Factors associated with loneliness in middle-aged and older patients with breast cancer.

Objective: Loneliness is associated with adverse mental and physical health conditions and increased mortality. In this study, we identified significant factors associated with loneliness in middle-aged and older patients with breast cancer (BC). Methods: For this cross-sectional study, we enrolled 200 patients (aged from 20 to 60 years) with BC from two hospitals in Indonesia through convenience sampling. Demographic characteristics, distress symptoms (Symptom Distress Scale), social support (Multidimensional Scale of Perceived Social Support), frailty (Groningen Frailty Indicator), and loneliness (UCLA Loneliness Scale, version 3) were measured. Multivariate logistic regression was performed to identify significant factors associated with loneliness in our cohort. Results: Loneliness risk was negatively correlated with social support but positively correlated with unemployment and frailty. Thus, the patients received a high level of social support (odds ratio [OR]: 0.96; 95% confidence interval [CI]: 0.92-0.99) and had a low risk of severe loneliness. By contrast, patients who were unemployed (OR: 4.00; 95% CI: 1.65-9.66) and those who had frailty (OR: 5.79; 95% CI: 2.50-13.42) had an elevated risk of severe loneliness. Conclusions: Unemployment, social support, and frailty may significantly influence the risk of loneliness in patients with BC. Early and regular assessments of loneliness should be integrated in the care of these patients. Suitable strategies aimed at increasing social support and mitigating frailty may benefit middle-aged and older patients with BC, particularly unemployed patients, by reducing their risk of loneliness.

Effect of a Nutritional Education Program on Children's Undernutrition in Indonesia: A Randomized Controlled Trial.

INTRODUCTION: To assess effects of a nutritional education program on improving mothers' undernutrition knowledge, self-efficacy, and complementary feeding practices, and reducing undernutrition in children aged <2 years. METHOD: A randomized controlled trial was conducted at a community healthcare center in Indonesia. The intervention group participated in a 4-week nutritional education program; the control group received standard care (n = 80; 1:1 ratio). Measurements consisted of mothers' knowledge of undernutrition, self-efficacy, and complementary feeding practices, and children's anthropometric indicators. RESULTS: Intervention group mothers improved their understanding of undernutrition, self-efficacy, and complementary feeding practices compared to the control group. Additionally, children in the intervention group exhibited increased mean Z-scores for stunting, wasting, and being underweight at 12 and 24 weeks following the intervention. DISCUSSION: Healthcare professionals can regularly provide nutritional education programs related to managing undernutrition and complementary feeding practices for mothers with children aged <2 years to prevent and improve undernutrition.

Diagnostic Accuracy of the FRAIL Scale, Groningen Frailty Indicator, Tilburg Frailty Indicator, and PRISMA-7 for Frailty Screening Among Older Adults in Community Settings: A Systematic Review and Network Meta-Analysis.

BACKGROUND AND OBJECTIVES: This study aimed to investigate the diagnostic accuracy of four questionnaire-based tools (i.e., the FRAIL scale, Groningen Frailty Indicator [GFI], Tilburg Frailty Indicator [TFI], and PRISMA-7) for screening frailty in older adults. RESEARCH DESIGN AND METHODS: The 4 databases comprising the Cumulative Index to Nursing and Allied Health Literature, Embase, PubMed, and ProQuest were searched from inception to June 20, 2023. Study quality comprising risks of bias and applicability was assessed via a QUADAS-2 questionnaire. A bivariate network meta-analysis model and Youden's index were performed to identify the optimal tool and cutoff points. RESULTS: In total, 20 studies comprising 13 for FRAIL, 7 for GFI, 6 for TFI, and 5 for PRISMA-7 were included. Regarding study quality appraisal, all studies had high risks of bias for study quality assessment domains. Values of the pooled sensitivity of the FRAIL scale, GFI, TFI, and PRISMA-7 were 0.58, 0.74, 0.66, and 0.73, respectively. Values of the pooled specificity of the FRAIL scale, GFI, TFI, and PRISMA-7 were 0.92, 0.77, 0.84, and 0.86, respectively. The Youden's index was obtained for the FRAIL scale with a cutoff of 2 points (Youden's index = 0.65), indicating that the FRAIL scale with a cutoff of 2 points was the optimal tool for frailty screening in older adults. DISCUSSION AND IMPLICATIONS: The FRAIL scale comprising 5 self-assessed items is a suitable tool for interview older adults for early frailty detection in community settings; it has the advantages of being short, simple, and easy to respond to.

Psychometric properties and structural validity of traditional Chinese version of the Richards-Campbell Sleep Questionnaire in intensive care unit patients without physical restraint.

BACKGROUND: Sleep assessment in the intensive care unit (ICU) is difficult and often unreliable. The most commonly used questionnaire for assessing ICU sleep, the Richards-Campbell Sleep Scale (RCSQ), has not been tested for reliability and construct validity in the Mandarin-Taiwanese speaking population. OBJECTIVE: The objective of this study was to test the construct validity and criterion validity of the traditional Chinese version of RCSQ (TC-RCSQ) in critically ill patients without physical restraint. METHODS: We adopted a cross-sectional study design. Adults aged 20 years and above were recruited from a plastic surgery ICU of a medical center. The Cronbach's alpha was used to test internal consistency; the validity testing included content validity, criterion validity, and construct validity. Criterion validity was analysed by testing the association of TC-RCSQ with the Chinese version of Verran and Snyder-Halpern Sleep Questionnaire and sleep parameter of actigraphy using the Pearson correlation coefficient; construct validity was analysed using exploratory factor analysis. RESULTS: A total of 100 patients were included with a mean age of 49.78 years. Internal consistency reliability suggested Cronbach's alpha of 0.93. Moderate to strong correlations of TC-RCSQ with Verran-Snyder-Halpern Sleep Questionnaire were identified (r = 0.36 to 0.80, P < 0.05). We found significant correlations of actigraphic sleep efficiency with difficulty of falling sleep, awakening times, sleep quality, and total score of the TC-RCSQ (r = 0.23, 0.23, 0.20, and 0.23, P < 0.05). One factor (named as overall sleep quality) was extracted by exploratory factor analysis with a total variance explained of 78.40 %, which had good construction validity. CONCLUSIONS: The TC-RCSQ yields satisfactory reliability and validity in critically ill patients. Actigraphic sleep efficiency may be a single index for objectively sleep assessment of sleep quality in patients without physical restraint. Both the TC-RCSQ and actigraphy can aid nurses to evaluate the sleep quality in critically ill patients without physical restraint.

Ubiquitin-Specific Protease 6 n-Terminal-like Protein (USP6NL) and the Epidermal Growth Factor Receptor (EGFR) Signaling Axis Regulates Ubiquitin-Mediated DNA Repair and Temozolomide-Resistance in Glioblastoma.

Glioblastoma multiforme (GBM) is the most malignant glioma, with a 30-60% epidermal growth factor receptor (EGFR) mutation. This mutation is associated with unrestricted cell growth and increases the possibility of cancer invasion. Patients with EGFR-mutated GBM often develop resistance to the available treatment modalities and higher recurrence rates. The drug resistance observed is associated with multiple genetic or epigenetic factors. The ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) is a GTPase-activating protein that functions as a deubiquitinating enzyme and regulates endocytosis and signal transduction. It is highly expressed in many cancer types and may promote the growth and proliferation of cancer cells. We hypothesized that USP6NL affects GBM chemoresistance and tumorigenesis, and that its inhibition may be a novel therapeutic strategy for GBM treatment. The USP6NL level, together with EGFR expression in human GBM tissue samples and cell lines associated with therapy resistance, tumor growth, and cancer invasion, were investigated. Its pivotal roles and potential mechanism in modulating tumor growth, and the key mechanism associated with therapy resistance of GBM cells, were studied, both in vitro and in vivo. Herein, we found that deubiquitinase USP6NL and growth factor receptor EGFR were strongly associated with the oncogenicity and resistance of GBM, both in vitro and in vivo, toward temozolomide, as evidenced by enhanced migration, invasion, and acquisition of a highly invasive and drug-resistant phenotype by the GBM cells. Furthermore, abrogation of USP6NL reversed the properties of GBM cells and resensitized them toward temozolomide by enhancing autophagy and reducing the DNA damage repair response. Our results provide novel insights into the probable mechanism through which USP6NL/EGFR signaling might suppress the anticancer therapeutic response, induce cancer invasiveness, and facilitate reduced sensitivity to temozolomide treatment in GBM in an autolysosome-dependent manner. Therefore, controlling the USP6NL may offer an alternative, but efficient, therapeutic strategy for targeting and eradicating otherwise resistant and recurrent phenotypes of aggressive GBM cells.

Applying classification and regression tree analysis to identify risks of developing sarcopenia in the older population.

BACKGROUND AND OBJECTIVE: Variations in the risk factors for sarcopenia can lead to differences in the likelihood of developing sarcopenia among older adults; however, few studies have explored the interactions among the risk factors. This study examined the interactions among risk factors and identified a discriminative pathway for groups at risk of sarcopenia in community-dwelling older adults. METHODS: A cross-sectional study was conducted between July and August 2019 to recruit 200 older adults from an outpatient department of a hospital providing care for older people. Data on various risk factors, namely demographics (age, gender, education, comorbidities, and body mass index [BMI]), dietary habits (weekly consumption of milk, coffee, and meat), lifestyle behaviours (vitamin D supplementation, smoking, drinking, and physical activity), and depression symptoms were collected. Sarcopenia was defined according to the Asian Working Group for Sarcopenia criteria. A classification and regression tree (CART) model was used to examine interactions among these factors and identify groups at risk of sarcopenia. FINDINGS: The prevalence of sarcopenia was 38.5%. The CART model identified two end groups at differential risks of sarcopenia, with a minimum of one and a maximum of three risk factors. In the first group, low BMI (<18.5 kg/m2 ) was a predominant risk factor for sarcopenia among older people. In the second group, older adults with a normal BMI, aged ≥68 years, and without a regular walking habit had a higher probability of developing sarcopenia than did their counterparts. CONCLUSIONS: The interactive effects among older age, BMI, and walking may cause different probabilities of developing sarcopenia in the older population. IMPLICATIONS FOR PRACTICE: Older adults with a low or normal BMI but without a regular walking habit could be a predominant risk group for sarcopenia. The appropriate maintenance of body weight and regular walking activity is suggested to prevent sarcopenia in community-dwelling older adults.

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Soil acidification is an important factor leading to poor growth and root rot disease of Panax notoginseng in the understorey of forests. In this study, different amounts of quicklime (0, 500, 1000, 1500 and 2000 kg·hm-2) were amended into acid soil under forest. We evaluated the effect of quikelime addition on soil chemical properties, phenols, rhizosphere microorganisms and growth of P. notoginseng. The results showed that an appro-priate amount of quicklime addition (500-1000 kg·hm-2) could significantly increase soil pH, decrease the content of phenols (p-hydroxybenzoic acid, vanillin, syringic acid, ferulic acid and vanillic acid), promote P. notoginseng growth, and reduce the incidence of root rot disease. An appropriate amount of quicklime (500-1000 kg·hm-2) could significantly reduce the fungi:bacteria ratio, increase bacteria diversity, and increase the relative abundance of Ascomycota and Proteobacteria as well as Massilia and Sphingomonas. However, excessive quicklime addition (1500-2000 kg·hm-2) could reduce the content of available nitrogen and organic matter, and inhibit P. notoginseng growth. Therefore, 500-1000 kg·hm-2 of quicklime amendment could improve the chemical properties and microbial community of acid soil under forest, thereby promoting P. notoginseng growth, and reducing the incidence of root rot disease.

Dynamic Prevalence of Sleep Disorders Following Stroke or Transient Ischemic Attack: Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: The exact prevalence of sleep disorders following stroke or transient ischemic attack (TIA) remains unclear. We aimed to determine the prevalence of sleep-disordered breathing, insomnia, periodic leg movement during sleep, and restless leg syndrome following stroke or TIA in acute, subacute, and chronic phases and examine the moderating effects of patient characteristics (eg, age) and methodological features (eg, study quality) on the prevalence. METHODS: We performed a systematic review and meta-analysis. Embase and PubMed were searched from inception to December 18, 2019. We included 64 047 adults in 169 studies (prospective, retrospective, case-control, and cross-sectional study designs) reporting the prevalence of sleep disorders following stroke or TIA. RESULTS: In the acute phase, the overall prevalence of mild, moderate, and severe sleep-disordered breathing was 66.8%, 50.3%, and 31.6% (95% CIs, 63.8-69.7, 41.9-58.7, and 24.9-39.1). In the subacute phase, the prevalence of mild, moderate, and severe sleep-disordered breathing was 65.5%, 44.3%, and 36.1% (95% CIs, 58.9-71.5, 36.1-52.8, and 22.2-52.8). In the chronic phase, the summary prevalence of mild, moderate, and severe sleep-disordered breathing was 66.2%, 33.1%, and 25.1% (95% CIs, 58.6-73.1, 24.8-42.6, and 10.9-47.6). The prevalence rates of insomnia in the acute, subacute, and chronic phases were 40.7%, 42.6%, and 35.9% (95% CIs, 31.8-50.3, 31.7-54.1, and 28.6-44.0). The pooled prevalence of periodic leg movement during sleep in the acute, subacute, and chronic phases was 32.0%, 27.3%, and 48.2% (95% CIs, 7.4-73.5, 11.6-51.7, and 33.1-63.5). The summary prevalence of restless leg syndrome in the acute and chronic phases was 10.4% and 13.7% (95 CIs, 6.4-16.4 and 2.3-51.8). Age, sex, comorbidities, smoking history, and study region had significant moderating effects on the prevalence of sleep disorders. CONCLUSIONS: Sleep disorders following stroke or TIA are highly prevalent over time. Our findings indicate the importance of early screening and treating sleep disorders following stroke or TIA.

Cervical cancer screening behavior of African women: The Rosenstock health belief model assessment.

Our paper is a narrative synthesis of the health belief model (HBM), which was developed in the early 1950s by social psychologists Hochbaum, Rosenstock, and Kegels working in the US Public Health Services. The HBM has been adapted to explore various long- and short-term health behaviors. In this narrative synthesis, we provide the analysis of the utilization of HBM and cervical cancer screening in Africa from 2009 to 2017 and critically evaluate the HBM in the context of different African countries. We also elucidate cervical cancer screening behavior among women living in Africa through a compassionate approach. Our results provide insights into individuals' health-seeking behavior and their place of residence, which provide valuable evidence for the development of further preventative medicine.

Associations of dietary carbohydrate and salt consumption with esophageal cancer risk: a systematic review and meta-analysis of observational studies.

CONTEXT: Evidence has shown that essential nutrients are highly correlated with the occurrence of esophageal cancer (EC). However, findings from observational studies on the associations between dietary carbohydrate, salt consumption, and the risk of EC remain controversial. OBJECTIVE: The aim of this study was to conduct a systematic review and meta-analysis to confirm the associations of dietary carbohydrate and salt consumption with EC risk. DATA SOURCE: Various electronic databases (PubMed, MEDLINE, Embase, Google Scholar, Cochrane Library, Chinese Electronic Periodical Services, and China Knowledge Resource Integrated) were searched up until January 31, 2019. DATA EXTRACTION: Data related to patient characteristics and study characteristics were extracted by 2 independent reviewers. The risk ratio reported as relative risk (RR) or odds ratio (OR) was extracted, and random-effects models were performed to estimate the summary risk ratio. RESULTS: In total, 26 studies were included in this analysis, of which 12 studies, including 11 case-control studies and 1 cohort study, examined dietary carbohydrates, and 18 studies, including 16 case-control studies and 2 cohort studies, examined dietary salt. The pooled OR showed that dietary carbohydrate intake was inversely related to EC risk (OR = 0.62; 95% confidence interval [CI], 0.50-0.77), but positive correlations between dietary salt intake and the risk of EC were supported by the recruited case-control studies (OR = 1.97; 95% CI, 1.50-2.61) and cohort studies (RR = 1.04; 95% CI, 1.00-1.08). CONCLUSIONS: Salt is an essential nutrient for body functions and biochemical processes. Providing health education and management regarding proper use of salt in daily foods and labeling the amount of sodium in manufactured products to reduce the risk of developing EC should be more appropriately performed in the general population.

Association of Time-Varying Rest-Activity Rhythm With Survival in Older Adults With Lung Cancer.

BACKGROUND: To the best of our knowledge, this is the first study to examine the relationship of rest-activity rhythm with survival in older adults with lung cancer and to consider variations in rest-activity rhythm over time. OBJECTIVE: The aim of this study was to explore the relationship between rest-activity rhythm variations and survival in 33 older adults with lung cancer by considering rest-activity rhythm as a time-dependent covariate over time. METHODS: In this prospective study with 5 repeated measurements, patients' rest-activity rhythm over 3 days was measured using actigraphy. The rest-activity rhythm was represented using the dichotomy index I (in-bed activity) < O (out-of-bed activity). The median I < O was used as the cutoff point, with an I < O of greater than or equal to 85.59% and less than 85.59% indicating robust and disrupted rest-activity rhythms, respectively. Data were analyzed using the Cox regression model with time-dependent repeated measurements of a covariate. RESULTS: In the time-dependent multivariate Cox model, a disrupted rest-activity rhythm was independently associated with a higher risk of death than was a robust rest-activity rhythm (hazard ratio, 16.05; P = .009). CONCLUSION: A time-varying rest-activity rhythm is incrementally associated with mortality in older adults with lung cancer and represents a rigorous and independent prognostic factor for their survival. IMPLICATIONS FOR PRACTICE: Clinicians may need to pay more attention to the rest-activity rhythms of older adults with lung cancer during disease progression. Future studies should account for the variation in rest-activity rhythm over time.

Combinations of SERPINB5 gene polymorphisms and environmental factors are associated with oral cancer risks.

BACKGROUND: We identified rs17071138 T/C, rs3744941 C/T, and rs8089104 T/C gene polymorphisms of SERPINB5 (mammary serine protease inhibitor) that are specific to patients with oral cancer susceptibility and their clinicopathological status. METHODOLOGY/PRINCIPAL FINDINGS: In total, 1342 participants, including 601 healthy controls and 741 patients with oral cancer, were recruited for this study. Allelic discrimination of rs17071138 T/C, rs3744941 C/T, and rs8089104 T/C of the SERPINB5 gene was assessed by a real-time PCR with a TaqMan assay. We found that individuals carrying the polymorphic rs17071138 and rs8089104 are more susceptible to oral cancer (OR, 1.57; 95% CI, 1.07~2.31 and OR, 1.58; 95% CI, 1.04~2.39, respectively). Among oral cancer-related risk factor exposures, the individuals carrying the polymorphic rs17071138 had 4.26- (95% CI: 1.65~11.01; p = 0.002), 2.34- (95% CI: 1.19~4.61; p = 0.01), and 2.34-fold (95% CI: 1.38~3.96; p = 0.001) higher risks of developing oral cancer. CONCLUSIONS: Heterozygous TC of the SERPINB5 rs17071138 polymorphism may be a factor that increases susceptibility to oral cancer. Interactions of gene-to-gene and gene-to-oral cancer-related environmental risk factors have a synergetic effect that can further enhance oral cancer development.

Longitudinal transition trajectory of gouty arthritis and its comorbidities: a population-based study.

The aim of the study was to investigate the longitudinal transition trajectory of gout and its comorbidities in male patients with gout in different age groups. A total of 3973 male patients who received a new diagnosis of gouty arthritis were identified from the Taiwan Longitudinal Health Insurance Database and divided into two age cohorts (<50 and ≥50 years). Each patient was individually followed from 2000 to 2009 to identify associated comorbidities, namely hypertension, hypercholesterolemia, diabetes mellitus, cardiovascular diseases, and chronic kidney disease. Two outcome measurements of stroke and all-cause cancer were further identified until 2010. The transition trajectory was divided into the following five phenotype groups: persistent hypertension combined with a high prevalence of various gout-related comorbidities, persistent hypercholesterolemia combined with a moderate prevalence of various gout-related comorbidities, persistent low prevalence of various gout-related comorbidities, moderate to high prevalence of various gout-related comorbidities, and low to high prevalence of various gout-related comorbidities. Although the younger and older patients had a similar longitudinal transition trajectory of gout-related comorbidities, the older patients had a higher 10-year likelihood of transition from a low or moderate to a high prevalence of various gout-related comorbidities. In addition, the incidences of stroke and all-cause cancer were higher in the groups with high and moderate to high prevalences of various gout-related comorbidities than in the other groups. The occurrence of gouty arthritis in different life stages can cause cluster effects involving varying degrees of comorbidities over time. The findings of the current study can provide additional knowledge and increase clinical awareness regarding the early assessment and management of gout-related comorbidities in clinical practice.

Time-Varying Effects of Psychological Distress on the Functional Recovery of Stroke Patients.

OBJECTIVE: To explore the temporal effects of psychological distress on the functional recovery of stroke survivors. DESIGN: A longitudinal follow-up study. All participants were interviewed at 5 days after stroke onset, and at 1, 2, 3, and 6 months after discharge from acute care hospitals. SETTING: Neurology inpatient and outpatient departments and rehabilitation clinics. PARTICIPANTS: First-time stroke participants (N=62) without cognitive impairment, psychiatric disorders, or cancer were recruited. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Measurements consisted of demographic characteristics, disease severity, social support, the Chinese version of the Emotional and Social Dysfunction Questionnaire (ESDQ_C), and the Barthel Index. RESULTS: Our findings showed that psychological distress had a dynamic effect on functional recovery over time, and as the total ESDQ_C score increased by 1 point, the concurrent functional recovery decreased by .23 points (P<.001). Additionally, 5 subscales of the ESDQ_C including anger, emotional dyscontrol, helplessness, indifference, and euphoria also had dynamic effects on functional recovery over time (P<.05). Regardless of when a single form or various forms of psychological distress occurred over time from stroke onset, the functional recovery over time was simultaneously affected. CONCLUSIONS: The time-varying effect of psychological distress on functional recovery was significant. Adopting comprehensive instruments and regular assessments for the early detection of various psychological distresses while under clinical care is needed. Effective interventions targeting both physical and mental functions would further improve the functional recovery and overall health of stroke patients.

Impact of Maspin Polymorphism rs2289520 G/C and Its Interaction with Gene to Gene, Alcohol Consumption Increase Susceptibility to Oral Cancer Occurrence.

BACKGROUND: The purpose of this study was to identify gene polymorphisms of mammary serine protease inhibitor (Maspin) specific to patients with oral cancer susceptibility and clinicopathological status. METHODOLOGY/PRINCIPAL FINDINGS: Three single-nucleotide polymorphisms (SNPs) of the Maspin gene from 741 patients with oral cancer and 601 non-cancer controls were analyzed by real-time PCR. The participants with G/G homozygotes or with G/C heterozygotes of Maspin rs2289520 polymorphism had a 2.07-fold (p = 0.01) and a 2.01-fold (p = 0.02) risk of developing oral cancer compared to those with C/C homozygotes. Moreover, gene-gene interaction increased the risk of oral cancer susceptibility among subjects expose to oral cancer related risk factors, including areca, alcohol, and tobacco consumption. CONCLUSION: G allele of Maspin rs2289520 polymorphism may be a factor that increases the susceptibility to oral cancer. The interactions of gene to oral cancer-related environmental risk factors have a synergetic effect that can further enhance oral cancer development.

Walking improves sleep in individuals with cancer: a meta-analysis of randomized, controlled trials.

PURPOSE/OBJECTIVES: To evaluate the effectiveness of walking exercise on sleep in people with cancer.
 DATA SOURCES: Databases searched included China Knowledge Resource Integrated Database, CINAHL®, Cochrane Central Register of Controlled Trials, EMBASE, PsycINFO®, PubMed, Wanfang Data, and Web of Science. 
 DATA SYNTHESIS: Nine randomized, controlled trials involving 599 patients were included. Most of the studies used moderate-intensity walking exercise. Overall, walking exercise significantly improved sleep in people with cancer (Hedges' g = ­0.52). Moderator analyses showed that walking exercise alone and walking exercise combined with other forms of interventions yielded comparable effects on sleep improvement, and that the effect size did not differ among participants who were at different stages of cancer. The effect sizes for studies involving individuals with breast cancer and for studies including individuals with other types of cancer were similar.
 CONCLUSIONS: Moderate-intensity walking exercise is effective in improving sleep in individuals with cancer. 
 IMPLICATIONS FOR NURSING: The authors' findings support the inclusion of walking exercise into the multimodal approaches to managing sleep in people with cancer. Healthcare providers must convey the benefits of walking exercise to individuals with cancer who are suffering from sleep problems. 


Multiple roles for glycogen synthase kinase-3 as a drug target in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder that presents clinically as inexorable cognitive impairment and decline in performance of activities of daily living. AD is characterized pathologically by neuronal depopulation, extracellular amyloid plaques, and intraneuronal accumulation of neurofibrillary tangles (NFTs). Accumulation of these polypeptide aggregates is generally believed to be integral to the pathogenesis of AD. Recent evidence implicates the protein kinase glycogen synthase kinase 3 (GSK-3) in the regulation of both of these processes. GSK-3 has long been studied as one of several tau protein kinases, and has more recently been shown to be involved in the generation of Abeta peptides. GSK-3 activity may also promote cell death and conversely, inhibition of GSK-3 has been associated with increased cell survival under a variety of cytotoxic conditions. Thus drugs that target GSK-3 could attack AD pathogenesis on multiple fronts simultaneously. Here we will briefly review the molecular understanding of AD pathogenesis as it stands at this point, and then discuss the emerging role of GSK-3 in regulating these processes.

The Frizzled family: receptors for multiple signal transduction pathways.

Frizzled genes encode integral membrane proteins that function in multiple signal transduction pathways. They have been identified in diverse animals, from sponges to humans. The family is defined by conserved structural features, including seven hydrophobic domains and a cysteine-rich ligand-binding domain. Frizzled proteins are receptors for secreted Wnt proteins, as well as other ligands, and also play a critical role in the regulation of cell polarity. Frizzled genes are essential for embryonic development, tissue and cell polarity, formation of neural synapses, and the regulation of proliferation, and many other processes in developing and adult organisms; mutations in human frizzled-4 have been linked to familial exudative vitreoretinopathy. It is not yet clear how Frizzleds couple to downstream effectors, and this is a focus of intense study.

Interactions between BMP and Wnt signaling pathways in mammalian cancers.

The bone morphogenetic protein (BMP) and Wnt signaling pathways have been extensively studied in the regulation of early embryonic development and in the control of cell proliferation in adult tissues. Genetic interaction between these highly conserved and ubiquitous signaling pathways has been observed in multiple settings in fruit flies, amphibians, zebrafish, and mammals. While the importance of Wnt signaling in carcinogenesis has been well established, more recent work has also implicated BMP signaling in apoptosis and as a negative regulator of proliferation. In this issue of Cancer Biology & Therapy, Nishanian et al. extend these studies and propose interesting potential interactions between BMP and Wnt signaling in transformed mammalian cells that could have important implications for the control of human cancers.

SANE, a novel LEM domain protein, regulates bone morphogenetic protein signaling through interaction with Smad1.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) superfamily that play important roles in bone formation, embryonic patterning, and epidermal-neural cell fate decisions. BMPs signal through pathway specific mediators such as Smads1 and 5, but the upstream regulation of BMP-specific Smads has not been fully characterized. Here we report the identification of SANE (Smad1 Antagonistic Effector), a novel protein with significant sequence similarity to nuclear envelop proteins such as MAN1. SANE binds to Smad1/5 and to BMP type I receptors and regulates BMP signaling. SANE specifically blocks BMP-dependent signaling in Xenopus embryos and in a mammalian model of bone formation but does not inhibit the TGF-beta/Smad2 pathway. Inhibition of BMP signaling by SANE requires interaction between SANE and Smad1, because a SANE mutant that does not bind Smad1 does not inhibit BMP signaling. Furthermore, inhibition appears to be mediated by inhibition of BMP-induced Smad1 phosphorylation, blocking ligand-dependent nuclear translocation of Smad1. These studies define a new mode of regulation for intracellular BMP/Smad1 signaling.