Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment.

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.

A study on the effect of music listening on people with high neurotic tendency as evidenced by negative affective scores and physiological responses.

BACKGROUND: Music listening has been found to be effective in reducing stress levels with different participant samples. Relatively little evidence has been obtained from people with high neurotic tendency (HNT), whose dispositional psychological characteristics might dampen the effect of music listening. This study therefore tried to examine the immediate effect of music listening in reducing stressful feelings of participants with either high or low neurotic tendency. PARTICIPANTS AND PROCEDURE: Seventy-nine undergraduate participants who were identified as having either HNT or low neurotic tendency (LNT) accomplished a stressful task before listening to a comforting music piece. Negative affect (NA) scores and heart rate were measured at different phases. RESULTS: Results in a within-subjects analysis showed that the stressor and music listening could significantly alter the stressful feeling of both participant groups. Although the percentage changes in heart rate were similar between the groups, the changes of NA score which were measured after either the stressful task or the music listening session were consistently lower in the HNT group than the LNT group. CONCLUSIONS: The divergence revealed a loose connection between the subjective feelings and the bodily changes in the HNT group, which could be important for clinicians and practitioners to take into consideration in psychology when evaluating the stressful feelings for their clients with HNT.

Delineating the role of nuclear receptors in colorectal cancer, a focused review.

Colorectal cancer (CRC) stands as one of the most prevalent form of cancer globally, causing a significant number of deaths, surpassing 0.9 million in the year 2020. According to GLOBOCAN 2020, CRC ranks third in incidence and second in mortality in both males and females. Despite extensive studies over the years, there is still a need to establish novel therapeutic targets to enhance the patients' survival rate in CRC. Nuclear receptors (NRs) are ligand-activated transcription factors (TFs) that regulate numerous essential biological processes such as differentiation, development, physiology, reproduction, and cellular metabolism. Dysregulation and anomalous expression of different NRs has led to multiple alterations, such as impaired signaling cascades, mutations, and epigenetic changes, leading to various diseases, including cancer. It has been observed that differential expression of various NRs might lead to the initiation and progression of CRC, and are correlated with poor survival outcomes in CRC patients. Despite numerous studies on the mechanism and role of NRs in this cancer, it remains of significant scientific interest primarily due to the diverse functions that various NRs exhibit in regulating key hallmarks of this cancer. Thus, modulating the expression of NRs with their agonists and antagonists, based on their expression levels, holds an immense prospect in the diagnosis, prognosis, and therapeutical modalities of CRC. In this review, we primarily focus on the role and mechanism of NRs in the pathogenesis of CRC and emphasized the significance of targeting these NRs using a variety of agents, which may represent a novel and effective strategy for the prevention and treatment of this cancer.

Seeing through a robot's eyes: A cross-sectional exploratory study in developing a robotic screening technology for autism.

The present exploratory cross-sectional case-control study sought to develop a reliable and scalable screening tool for autism using a social robot. The robot HUMANE, installed with computer vision and linked with recognition technology, detected the direction of eye gaze of children. Children aged 3-8 (M = 5.52; N = 199) participated, 87 of whom had been confirmed with autism, 55 of whom were suspected to have autism, and 57 of whom were not considered to cause any concern for having autism. Before a session, a human experimenter instructed HUMANE to narrate a story to a child. HUMANE prompted the child to return his/her eye gaze to the robot if the child looked away, and praised the child when it re-established its eye gaze quickly after a prompt. The reliability of eye gaze detection was checked across all pairs of human raters and HUMANE and reached 0.90, indicating excellent interrater agreement. Using the pre-specified reference standard (Autism Spectrum Quotient), the sensitivity and specificity of the index tests (i.e., the number of robot prompts and duration of inattentiveness) reached 0.88 or above and the Diagnostic Odds Ratios were beyond 190. These results show that social robots may detect atypical eye patterns, suggesting a potential future for screening autism using social robots.

SHP2 inhibitors maintain TGFß signalling through SMURF2 inhibition.

Despite the promising antitumor activity of SHP2 inhibitors in RAS-dependent tumours, overall responses have been limited by their narrow therapeutic window. Like with all MAPK pathway inhibitors, this is likely the result of compensatory pathway activation mechanisms. However, the underlying mechanisms of resistance to SHP2 inhibition remain unknown. The E3 ligase SMURF2 limits TGFß activity by ubiquitinating and targeting the TGFß receptor for proteosome degradation. Using a functional RNAi screen targeting all known phosphatases, we identify that the tyrosine phosphatase SHP2 is a critical regulator of TGFß activity. Specifically, SHP2 dephosphorylates two key residues on SMURF2, resulting in activation of the enzyme. Conversely, SHP2 depletion maintains SMURF2 in an inactive state, resulting in the maintenance of TGFß activity. Furthermore, we demonstrate that depleting SHP2 has significant implications on TGFß-mediated migration, senescence, and cell survival. These effects can be overcome through the use of TGFß-targeted therapies. Consequently, our findings provide a rationale for combining SHP2 and TGFß inhibitors to enhance tumour responses leading to improved patient outcomes.

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

Knowledge and attitude regarding organ donation among medical students in Hong Kong: a cross-sectional study.

OBJECTIVES: The rate of organ donation in Hong Kong is among the lowest in developed regions. Since medical students will play an important role in counselling patients for organ donation and identifying potential donors in the future, their knowledge, attitudes and action for organ donation are important. This study aims to understand knowledge, attitudes and actions with regard to organ donation among medical students and investigate the factors determining the knowledge and attitudes. DESIGN: A cross-sectional study. SETTING AND PARTICIPANTS: Medical students in Hong Kong were invited to complete a questionnaire. 377 medical students participated in the study. METHODS: The questionnaire assessed their attitudes, knowledge, action of organ donation, belief and perception on organ donation, and other factors. Linear regression analyses and logistic regression were performed to analyse the effect of the variables on knowledge, attitudes and action for organ donation. RESULTS: Almost all medical students (99.5%) held a positive attitude towards organ donation, but only 28.1% have signed up as organ donors. Determinants of knowledge of organ donation included belief in preservation of intact body after death (ß = -0.14, 95% CI = -0.24 to -0.04) and perceived confidence and competence of organ donation discussion (ß = -0.12, 95% CI = -0.22 to -0.02). Predictors of organ donor registration status included knowledge of organ donation (OR=1.03, 95% CI=1.00 to 1.06), perceived convenience of organ donation registration (OR=3.75, 95% CI=1.62 to 8.71), commitment to organ donation (OR=3.81, 95% CI=2.01 to 7.21) and exposure to organ donation (OR=4.28, 95% CI=2.37 to 7.74). CONCLUSIONS: Knowledge is positively associated with organ donation action. The above determinants of organ donation could be emphasised in medical education.

Fc gamma receptor is not required for in vivo processing of radio- and drug-conjugates of the dead tumor cell-targeting monoclonal antibody, APOMAB®.

The Fc region of a monoclonal antibody (mAb) can play a crucial role in its biodistribution and therapeutic activity. The chimeric mAb, chDAB4 (APOMAB®), which binds to dead tumor cells after DNA-damaging anticancer treatment, has been studied pre-clinically in both diagnostic and therapeutic applications in cancer. Given that macrophages contribute to the tumor accumulation of chDAB4 and its potency as an antibody drug conjugate in vivo, we next wanted to determine whether the Fc region of the chDAB4 mAb also contributed. We found that, regardless of prior labeling with chDAB4, dead EL4 lymphoma or Lewis Lung (LL2) tumor cells were phagocytosed equally by wild-type or Fcγ knock-down macrophage cell lines. A similar result was seen with bone marrow-derived macrophages from wild-type, Fcγ knock-out (KO) and NOTAM mice that express Fcγ but lack immunoreceptor tyrosine-based activation motif (ITAM) signaling. Among EL4 tumor-bearing wild-type, Fcγ KO or NOTAM mice, no differences were observed in post-chemotherapy uptake of 89Zr-labeled chDAB4. Similarly, no differences were observed between LL2 tumor-bearing wild-type and Fcγ KO mice in post-chemotherapy uptake of 89Zr-chDAB4. Also, the post-chemotherapy activity of a chDAB4-antibody drug conjugate (ADC) directed against LL2 tumors did not differ among tumor-bearing wild-type, Fcγ KO and NOTAM mice, nor did the proportions and characteristics of the LL2 tumor immune cell infiltrates differ significantly among these mice. In conclusion, Fc-FcγR interactions are not essential for the diagnostic or therapeutic applications of chDAB4 conjugates because the tumor-associated macrophages, which engulf the chDAB4-labelled dead cells, respond to endogenous 'eat me' signals rather than depend on functional FcγR expression for phagocytosis.

Biomimetic synthesis of the non-canonical PPAP natural products yezo'otogirin C and hypermogin D, and studies towards the synthesis of norascyronone A.

Oxidative degradation and rearrangement of polycyclic polyprenylated acylphloroglucinols (PPAPs) has created diverse families of unique natural products that are attractive targets for biomimetic synthesis. Herein, we report a racemic synthesis of hyperibrin A and its oxidative radical cyclization to give yezo'otogirin C, followed by epoxidation and House-Meinwald rearrangement to give hypermogin D. We also investigated the biomimetic synthesis of norascyronone A via a similar radical cyclization pathway, with unexpected results that give insight into its biosynthesis.

Efficacy of physical therapy interventions on quality of life and upper quadrant pain severity in women with post-mastectomy pain syndrome: a systematic review and meta-analysis.

PURPOSE: To determine the efficacy of physical therapy interventions on quality of life (QoL) and pain severity in post-mastectomy pain syndrome (PMPS). METHODS: Multiple databases were searched from database inception to October 2020. Searches were limited to human studies published in either English or Chinese in peer-reviewed journals with full text available for randomized controlled trials conducted on females. Trials comparing the effectiveness of physical therapy interventions against control conditions on QoL and pain were included. RESULTS: Eighteen trials were included in the review. The pooled analysis of the four exercise trials revealed a significant effect of the intervention on general [standardized mean difference [SMD]: 0.87 (95%CI: 0.36, 1.37); p = 0.001], physical [SMD: 0.34 (95%CI: 0.01, 0.66); p = 0.044], and mental health components [SMD: 0.27 (95%CI: 0.03, 0.51); p = 0.027] of QoL compared with the control condition. Meta-analyses of six exercise trials, two myofascial release trials, and two acupuncture trials revealed a significant improvement in pain severity in the treatment group than in the control group. However, meta-analyses of two studies revealed a non-significant effect of compression therapy compared to control on pain severity. CONCLUSION: Our meta-analyses found that exercise is beneficial for improving the QoL and pain severity of women with PMPS. Future studies are needed to determine the optimal parameters for exercise interventions designed to improve QoL and pain severity in women with PMPS. The effect of acupuncture, myofascial release, and compression therapy remains inconclusive, and future research is required to validate the effect of these interventions on PMPS.

The estimated age-group specific influenza vaccine coverage rates in Hong Kong and the impact of the school outreach vaccination program.

Previous studies have shown that seasonal influenza strikes annually causing millions to fall sick and several hundred thousand to die globally. Hence, universal vaccination is a public health aim to control influenza. The Hong Kong Government started to introduce the School Outreach Vaccination (SOV) program in 2018 to increase vaccination rates in children. This study looked at the impact this had on hospital admissions and estimated vaccination rates in the total population, using a questionnaire-based tool. The SOV program significantly increased vaccination coverage rates with a 1% increase associated with a reduction of 4.3 influenza-related hospital admissions of school-aged children. The estimation of vaccine coverage rates among the under 5-year olds (48.5%), primary school children (69.3%) and over 65-year olds (45.7%), through the questionnaire-based tool, was within the 95% confidence interval of the coverage rates published by the Center for Health Protection of the Hong Kong Government, 47.4%, 68.1% and 45.8%, respectively. Extension of the SOV program should be considered in secondary schools to increase the coverage rates in adolescents. The questionnaire survey may inform government how to achieve universal vaccination for specific age groups.

The efficacy of integrated cognitive behavioral therapy (CBT) and acupressure versus CBT for insomnia: a three-arm pilot randomized controlled trial.

OBJECTIVES: This pilot study aimed to examine the efficacy of integrated cognitive behavioral therapy (CBT) and acupressure in treating insomnia and its daytime impairments in a Chinese adult population. METHODS: 40 eligible participants with insomnia were randomly assigned to either the integrated CBT and acupressure (CBTAcup) group (n = 14), the CBT group (n = 13), or the waitlist control (WL) group (n = 13). Participants in the CBTAcup group attended a 2-hour integrated CBT and self-administered acupressure group treatment once per week for six consecutive weeks, while participants in the CBT group attended six weekly 2-hour CBT for insomnia. Sleep, mood, daytime impairments, quality of life, and treatment credibility and adherence were assessed at baseline, immediate post-treatment (Week 7), and 4-week post-treatment (Week 11). RESULTS: Linear mixed-effects models showed that both the CBTAcup and CBT groups had significantly lower insomnia severity (d = -1.74 and d = -2.61), dysfunctional beliefs related to sleep (d = -2.17 and -2.76), and mental fatigue (d = -1.43 and -1.60) compared with the WL group at Week 7. The CBTAcup group provided additional benefits in reducing total fatigue (d = -1.43) and physical fatigue (d = -1.45). Treatment credibility was found to be improved in the CBTAcup group from baseline to Week 7. CONCLUSIONS: Integrated CBT and acupressure demonstrated comparable efficacy to pure CBT in treating insomnia symptoms, with additional advantages to improve fatigue symptoms and acceptability in the Chinese population. Further methodologically rigorous studies on a larger scale and longer follow-up are warranted to confirm these findings.

Membrane anchoring facilitates colocalization of enzymes in plant cytochrome P450 redox systems.

Plant metabolism depends on cascade reactions mediated by dynamic enzyme assemblies known as metabolons. In this context, the cytochrome P450 (P450) superfamily catalyze key reactions underpinning the unique diversity of bioactive compounds. In contrast to their soluble bacterial counterparts, eukaryotic P450s are anchored to the endoplasmic reticulum membrane and serve as metabolon nucleation sites. Hence, membrane anchoring appears to play a pivotal role in the evolution of complex biosynthetic pathways. Here, a model membrane assay enabled characterization of membrane anchor dynamics by single molecule microscopy. As a model system, we reconstituted the membrane anchor of cytochrome P450 oxidoreductase (POR), the ubiquitous electron donor to all microsomal P450s. The transmembrane segment in the membrane anchor of POR is relatively conserved, corroborating its functional importance. We observe dynamic colocalization of the POR anchors in our assay suggesting that membrane anchoring might promote intermolecular interactions and in this way impact assembly of metabolic multienzyme complexes.

Mast cells: Therapeutic targets for COVID-19 and beyond.

Mast cells (MCs) are innate immune cells that widely distribute throughout all tissues and express a variety of cell surface receptors. Upon activation, MCs can rapidly release a diverse array of preformed mediators residing within their secretory granules and newly synthesize a broad spectrum of inflammatory and immunomodulatory mediators. These unique features of MCs enable them to act as sentinels in response to rapid changes within their microenvironment. There is increasing evidence now that MCs play prominent roles in other pathophysiological processes besides allergic inflammation. In this review, we highlight the recent findings on the emerging roles of MCs in the pathogenesis of coronavirus disease-2019 (COVID-19) and discuss the potential of MCs as novel therapeutic targets for COVID-19 and other non-allergic inflammatory diseases.

Machine learning application for the prediction of SARS-CoV-2 infection using blood tests and chest radiograph.

Triaging and prioritising patients for RT-PCR test had been essential in the management of COVID-19 in resource-scarce countries. In this study, we applied machine learning (ML) to the task of detection of SARS-CoV-2 infection using basic laboratory markers. We performed the statistical analysis and trained an ML model on a retrospective cohort of 5148 patients from 24 hospitals in Hong Kong to classify COVID-19 and other aetiology of pneumonia. We validated the model on three temporal validation sets from different waves of infection in Hong Kong. For predicting SARS-CoV-2 infection, the ML model achieved high AUCs and specificity but low sensitivity in all three validation sets (AUC: 89.9-95.8%; Sensitivity: 55.5-77.8%; Specificity: 91.5-98.3%). When used in adjunction with radiologist interpretations of chest radiographs, the sensitivity was over 90% while keeping moderate specificity. Our study showed that machine learning model based on readily available laboratory markers could achieve high accuracy in predicting SARS-CoV-2 infection.

Intramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: A multi-centre, double-blind, randomised clinical trial.

BACKGROUND: The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated. METHODS: A pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18-75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam (n = 56), olanzapine (n = 54), or haloperidol (n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118). FINDINGS: Of 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine (p = 0·03) and haloperidol (p = 0·002). Adverse event rates were similar across the three arms. Dystonia (n = 1) and cardiac arrest (n = 1) were reported in the haloperidol group. INTERPRETATION: Midazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects. FUNDING: Research Grants Council, Hong Kong.