Digital Phenotyping for Monitoring Mental Disorders: Systematic Review.

BACKGROUND: The COVID-19 pandemic has increased the impact and spread of mental illness and made health services difficult to access; therefore, there is a need for remote, pervasive forms of mental health monitoring. Digital phenotyping is a new approach that uses measures extracted from spontaneous interactions with smartphones (eg, screen touches or movements) or other digital devices as markers of mental status. OBJECTIVE: This review aimed to evaluate the feasibility of using digital phenotyping for predicting relapse or exacerbation of symptoms in patients with mental disorders through a systematic review of the scientific literature. METHODS: Our research was carried out using 2 bibliographic databases (PubMed and Scopus) by searching articles published up to January 2023. By following the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines, we started from an initial pool of 1150 scientific papers and screened and extracted a final sample of 29 papers, including studies concerning clinical populations in the field of mental health, which were aimed at predicting relapse or exacerbation of symptoms. The systematic review has been registered on the web registry Open Science Framework. RESULTS: We divided the results into 4 groups according to mental disorder: schizophrenia (9/29, 31%), mood disorders (15/29, 52%), anxiety disorders (4/29, 14%), and substance use disorder (1/29, 3%). The results for the first 3 groups showed that several features (ie, mobility, location, phone use, call log, heart rate, sleep, head movements, facial and vocal characteristics, sociability, social rhythms, conversations, number of steps, screen on or screen off status, SMS text message logs, peripheral skin temperature, electrodermal activity, light exposure, and physical activity), extracted from data collected via the smartphone and wearable wristbands, can be used to create digital phenotypes that could support gold-standard assessment and could be used to predict relapse or symptom exacerbations. CONCLUSIONS: Thus, as the data were consistent for almost all the mental disorders considered (mood disorders, anxiety disorders, and schizophrenia), the feasibility of this approach was confirmed. In the future, a new model of health care management using digital devices should be integrated with the digital phenotyping approach and tailored mobile interventions (managing crises during relapse or exacerbation).

Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy.

Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1-14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15-17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Discovery of PIM-1 kinase inhibitors based on the 2,5-disubstituted 1,3,4-oxadiazole scaffold against prostate cancer: Design, synthesis, in vitro and in vivo cytotoxicity investigation.

PIM-1 kinases play an established role in prostate cancer development and progression. This research work tackles the design and synthesis of new PIM-1 kinase targeting 2,5-disubstituted-1,3,4-oxadiazoles 10a-g&11a-f, and investigation thereof as potential anti-cancer agents through in vitro cytotoxicity assay followed by in vivo studies along with exploration of this chemotype's plausible mechanism of action. In vitro cytotoxicity experiments have disclosed 10f as the most potent derivative against PC-3 cells (IC50 = 16 nM) compared to the reference drug Staurosporine (IC50 = 0.36 µM), also eliciting good cytotoxicity against HepG2 and MCF-7 cells (IC50 = 0.13 and 5.37 µM, respectively). Investigating PIM-1 kinase inhibitory activity of compound 10f revealed an IC50 of 17 nM paralleled to that of Staurosporine (IC50 = 16.7 nM). Furthermore, compound 10f displayed an antioxidant activity eliciting a DPPH inhibition ratio of 94% as compared to Trolox (96%). Further investigation demonstrated that 10f induced apoptosis in treated PC-3 cells by 43.2-fold (19.44%) compared to 0.45% in control. 10f also disrupted the PC-3 cell cycle by increasing the cell population at the PreG1-phase by 19.29-fold while decreasing the G2/M-phase by 0.56-fold compared to control. Moreover, 10f affected a downregulation of JAK2, STAT3 and Bcl-2 and upregulation of caspases 3, 8 and 9 levels that activated the caspase-dependent apoptosis. Finally, in vivo 10f-treatment caused a significant increase in tumor inhibition by 64.2% compared to 44.5% in Staurosporine treatment of the PC-3 xenograft mouse model. Additionally, it improved the hematological, biochemical parameters, and histopathological examinations compared to control untreated animals. Finally, docking of 10f with the ATP-binding site of PIM-1 kinase demonstrated good recognition of and effective binding to the active site. In conclusion, compound 10f represents a promising lead compound that merits further future optimization for controlling prostate cancer.

Production and Clinical Evaluation of Norwalk GI.1 Virus Lot 001-09NV in Norovirus Vaccine Development.

BACKGROUND: Human noroviruses (HuNoV) are the leading cause of gastroenteritis. No vaccine is currently available to prevent norovirus illness or infection. Safe, infectious challenge strains are needed to assess vaccine efficacy in the controlled human infection model (CHIM). METHODS: A stock of HuNoV strain Norwalk virus ([NV] GI.1) was prepared. Healthy, genetically susceptible adults were inoculated with NV Lot 001-09NV and monitored for infection, gastroenteritis symptoms, and immune responses. RESULTS: Lot 001-09NV induced gastroenteritis in 9 (56%) and infection in 11 (69%) of 16 genetically susceptible subjects. All infected subjects developed strong immune responses to GI.1 with a 30-fold (geometric mean titer) increase in blocking titers (BT50) and a 161-fold increase in GI.1-specific immunoglobulin (Ig)G titers when compared with baseline. GI.1-specific cellular responses in peripheral blood were observed 9 days postchallenge with an average of 3253 IgA and 1227 IgG antibody-secreting cells per million peripheral blood mononuclear cells. CONCLUSIONS: GI.1 Lot 001-09NV appears to be similar in virulence to previous passages of NV strain 8fIIa. The safety profile, attack rate, and duration of illness make GI.1 Lot 001-09NV a useful challenge strain for future vaccine studies aimed at establishing immune correlates.

Synthesis, molecular, electronic structure, linear and non-linear optical and phototransient properties of 8-methyl-1,2-dihydro-4H-chromeno[2,3-b]quinoline-4,6(3H)-dione (MDCQD): Experimental and DFT investigations.

Base catalysed ring opening ring closure (RORC) reaction of 6-methylchromone-3­carbonitrile (1) with 1,3-cyclohexanedione afforded 8-methyl-1,2-dihydro-4H-chromeno[2,3-b]quinoline-4,6(3H)-dione (MDCQD). Theoretical calculations by Density Functional Theory (DFT) at the B3LYP/6-311G (d,p) level of theory was utilized to illustrate the equilibrium geometries of MDCQD. Also, the nonlinear optical properties, simple harmonic vibrational frequencies, thermo-chemical parameters and Mullikan atomic charges were calculated. In addition, the electronic absorption spectra in polar and non polar solvents were discussed on the basis of TD-DFT calculations. A nanofiber-like structure with high aggregation was resolved by using scanning electron microscopy images and its particle sizes were measured by particle size analyzer. The spectroscopic characteristics of the prepared thin film of MDCQD were studied in a wide spectral range of 200-2500nm. The analysis of the absorption edges affords two direct optical band gaps with energies of 1.00 and 2.76eV. A characteristic emission peak of photoluminescence spectrum in the visible region was detected and has a red-shift as a result of solvent polarity. The MDCQD film based heterojunction showed rectification behavior and diode-like characteristics. The photovoltaic characteristics under illumination of 100mW/cm2 were studied. The open-circuit voltage and short-circuit current were found to be 0.22V and 4.25×10-7A/cm2, respectively. Moreover, the prepared heterojunction showed remarkable phototransient characteristics which afford the probability for the operation as a photodiode.