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Simple Summary: Head and neck squamous cell carcinoma (HNSCC) is a common cancer in older adults, but treatment decisions for these patients can be challenging due to age-related factors, such as frailty. This study aimed to evaluate how pre-treatment frailty assessment can help predict survival outcomes and treatment-related side effects in older patients with HNSCC who undergo radiotherapy, with or without chemotherapy. We found that frailty plays a significant role in determining overall survival, but it was not directly related to acute radiation toxicity. Our findings suggest that incorporating frailty assessment into treatment planning could help personalize therapy for older patients, improving decision-making and potentially enhancing long-term outcomes. Background/Objectives: Over 60% of diagnoses of head and neck squamous cell carcinoma (HNSCC) occur in patients aged over 65. The benefits of radiotherapy (RT) combined with chemotherapy remain controversial in geriatric patients. Frailty stratification is underutilized in clinical practice despite evidence suggesting its predictive power. We aimed to assess the impact of pre-treatment frailty stratification on overall survival (OS) and acute radiation-related toxicity in a cohort of older patients with HNSCC. Methods: A prospective cohort of 117 patients aged ≥65 years with newly diagnosed HNSCC was enrolled between 2017 and 2022. Patients received RT with or without chemotherapy. Frailty was assessed using the 40-item Frailty Index (FI) as part of a comprehensive geriatric assessment. The primary outcomes were OS and acute RT toxicity, defined as a grade ≥ 3 based on CTCAE 5.0. Cox proportional hazard models and logistic regression models, adjusted for age, tumor stage, and chemotherapy, were used. Results: After a median follow-up of 819 days, FI (HR 1.478, 95% CI 1.182–1.848, p < 0.001) was an independent predictor of OS. Grade ≥ 3 toxicities were observed in 38% of patients, but frailty was not significantly associated with toxicity. A sub-analysis of oropharyngeal carcinoma patients demonstrated improved OS in HPV-positive patients (HR 0.231, 95% CI 0.078–0.686, p = 0.008). Conclusions: the standardized introduction of frailty assessment in the evaluation of older HNSCC patients holds great promise for predicting long-term survival. This approach could be crucial in tailoring treatment protocols that account for the biological heterogeneity of older adults. [ABSTRACT FROM AUTHOR]

In this cross-sectional study, we assessed palliative care (PC) needs in older adults with dementia. Using the NECPAL CCOMS-ICO© 3.1 tool and comprehensive geriatric assessment, 16.25% of the 554 evaluated patients required PC, which had clinical frailty and a moderate stage of dementia. Advanced frailty was associated with the poorest prognosis, according to the PC-based stratification. Our findings support the use of PC assessment in dementia care, which focuses on a person-centered approach while minimizing unnecessary or ineffective treatments and meeting the real-world patient's needs. PC care may fulfill the multidimensional nature of dementia, shifting towards personalized palliative approaches. [ABSTRACT FROM AUTHOR]

Background: As the population ages, the concept of frailty becomes increasingly relevant and may be considered a precursor between aging and the development of dementia in later life. Similarly, the construct of cognitive reserve (CR) is an accepted model of cognitive resilience that may account for individual differences in trajectories of brain aging, mitigating the clinical expression of dementia. Objective: We aim to estimate the role of CR and frailty in moderating the prediction of dementia in the population aged over 80 who are attending an Italian outpatient memory clinic. Methods: Comprehensive Geriatric Assessment, Clinical Frailty Scale (CFS) to screen for frailty, and Cognitive Reserve Index questionnaire (CRIq) to evaluate CR, were used to assess patients systematically. We performed multivariate logistic regression to assess associations with dementia. Model performance and interaction between frailty and cognitive reserve were then evaluated. Results: 166 patients were consecutively enrolled (mean age was 85.7 years old, females composed 68%); 25% had a diagnosis of amnestic mild cognitive impairment, and 75% had a diagnosis of dementia. Multivariate regression analysis showed that CRIq and CFS were the main clinical assessment tools associated with the presence of dementia, even after collinearity adjustment. No significant interaction of CFS*CRIq was found. Conclusions: To our knowledge, this is the first study to investigate the association between CR, frailty, dementia, and their related interacting terms in a real-world population of very old patients. Our findings may suggest that both CR and frailty shape an individual's resilience throughout their lifetime. This may potentially counteract the effects of brain neuropathology, in line with the hypothesis that meaningful associations exist between CR, frailty, and cognition in later life. [ABSTRACT FROM AUTHOR]

Background: The aging population is associated with a net increase in the incidence and prevalence of chronic-degenerative diseases, particularly neurocognitive disorders. Therefore, the identification of preventative strategies to restrain the burden of such chronic conditions is of key relevance. Red wine and its components have accumulated evidence regarding their positive effects in terms of neurological pathologies associated with neurocognitive symptoms. Methods: Based on this background, the present narrative review aims to summarize the state-of-the-art evidence on the effects of red wine and its components on neurocognitive disorders in both preclinical and clinical settings. Results: The main findings highlight a protective effect of wine polyphenols present in red wine on dementia in different preclinical models of cognitive decline. The current translational clinical evidence remains uncertain, especially considering the risk-to-benefit ratio of alcohol consumption on brain health. Conclusions: Given the overall health risks associated with red wine consumption and consistent with the prevailing guidelines in the literature, there is insufficient evidence to support light-to-moderate red wine consumption as an effective strategy for preventing these diseases. However, the largely preclinical findings on polyphenols derived from red wine remain of significant interest in this context. [ABSTRACT FROM AUTHOR]

Purpose: In recent times, growing uncertainty has emerged regarding the effectiveness of standard pressure ulcer (PU) risk assessment tools, which are suspected to be no better than clinical judgment, especially in the frail and comorbid elderly population. This study aimed to identify the primary clinical predictive variables for PU development and severity in hospitalized older adults, utilizing a multidimensional frailty assessment, and compare them with the Braden scale. Patients and methods: The population consisted of 316 patients, admitted to the Geriatric Unit and Transitional Care of San Bartolomeo Hospital in Sarzana (Italy) during the period 21/02/22-01/07/22. The collected information included both anamnestic and laboratory data. A comprehensive geriatric assessment was performed, including also anthropometric and physical performance measurements. Multivariate logistic analysis was used, both in a binary classification test and in the subsequent ordinal classification test of severity levels. The final performance of the model was assessed by ROC curve estimation and AUC comparison with the Braden scale. Results: Within the population, 152 subjects (48%) developed PU at different levels of severity. The results showed that age, Braden scale (subscales of mobility and friction/shear), Barthel scale, Mini Nutritional Assessment, hemoglobin, and albumin are predictors associated with the development of PU (AUC 85%). The result is an improvement over the use of the Braden scale alone (AUC 75%). Regarding the identification of predictive factors for PU severity, 4AT also emerges as potentially relevant. Conclusion: Assessing the subject's nutritional status, physical performance, and functional autonomies enables the effective integration of the Braden scale in identifying patients most susceptible to developing PU. Our findings support the integration of a comprehensive set of methodologically robust frailty determinants into traditional risk assessment tools. This integration reflects the mutual interplay between patients' frailty, skin frailty, and PU development in very old hospitalized patients. [ABSTRACT FROM AUTHOR]

A recent study by Ding et al. explores the integration of artificial intelligence (AI) in predicting dementia risk over a 10-year period using a multimodal approach. While revealing the potential of machine learning models in identifying high-risk individuals through neuropsychological testing, MRI imaging, and clinical risk factors, the imperative of dynamic frailty assessment emerges for accurate late-life dementia prediction. The commentary highlights challenges associated with AI models, including dimensionality and data standardization, emphasizing the critical need for a dynamic, comprehensive approach to reflect the evolving nature of dementia and improve predictive accuracy. [ABSTRACT FROM AUTHOR]

As research uncovers the underpinnings of cancer biology, new targeted therapies have been developed. Many of these therapies are small molecules, such as kinase inhibitors, that target specific proteins; however, only 1% of the genome encodes for proteins and only a subset of these proteins has 'druggable' active binding sites. In recent decades, RNA therapeutics have gained popularity due to their ability to affect targets that small molecules cannot. Additionally, they can be manufactured more rapidly and cost-effectively than small molecules or recombinant proteins. RNA therapeutics can be synthesised chemically and altered quickly, which can enable a more personalised approach to cancer treatment. Even though a wide range of RNA therapeutics are being developed for various indications in the oncology setting, none has reached the clinic to date. One of the main reasons for this is attributed to the lack of safe and effective delivery systems for this type of therapeutic. This review focuses on current strategies to overcome these challenges and enable the clinical utility of these novel therapeutic agents in the cancer clinic. [ABSTRACT FROM AUTHOR]

Anticancer antibiotics: Lung and bladder cancers are difficult to treat because of the development of drug-refractory metastases. Chrysostomou et al. show that the p90 ribosomal protein S6 kinase 4 (RSK4) is involved in the development of chemotherapy resistance and metastatic invasion in both in vitro and in vivo models. Identification of a binding site for floxacin antibiotics on RSK4 led to the finding that trovofloxacin enhanced cisplatin efficacy in mouse models of lung and bladder cancer. Combined with the finding that levofloxacin improved patient survival in a large clinical trial, this work suggests that floxacins may be repurposable against lung and bladder cancers. Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer. [ABSTRACT FROM AUTHOR]

Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n = 90), including primary SBNETs (n = 28), adjacent normal small bowel (NSB; n = 14), matched lymph node (LN) metastases (n = 24), normal LNs (n = 7), normal liver (n = 2) and liver metastases (n = 15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted. [ABSTRACT FROM AUTHOR]

Despite its identification over 100 years ago, new discoveries continue to add to the complexity of the regulation of the endocrine system. Today the nuclear receptors (NRs) that play such a pivotal role in the extensive communication networks of hormones and gene expression remain an area of intense research. By orchestrating core processes, from metabolism to organismal development, the gene expression programs they control are dependent on their cellular context, their own levels, and those of numerous co-regulatory proteins. A previously unknown component of these networks, noncoding RNAs (ncRNAs) are now recognized as potent regulators of NR signaling, influencing receptor and co-factor levels and functions while being reciprocally regulated by the NRs themselves. This review explores the regulation enacted by microRNAs and long ncRNAs on NR function, using representative examples to show the varied roles of ncRNAs, in turn producing significant effects on the NR functional network in health and disease. [ABSTRACT FROM AUTHOR]

Background: The growth arrest-specific transcript 5 gene (GAS5) encodes a long noncoding RNA (lncRNA) and hosts a number of small nucleolar RNAs (snoRNAs) that have recently been implicated in multiple cellular processes and cancer. Here, we investigate the relationship between DNA damage, p53, and the GAS5 snoRNAs to gain further insight into the potential role of this locus in cell survival and oncogenesis both in vivo and in vitro. Methods: We used quantitative techniques to analyse the effect of DNA damage on GAS5 snoRNA expression and to assess the relationship between p53 and the GAS5 snoRNAs in cancer cell lines and in normal, pre-malignant, and malignant human colorectal tissue and used biological techniques to suggest potential roles for these snoRNAs in the DNA damage response. Results: GAS5-derived snoRNA expression was induced by DNA damage in a p53-dependent manner in colorectal cancer cell lines and their levels were not affected by DICER. Furthermore, p53 levels strongly correlated with GAS5-derived snoRNA expression in colorectal tissue. Conclusions: In aggregate, these data suggest that the GAS5-derived snoRNAs are under control of p53 and that they have an important role in mediating the p53 response to DNA damage, which may not relate to their function in the ribosome. We suggest that these snoRNAs are not processed by DICER to form smaller snoRNA-derived RNAs with microRNA (miRNA)-like functions, but their precise role requires further evaluation. Furthermore, since GAS5 host snoRNAs are often used as endogenous controls in qPCR quantifications we show that their use as housekeeping genes in DNA damage experiments can lead to inaccurate results. [ABSTRACT FROM AUTHOR]

The development and growth of prostate cancer is dependent on androgens; thus, the identification of androgen-regulated genes in prostate cancer cells is vital for defining the mechanisms of prostate cancer development and progression and developing new markers and targets for prostate cancer treatment. Glycine N-methyltransferase (GNMT) is a S-adenosylmethionine-dependent methyltransferase that has been recently identified as a novel androgen-regulated gene in prostate cancer cells. Although the importance of this protein in prostate cancer progression has been extensively addressed, little is known about the mechanism of its androgen regulation. Here, we show that GNMT expression is stimulated by androgen in androgen receptor (AR) expressing cells and that the stimulation occurs at the mRNA and protein levels. We have identified an androgen response element within the first exon of the GNMT gene and demonstrated that AR binds to this element in vitro and in vivo. Together, these studies identify GNMTas a direct transcriptional target of the AR. As this is an evolutionarily conserved regulatory element, this highlights androgen regulation as an important feature of GNMT regulation. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

We identified that transforming growth factor-β (TGF-β) induces long non-coding RNA (lncRNA) MIR100HG along with its host microRNAs (miRNAs) miR-100 and miR-125b, to regulate its response in pancreatic ductal adenocarcinoma (PDAC). Importantly let-7a, despite originating from MIR100HG, remains unchanged because post-transcriptionally repressed by lin-28 homolog B (LIN28B). A novel method for global miRNA-target discovery identified that miR-100/125b regulates crucial PDAC pathways. [ABSTRACT FROM AUTHOR]

The article presents research report on Janus kinase inhibitors (JAK) inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Topics include mortality benefit in patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse event; and cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

Polymer chemistry, composition and molar mass are factors that are known to affect cytotoxicity, however the influence of polymer architecture has not been investigated systematically. In this study the influence of the position of the cationic charges along the polymer chain on cytotoxicity was investigated while keeping constant the other polymer characteristics. Specifically, copolymers of various architectures, based on a cationic pH responsive monomer, 2-(dimethylamino)ethyl methacrylate (DMAEMA) and a non-ionic hydrophilic monomer, oligo(ethylene glycol)methyl ether methacrylate (OEGMA) were engineered and their toxicity towards a panel of cell lines investigated. Of the seven different polymer architectures examined, the block-like structures were less cytotoxic than statistical or gradient/tapered architectures. These findings will assist in developing future vectors for nucleic acid delivery., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

In many tumors, cells transition reversibly between slow-proliferating tumor-initiating cells (TIC) and their differentiated, faster-growing progeny. Yet, how transcriptional regulation of cell-cycle and self-renewal genes is orchestrated during these conversions remains unclear. In this study, we show that as breast TIC form, a decrease in cell-cycle gene expression and increase in self-renewal gene expression are coregulated by SOX2 and EZH2, which colocalize at CpG islands. This pattern was negatively controlled by a novel long noncoding RNA (lncRNA) that we named Stem Cell Inhibitory RNA Transcript (SCIRT), which was markedly upregulated in tumorspheres but colocalized with and counteracted EZH2 and SOX2 during cell-cycle and self-renewal regulation to restrain tumorigenesis. SCIRT specifically interacted with EZH2 to increase EZH2 affinity to FOXM1 without binding the latter. In this manner, SCIRT induced transcription at cell-cycle gene promoters by recruiting FOXM1 through EZH2 to antagonize EZH2-mediated effects at target genes. Conversely, on stemness genes, FOXM1 was absent and SCIRT antagonized EZH2 and SOX2 activity, balancing toward repression. These data suggest that the interaction of an lncRNA with EZH2 can alter the affinity of EZH2 for its protein-binding partners to regulate cancer cell state transitions. SIGNIFICANCE: These findings show that a novel lncRNA SCIRT counteracts breast tumorigenesis by opposing transcriptional networks associated with cell cycle and self-renewal. See related commentary by Pardini and Dragomir, p. 535 ., (©2020 American Association for Cancer Research.)

Background: Baricitinib is approved for the treatment of rheumatoid arthritis (RA). The authors retrospectively investigated adverse events (AEs) by data-mining a self-reporting database to better understand toxicities, especially since it has been used during the coronavirus disease 2019 (COVID-19) pandemic., Methods: A reporting odds ratio (ROR) was used to detect the risk signals from the data in the US Food and Drug Administration (FDA) adverse event reporting system database (FAERS). The definition relied on system organ class (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA)., Results: The search retrieved 1,598 baricitinib-associated cases within the reporting period: 86 PTs with significant disproportionality were retained. Infections including 'herpes zoster,' 'oral herpes,' and 'herpes virus infection' were found at a similar rate to those reported in trials, and such events were rare. Reports emerged for several thrombotic adverse events, while these events were also rare. Unexpected safety signals as opportunistic infections were detected. Serious outcomes as death and life-threatening outcomes accounted for 9.76% of the reported cases., Conclusions: The incidence of these AEs does not appear above the background expected. These data are consistent with routine clinical observations and suggest the importance of pharmacovigilance.

Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including estrogen receptor (ER)-α. Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC 50 of 40 nmol/L; IC 50 values for CDK1, CDK2, CDK5, and CDK9 were 45-, 15-, 230-, and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI 50 values ranging between 0.2 and 0.3 μmol/L. In xenografts of both breast and colorectal cancers, the drug has substantial antitumor effects. In addition, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia and small-cell lung cancer. Mol Cancer Ther; 17(6); 1156-66. ©2018 AACR ., (©2018 American Association for Cancer Research.)

The Nuclear Receptor (NR) superfamily of transcription factors comprises 48 members, several of which have been implicated in breast cancer. Most important is estrogen receptor-α (ERα), which is a key therapeutic target. ERα action is facilitated by co-operativity with other NR and there is evidence that ERα function may be recapitulated by other NRs in ERα-negative breast cancer. In order to examine the inter-relationships between nuclear receptors, and to obtain evidence for previously unsuspected roles for any NRs, we undertook quantitative RT-PCR and bioinformatics analysis to examine their expression in breast cancer. While most NRs were expressed, bioinformatic analyses differentiated tumours into distinct prognostic groups that were validated by analyzing public microarray data sets. Although ERα and progesterone receptor were dominant in distinguishing prognostic groups, other NR strengthened these groups. Clustering analysis identified several family members with potential importance in breast cancer. Specifically, RORγ is identified as being co-expressed with ERα, whilst several NRs are preferentially expressed in ERα-negative disease, with TLX expression being prognostic in this subtype. Functional studies demonstrated the importance of TLX in regulating growth and invasion in ERα-negative breast cancer cells.

Background: The growth arrest-specific transcript 5 gene (GAS5) encodes a long noncoding RNA (lncRNA) and hosts a number of small nucleolar RNAs (snoRNAs) that have recently been implicated in multiple cellular processes and cancer. Here, we investigate the relationship between DNA damage, p53, and the GAS5 snoRNAs to gain further insight into the potential role of this locus in cell survival and oncogenesis both in vivo and in vitro., Methods: We used quantitative techniques to analyse the effect of DNA damage on GAS5 snoRNA expression and to assess the relationship between p53 and the GAS5 snoRNAs in cancer cell lines and in normal, pre-malignant, and malignant human colorectal tissue and used biological techniques to suggest potential roles for these snoRNAs in the DNA damage response., Results: GAS5-derived snoRNA expression was induced by DNA damage in a p53-dependent manner in colorectal cancer cell lines and their levels were not affected by DICER. Furthermore, p53 levels strongly correlated with GAS5-derived snoRNA expression in colorectal tissue., Conclusions: In aggregate, these data suggest that the GAS5-derived snoRNAs are under control of p53 and that they have an important role in mediating the p53 response to DNA damage, which may not relate to their function in the ribosome. We suggest that these snoRNAs are not processed by DICER to form smaller snoRNA-derived RNAs with microRNA (miRNA)-like functions, but their precise role requires further evaluation. Furthermore, since GAS5 host snoRNAs are often used as endogenous controls in qPCR quantifications we show that their use as housekeeping genes in DNA damage experiments can lead to inaccurate results.