation outcome of posttraumatic stress disorder (PTSD), major depressive episode (MDE), quality of life and the impact of risk factors in the survivors of Morakot typhoon within two years. Method: We conducted the pilot project and 5,055 community survivors were received survey. Conducting a community with a mobile medical screening for case finding and classification (high, medium and low risk groups), and follow-up by providing the survivors care and service in the acute stage. Then, we conduct screening to investigate prevalence and risk factors, and provide follow-up care to the person who has mental and emotional disorders caused by posttraumatic stress syndrome, and the continuing community care also carry out by medical case management model from two aboriginal villages nearby two years later. All the subjects are investigated by the reliability and validity of the questionnaire --- Disaster-Related Psychological Test (DRPST) and short form-12 (SF-12) after disaster in acute stage, and two-year respectively data are analysis with SPSS 17.0 Chinese version. Results: The survivors who lived in more serious damage area had 41% probable PTSD and 59% MDE. When the survivors had probable PTSD, their quality of life was prominently lower than those of without probable PTSD. There were no prominently abnormal findings of quality of life between aborigines （338）and non-aborigines（88）except ‘’general health’’ and ‘’role limitations due to physical problems’’’. Conclusion: The more serious damage area the survivors lived in, the higher prevalence of probable PTSD or MDE, the survivor had. When the time passed away, the prevalence of probable PTSD or MDE decreased.conference pape