Blockade of CaV3 calcium channels and induction of G0/G1 cell cycle arrest in colon cancer cells by gossypol.

BACKGROUND AND PURPOSE: Gastrointestinal tumours overexpress voltage-gated calcium (CaV3) channels (CaV3.1, 3.2 and 3.3). CaV3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti-tumour properties and inhibits CaV3 currents. A systematic study was performed on gossypol blocking mechanism on CaV3 channels and its potential anticancer effects in colon cancer cells, which express CaV3 isoforms. EXPERIMENTAL APPROACH: Transcripts for CaV3 proteins were analysed in gastrointestinal cancers using public repositories and in human colorectal cancer cell lines HCT116, SW480 and SW620. The gossypol blocking mechanism on CaV3 channels was investigated by combining heterologous expression systems and patch-clamp experiments. The anti-tumoural properties of gossypol were estimated by cell proliferation, viability and cell cycle assays. Ca2+ dynamics were evaluated with cytosolic and endoplasmic reticulum (ER) Ca2+ indicators. KEY RESULTS: High levels of CaV3 transcripts correlate with poor prognosis in gastrointestinal cancers. Gossypol blockade of CaV3 isoforms is concentration- and use-dependent interacting with the closed, activated and inactivated conformations of CaV3 channels. Gossypol and CaV3 channels down-regulation inhibit colorectal cancer cell proliferation by arresting cell cycles at the G0/G1 and G2/M phases, respectively. CaV3 channels underlie the vectorial Ca2+ uptake by endoplasmic reticulum in colorectal cancer cells. CONCLUSION AND IMPLICATIONS: Gossypol differentially blocked CaV3 channel and its anticancer activity was correlated with high levels of CaV3.1 and CaV3.2 in colorectal cancer cells. The CaV3 regulates cell proliferation and Ca2+ dynamics in colorectal cancer cells. Understanding this blocking mechanism maybe improve cancer therapies.

Somos Esenciales, We are Essential: Our Mental Health is Essential. Research for, by and of the Latinx Community in the Mission District during the Pandemic.

We are Latinx immigrants and children of Latinx immigrants. We provided emergency volunteer services at the Mission Food Bank during the pandemic to provide food assistance to low-income families in the Mission District and the city of San Francisco. In March 2021, we were invited to lead a research project that we call "We are Essential". Here we share our process and a few of our findings on the mental health of San Francisco's Latinx community during the pandemic, with a focus on our children and youth. A full report of our findings will be published in 2024.

Patterns and predictors of mental health service use among older veterans with alcohol use disorder who received a video-enabled tablet.

Objectives: Video-based telehealth may expand access to mental health services among older veterans with alcohol use disorder (AUD). We examined the modalities through which mental health services were rendered, and predictors of video visits before and after video-enabled tablet receipt from the Veterans Health Administration. Method: 11,210 veterans aged 60 or older with a diagnosis of AUD who received a tablet between 1 April 2020 and 25 October 2021 were identified. The electronic health record was used to characterized encounters by modality of mental health care delivery in the six months pre/post tablet receipt. Logistic regression examined predictors of a video visit for mental health. Results: Phone was the most common modality; however, the proportion of video encounters increased from 8.7% to 26.2% after tablet receipt. Individuals who were older, male, and had more physical health conditions, were less likely to have a video visit. Individuals who were married, resided in urban areas, had a history of housing instability, and had more mental health conditions, were more likely to have a video visit. Conclusion: Video-enabled tablets may help older adults with AUD overcome access barriers to mental health services, although targeted support for certain groups may be necessary.

Determinants and outcome correlates of engagement with a mobile mental health intervention for depression and anxiety in middle-aged and older adults.

OBJECTIVES: To examine baseline factors (i.e., age, gender, mobile device proficiency, sensory impairment) associated with app engagement in a 12-week mental health app intervention and to explore whether app engagement predicts changes in depression and anxiety symptoms among middle-aged and older adults. METHOD: Mobile device proficiency, sensory impairment, depression, and anxiety symptoms were measured using questionnaires. App engagement was defined by metrics characterizing the core intervention features (i.e., messages sent to therapist, mindfulness meditation minutes, action tasks completed). Multiple regressions and multilevel models were conducted. RESULTS: Forty-nine participants (M age = 57.40, SD = 11.09 years) enrolled. Women (ß = .35, p < .05) and participants with less sensory impairment completed more action tasks (ß = -.40, p < .05). Depressive and anxiety symptoms measured within the app declined significantly across treatment. Clinical significant improvements were observed for depression in 48.9% and for anxiety in 40% of participants. App engagement metrics were not predictive of depression or anxiety symptoms, either incrementally in time-lagged models or cumulatively in hierarchical linear regression analyses. CONCLUSION: App engagement is multifaceted; participants engaged differently by gender and ability. Participation in this digital mental health intervention reduced depression and anxiety symptoms, but these findings should be interpreted with caution as the study did not include a control condition. Our findings underscore the importance of considering individual factors that may influence use of a digital mental health intervention.

Geri-Mobile Health: Feasibility of a VA Mental Health Mobile Apps Coaching Program for Older Veterans.

OBJECTIVES: This program evaluation examined the feasibility, acceptability, and preliminary effects of an individualized coaching program to help older Veterans use VA mental health mobile apps to address mental health and well-being goals. METHODS: The program delivers individual technical and clinical support to facilitate the use of mobile devices and VA apps. Participants completed assessments of mobile device proficiency, app use frequency, app comfort, quality of life, and mental health symptoms (completed by a subset, n = 11) pre- and post-participation. RESULTS: Of 24 enrollees, 17 completed the program and received an average of 7.58 (SD = 2.87) sessions including the initial assessment. Mobile device proficiency (t (16) = -3.80, p = .002) and number of days/week apps were used (t (16) = -2.34, p = .032) increased significantly from pre- to post-participation. Depressive and anxiety scores decreased significantly (t (10) = 3.16, p = .010; t (10) = 3.29, p = .008) among the subset completing those measures. Overall satisfaction was high; 100% reported they would recommend the program. CONCLUSIONS: Findings suggest the program is feasible, highly acceptable, and increases mobile device proficiency and use of apps. CLINICAL IMPLICATIONS: Coaching programs can equip older adults with the skills to use mental health apps.

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism.

Accumulation of excess nutrients hampers proper liver function and is linked to nonalcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the small ubiquitin-like modifier (SUMO) allows for a dynamic regulation of numerous processes including transcriptional reprogramming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and refed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the preservation of metabolic health.

The mRNA and protein levels of the glycolytic enzymes lactate dehydrogenase A (LDHA) and phosphofructokinase platelet (PFKP) are good predictors of survival time, recurrence, and risk of death in cervical cancer patients.

INTRODUCTION: Patients with cervical cancer (CC) may experience local recurrence very often after treatment; when only clinical parameters are used, most cases are diagnosed in late stages, which decreases the chance of recovery. Molecular markers can improve the prediction of clinical outcome. Glycolysis is altered in 70% of CCs, so molecular markers of this pathway associated with the aggressiveness of CC can be identified. METHODS: The expression of 14 glycolytic genes was analyzed in 97 CC and 29 healthy cervical tissue (HCT) with microarray; only LDHA and PFKP were validated at the mRNA and protein levels in 36 of those CC samples and in 109 new CC samples, and 31 HCT samples by qRT-PCR, Western blotting, or immunohistochemistry. A replica analysis was performed on 295 CC from The Cancer Genome Atlas (TCGA) database. RESULTS: The protein expression of LDHA and PFKP was associated with poor overall survival [OS: LDHA HR = 4.0 (95% CI = 1.4-11.1); p = 8.0 × 10-3 ; PFKP HR = 3.3 (95% CI = 1.1-10.5); p = 4.0 × 10-2 ] and disease-free survival [DFS: LDHA HR = 4.5 (95% CI = 1.9-10.8); p = 1.0 × 10-3 ; PFKP HR = 3.2 (95% CI = 1.2-8.2); p = 1.8 × 10-2 ] independent of FIGO clinical stage, and the results for mRNA expression were similar. The risk of death was greater in patients with overexpression of both biomarkers than in patients with advanced FIGO stage [HR = 8.1 (95% CI = 2.6-26.1; p = 4.3 × 10-4 ) versus HR = 7 (95% CI 1.6-31.1, p = 1.0 × 10-2 )] and increased exponentially as the expression of LDHA and PFKP increased. CONCLUSIONS: LDHA and PFKP overexpression at the mRNA and protein levels was associated with poor OS and DFS and increased risk of death in CC patients regardless of FIGO stage. The measurement of these two markers could be very useful for evaluating clinical evolution and the risk of death from CC and could facilitate better treatment decision making.

Oral or pulse glucocorticoid use at the onset of giant cell arteritis and its influence on the risk of relapse: a retrospective study.

The objective is to investigate whether initial therapy with intravenous methylprednisolone pulses (ivMTP) or oral glucocorticoid (OG) influences the relapse rate in giant cell arteritis (GCA) patients. This is a retrospective observational study of patients with GCA from 2004 to 2021. Demographics, clinical and laboratory variables, cumulative glucocorticoid dose and relapse rate at 6-month follow-up defined according to EULAR recommendations were recorded. Univariate and multivariate logistic regression models were used to determine possible risk factors for relapse. A total of 74 GCA patients were included for analysis (54 (73%) female, mean (SD) age 77.2 (7.4) years). Overall, 47 (63.5%) patients received ivMTP at disease onset and 27 (36.5%) OG. Mean (SD) cumulative prednisone dose (mg) at 6-month follow-up was 3790.7 (1832.7) for patients with ivMTP vs 4298.1 (2930.6) for the OG group, p = 0.37. A total of 15 (20.3%) relapses occurred at 6-month follow-up. Relapse rates did not differ according to the initial therapy (19.1 vs 22.2%, respectively, p = 0.75). In the multivariate analysis, fever at disease onset (OR 4.837; CI 1.1-21.6) and dyslipidemia (OR 5.651; CI 1.1-28.4) were independent predictors for relapse. Initial therapy with ivMTP or OG does not influence the relapse rate of GCA patients. Fever at disease onset and dyslipidemia are independent predictors of disease relapse.

Supporting Veterans, Caregivers, and Providers in Rural Regions With Tele-Geriatric Psychiatry Consultation: A Mixed Methods Pilot Study.

OBJECTIVES: Cross-facility tele-geriatric psychiatry consultation is a promising model for providing specialty services to regions lacking sufficient geriatric psychiatry expertise. This evaluation focused on assessing the feasibility and acceptability of a consultation program developed by a geriatric psychiatrist in a Veterans Health Administration regional telehealth hub. DESIGN: Concurrent, mixed methods program evaluation. SETTING: A region served by a VA health care system telehealth hub. PARTICIPANTS: Patients with at least 1 geriatric mental health encounter with a geriatric psychiatrist consultant during a 1 year-period; referring providers. INTERVENTION: Virtual psychiatric evaluation of Veterans with time-limited follow-up and e-consultation with providers. MEASUREMENTS: Interviews with consultant, medical record data, and referring provider surveys. RESULTS: Three hundred fifteen Veterans (M = 76.0 ± 9.64 years; 40% rural-dwelling) had 666 encounters (M = 2.11 ± 1.78) with most occurring via clinical video telehealth (n = 443; 67.6%), e-consultation (n = 99; 15.1%), or video to home (n = 95; 14.5%). Most encounters were related to neurocognitive disorders, depressive disorders, trauma-related disorders, or serious mental illness. Referring providers (N = 58) highly recommended the program, reported high satisfaction, followed through with recommendations, and believed that this program increased access to geriatric psychiatry. CONCLUSIONS: This single program was shown to be feasible, acceptable, and valued by the referring providers. The findings highlighted the complex presentations of Veterans referred, and the current unmet need of providers of such Veterans, providing impetus for wider implementation.

Effects of sulfur and phosphorus concentration on the lipid accumulation and fatty acid profile in Chlorella vulgaris (Chlorophyta).

Nutrient deficiency induces a variety of cellular responses, including an increase in lipid accumulation in microalgae. Nitrogen starvation is the most studied deprivation. Here, we determine the effects of phosphorus and sulfur limitation on lipid accumulation in Chlorella vulgaris. A set of 9 experiments were performed, varying the initial concentration of these nutrients (set to 0, 50, and 100% of their original composition in Bold's basal medium). According to our results, the variation of P and S modified the specific growth rate, lag phase, and cell generation time. The ratio of 50%P and 0%S significantly increased the total lipid concentration. The fatty acid profile was dominated by C16:0, C18:0, and C18:1; a considerable increase in C20:5 was observed with 0%P and 50%S and 0%P and 100%S. Regarding neutral lipids, the response surface methodology (RSM) indicates that the maximum was observed when S was between 40 and 60% and P was between 95 and 100%. Therefore, the enhanced production of lipids caused by P and S limitation may contribute to the efficient oil production useful for algal biofuels.

Delivering Virtual Care to Patients with Cognitive Impairment within the Veterans Health Administration: Multi-level Barriers and Solutions.

Older patients with cognitive impairment, including dementia, may benefit from virtual care that increases access to geriatric specialties. Here, we identify clinician-level strategies to address the numerous barriers that reduce utilization of virtual services. We describe two innovative programs in the Veterans Health Administration that deliver geriatric medicine and geriatric psychiatry services virtually. This commentary outlines concrete strategies addressing identified barriers, including technology access, digital literacy, and ambivalence and communication challenges during video visits. Two virtual care programs (tele-geriatric psychiatry consultation; tele-dementia care) that address complex medical and mental health issues in older adults with cognitive impairment are described. The Consolidated Framework for Implementation Research (CFIR) is used to categorize the clinician-level strategies and program elements as they relate to the implementation domains and constructs. Clinicians can use education strategies prior to and during virtual care visits to facilitate access to video, optimize the virtual experience, and promote information retention. These strategies rely on aspects of the inner setting, outer setting, and characteristics of individuals. The two virtual programs vary in their intervention characteristics and the inner setting, yet both programs share similar characteristics of individuals. Key elements contributing to adoption and sustainment of these virtual care programs for patients with cognitive impairment include the relative advantage of virtual care to leverage access to specialists over alternative solutions in each setting. Other factors to consider include the importance of communication, program champions, and the role of the Veterans Health Administration.

Impact of cardiovascular risk on the diagnostic accuracy of the ultrasound Halo Score for giant cell arteritis.

OBJECTIVE: To evaluate the impact of cardiovascular risk (CVR) on the diagnostic accuracy of the ultrasonographic (US) Halo Score in patients with suspected giant cell arteritis (GCA). METHODS: Retrospective observational study of patients referred to our US fast track clinic with suspected GCA for a 2-year period. The intima-media thickness (IMT) of cranial and extra-cranial arteries and the Halo Score was determined to assess the extent of vascular inflammation. The European Society of Cardiology Guidelines on CV Disease Prevention were used to define different categories of CVR and patients were classified according to the Systemic Coronary Risk Evaluation (SCORE). The gold standard for GCA diagnosis was clinical confirmation after a 6-month follow-up. RESULTS: Of the 157 patients included, 47 (29.9%) had GCA after a 6-month follow-up. Extra-cranial artery IMT was significantly higher in patients with high/very high CVR than in those with low/moderate CVR, but only among patients without GCA. Non-GCA patients with high/very high CVR had also a significantly higher Halo Score in contrast with low/moderate CVR [9.38 (5.93) vs 6.16 (5.22); p = 0.007]. The area under the ROC curve of the Halo Score to identify GCA was 0.835 (95% CI 0.756-0.914), slightly greater in patients with low/moderate CVR (0.965 [95% CI 0.911-1]) versus patients with high/very high CVR (0.798 [95% CI 0.702-0.895]). A statistically weak positive correlation was found between the Halo Score and the SCORE (r 0.245; c = 0.002). CONCLUSIONS: Elevated CVR may influence the diagnostic accuracy of the US Halo Score for GCA. Thus, CVR should be taken into consideration in the US screening for GCA.

Xenoimplant of Collagen Matrix Scaffold in Liver Tissue as a Niche for Liver Cells.

Hepatitis C virus-induced liver damage, chronic liver damage due to alcohol, and non-alcoholic liver disease-induced cellular alterations promote fibrosis, cirrhosis, and/or hepatocellular carcinoma. The recommended therapeutic option for advanced liver damage is liver transplantation. Extracellular matrix scaffolds have been evaluated as an alternative for tissue restoration. Studies on the biocompatibility and rejection of synthetic and natural scaffolds as an alternative to organ transplantation have been evaluated. Our group has recently described the xenoimplant of collagen matrix scaffold (CMS) in a rat model. However, no complete macroscopic and histological description of the liver parenchyma at the initial (day 3), intermediate (day 14), and advanced (day 21) stages has been obtained. In this study, we described and compared liver tissue from the CMS zone (CZ, CMS, and liver parenchyma), liver tissue from the normal zone (liver parenchyma close to the CMS), and basal tissue (resected tissue from the CMS implantation site). Our data strongly suggest that the collagen matrix xenoimplant is a good niche for hepatocytes, with no rejection, and does not affect liver function tests. The liver can regenerate after damage, but this capacity is inhibited in a chronic injury. At present, the use of CMS after liver damage has not been reported. This biomaterial could be a novel alternative in the field of regenerative medicine for liver diseases.

Real-time quantitative PCR method for detection and quantification of Clostridioides difficile cells and spores.

A quantitative PCR method was developed for the detection of Clostridioides difficile Chaperonin-60 gene. The method had a specificity for C. difficile strains of clinical and epidemiological importance and allowed for quantification of C. difficile cells and spores.

Development of a Real-Time Loop-Mediated Isothermal Amplification Assay for the Rapid Detection of Olea Europaea Geminivirus.

A real-time loop-mediated isothermal amplification (LAMP) assay was developed for simple, rapid and efficient detection of the Olea europaea geminivirus (OEGV), a virus recently reported in different olive cultivation areas worldwide. A preliminary screening by end-point PCR for OEGV detection was conducted to ascertain the presence of OEGV in Sicily. A set of six real-time LAMP primers, targeting a 209-nucleotide sequence elapsing the region encoding the coat protein (AV1) gene of OEGV, was designed for specific OEGV detection. The specificity, sensitivity, and accuracy of the diagnostic assay were determined. The LAMP assay showed no cross-reactivity with other geminiviruses and was allowed to detect OEGV with a 10-fold higher sensitivity than conventional end-point PCR. To enhance the potential of the LAMP assay for field diagnosis, a simplified sample preparation procedure was set up and used to monitor OEGV spread in different olive cultivars in Sicily. As a result of this survey, we observed that 30 out of 70 cultivars analyzed were positive to OEGV, demonstrating a relatively high OEGV incidence. The real-time LAMP assay developed in this study is suitable for phytopathological laboratories with limited facilities and resources, as well as for direct OEGV detection in the field, representing a reliable method for rapid screening of olive plant material.

A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis.

Fasting metabolism and immunity are tightly linked; however, it is largely unknown how immune cells contribute to metabolic homeostasis during fasting in healthy subjects. Here, we combined cell-type-resolved genomics and computational approaches to map crosstalk between hepatocytes and liver macrophages during fasting. We identified the glucocorticoid receptor (GR) as a key driver of fasting-induced reprogramming of the macrophage secretome including fasting-suppressed cytokines and showed that lack of macrophage GR impaired induction of ketogenesis during fasting as well as endotoxemia. Mechanistically, macrophage GR suppressed the expression of tumor necrosis factor (TNF) and promoted nuclear translocation of hepatocyte GR to activate a fat oxidation/ketogenesis-related gene program, cooperatively induced by GR and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes. Together, our results demonstrate how resident liver macrophages directly influence ketogenesis in hepatocytes, thereby also outlining a strategy by which the immune system can set the metabolic tone during inflammatory disease and infection.

Distinctions between depression and anxiety with fear of being a burden in late life.

Objectives: The perception of being a burden is a well-known risk factor for dying by suicide. Research on factors that precede the state of perceived burdensomeness, such as fearing being a burden, is necessary. We investigated the extent to which health status, elevated depressive symptoms, and elevated anxiety symptoms are associated with fear of being a burden in late life.Method: Older adult participants (N = 155) completed the Geriatric Anxiety Scale (GAS), Patient Health Questionnaire (PHQ-8), and demographic and health questions. Fear of being a burden, assessed with a supplemental item on the GAS, was categorically grouped as 'no fear' or 'some fear'. Using logistic regression, we examined predictors of fear of being a burden.Results: In the first step, elevated depression was associated with fear of being a burden (OR = 2.30, 95% CI: 1.09, 4.89, p = .03), but health status was not significant. In the second step, elevated anxiety was significant (OR = 2.63, 95% CI: 1.15, 5.99, p = .02); depression was no longer significant.Conclusion: Contrary to expectations, anxiety more strongly predicted fear of being a burden than depression. Future research should further investigate the role of anxiety in fear of being a burden and ways of intervening.