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Background: Functional near-infrared spectroscopy (fNIRS) is being increasingly utilized to visualize the brain areas involved in cognitive activity to understand the human brain better. Its portability and easy setup give it an advantage over other functional brain imaging tools. The current study utilizes fNIRS while performing a Stroop test, which is commonly used to assess the impairment of information selection in depression. Aim: To compare cortical activation during the Stroop test in depressed individuals to healthy controls. Methods: This cross-sectional study compared oxyhemoglobin (OxyHb) concentration changes in 39 individuals with depression to 40 healthy individuals. The Stroop test was construed in an event-related design with an intertrial interval of 2 seconds with jitter. A continuous wave fNIRS system was used for recording the cortical activity at 17 locations. Analysis of fNIRS data was done using statistical parametric mapping (SPM) for estimating general linear model (GLM) coefficients. Further analysis of the mean change of OxyHb concentrations during the 2 seconds after the presentation of congruent and incongruent stimuli was done between the groups using Mann--Whitney U test corrected for multiple comparisons with Bonferroni correction. Results: While the number of errors and correct responses were similar between the groups, the reaction time for correct responses was more in the depression group in comparison to healthy individuals (t = -2.39, P = 0.01). For both healthy and depressive individuals in incongruent versus congruent task contrast, deactivation was seen in the region between the left middle frontal sulcus and frontopolar area of the brain (t = 0.41 and t = 0.21, respectively, P < 0.05). The depressed group had a higher mean change in OxyHb concentration following incongruent stimuli in comparison to the HCs (mean rank: HC = 32.63, depression = 47.56). Conclusion: Our findings indicate that individuals with depression exhibited prolonged reaction times and distinct activation patterns of the frontal cortex compared to healthy individuals. The observed pattern of brain activation for congruent and incongruent tasks among both healthy and depressed individuals aligns with the findings of the prior studies, emphasizing the utility of fNIRS as a valuable instrument for assessing brain activity. [ABSTRACT FROM AUTHOR]

Background: The use of restraint in psychiatric inpatient settings is a contentious issue, balancing patient safety with ethical concerns. Despite India's Mental Healthcare Act of 2017, which prohibits seclusion and mandates stringent restraint regulations, restraint remains a critical intervention in managing acute behavioral crises. This study investigates the prevalence, patterns, and determinants of restraint use in a tertiary care psychiatric facility in Northern India. Materials and Methods: This hospital-based, observational, prospective study was conducted over 6 months in a 32-bedded psychiatry ward. Data were collected from ward registers, treatment charts, and patient records, documenting restraint events. Sociodemographic and clinical factors were analyzed using descriptive statistics, comparisons, and logistic regression. Results: Among 128 admissions (5,518 inpatient days), 35.1% of patients experienced restraint, yielding a restraint patient rate of 8.15 per 1000 inpatient days and an event rate of 26.1 per 1000 inpatient days. Chemical restraint was predominant (74.3% of events), followed by combined (22.9%) and physical restraint (2.8%). Restraint occurred primarily in young adults with mood and psychotic disorders, with no significant association between restraint use and sociodemographic or clinical factors. Most restraints were applied within the 1st week of admission. Conclusions: Restraint, primarily chemical, remains common in managing acute agitation and violence, especially early in hospitalization. The findings underscore the importance of balancing clinical needs with patient rights while striving for noncoercive, patient-centered psychiatric care. The findings also highlight the need for standardized reporting and continued training to minimize restraint use and promote ethical healthcare delivery. [ABSTRACT FROM AUTHOR]

Individuals with poor mental health often find themselves vulnerable to a myriad of factors such as poverty, social disadvantage, lower level of education, abuse, and personal vulnerability. For these reasons, they struggle to secure stable housing, which leads to a cycle of persistent poverty. In this background, we present a series of three adolescents who succumbed to homelessness due to their mental illnesses and subsequent social situations. The three adolescent girls were rescued by child welfare committees with the help of police and brought to the hospital. The challenges faced by the treating team included a lack of caregivers, difficulty in ruling out any sexual abuse, dealing with different jurisdictions, financial limitations of parents to travel long distances, COVID restrictions across states, and mental illness of patient impairing capacity. This also delayed their rehabilitation and prolonged hospital stay. We can conclude that clinicians should focus on stopping the vicious cycle at the earliest so that the long‐term consequences of mental illness, as well as homelessness, can be avoided. The current imperative is to establish a secure setting for children while also facilitating early detection and intervention for mental health issues, with a particular focus on homeless children. [ABSTRACT FROM AUTHOR]

Background: There is a limited number of studies from India investigating the role of transcranial direct current stimulation (tDCS) in treatment-resistant depression (TRD). This clinic-based study reports on the effectiveness of tDCS as an add-on treatment in individuals suffering from TRD. Materials and Methods: Twenty-six right-handed individuals suffering from major depressive disorder who failed to respond to adequate trials of at least two antidepressant drugs in the current episode received tDCS as an augmenting treatment. Twice daily sessions of conventional tDCS were given providing anodal stimulation at the left dorsolateral prefrontal cortex (DLPFC) and cathodal placement at the right DLPFC. A total of 20 sessions were given over 2 weeks. The outcome was assessed based on changes in scores of the Hamilton Rating Scale for Depression (HAMD) and Montgomery-Asberg Depression Rating Scale (MADRS). Results: There was a significant reduction in outcome assessment after tDCS intervention as compared to baseline, with more than 50% of the participants showing response in both scales, which increased further to approximately 77% by the end of 1 month of the follow-up period. Conclusion: Twice daily tDCS sessions with anodal stimulation of left DLPFC and cathodal stimulation of right DLPFC is an effective add-on treatment strategy in individuals with TRD. [ABSTRACT FROM AUTHOR]

Introduction: Substance use disorders are a global public health concern, necessitating a deeper understanding of the factors influencing sustainable recovery. This study investigates the roles of various factors influencing the recovery journey of abstinent substance users. By unravelling the roles of subjective happiness, daily spiritual experiences, and social support, we aim to contribute valuable knowledge to the fields of addiction research and social psychiatry. Methods: The study involves 150 male participants, aged 18-72 years, who have successfully abstained from substance use. Sociodemographic and clinical data of adult males with a diagnosis of opioid dependence or alcohol dependence were collected. Daily spiritual experiences, recovery capital, subjective happiness, and social support were evaluated using a validated DSE questionnaire, recovery capital Questionnaire, standardized subjective happiness Scale and the Multidimensional Scale of Perceived Social Support, respectively. Mediating/moderating analysis was studied using model 5 of Hayes' Process Macros. Institutional Review Board approval was obtained prior to initiating the study. Results: All 150 participants (100 opioid dependence, 50 alcohol dependence) had high substance use severity. The mean age was 39.8 years (±11.7). The mean age of onset of substance use was 21.6 years (±6.7), while onset of substance dependence was 24.8 years (±8.3), with an average duration of abstinence of 20 months. The correlation between social support and recovery capital was statistically significant and strong (r = 0.6, p < .001). Similarly, subjective happiness was positively correlated with both social support (r = 0.4, p < .001) and recovery capital (r = 0.5, p < .001), indicating that individuals reporting higher subjective happiness also tend to have greater social support and recovery capital (Table 1). Social support emerged as a significant predictor of recovery capital (ß = 0.55, p < .001), explaining approximately 29.7% of the variance in recovery capital. Subjective happiness partially (complimentary) mediated 18% of the variance in the relationship between social support and recovery capital (p < .001), with an indirect effect of 0.1585 (0.096-0.2327; p < .001). Daily spiritual experiences moderated the relationship between social support and recovery capital (ß = -0.008, p = .036) at both high and low daily spiritual experiences scores, and this significance was prominent when daily spiritual experiences scores exceeds 21.3 (Figure 1). Conclusion: These findings highlight intricate pathways to sustainable recovery. This emphasizes the role of positive emotional states in recovery and conditional effect of spirituality on recovery. These insights have implications for tailored interventions and support systems to enhance recovery outcomes, promote long-term abstinence, optimizing addiction treatment and recovery programs. [ABSTRACT FROM AUTHOR]

Abstract As the new economy shifts gears, we enter an era when the careful examination of value creation is not enough. By 2003, the portion of the economy driven by the electronic medium will be greater than that driven by industrial companies. In this new stage of the Internet economy, the focus moves away from examination and full throttle toward execution. The author uses a number of case studies to demonstrate the best practices that will lead to organization e- transformation. [ABSTRACT FROM AUTHOR]

An enhanced variant of the antimitotic toxin cryptophycin was conjugated to the anti-Her2 monoclonal antibody (mAb) Trastuzumab upon Michael addition. Either antibodies with freed hinge-region cysteines or THIOMAB formats with engineered cysteines in the mAbs light chain were added to a maleimide derivative of cryptophycin. These Antibody-Drug Conjugates (ADCs) showed retained binding to Her2 positive tumor cells and highly efficient cell killing in double-digit pM range on high Her2-expressing SK-BR-3 cells. Two ADCs (DAR 6, DAR 3) showed superior cell killing of the cell lines JIMT-1 and RT112 with medium receptor expression level in comparison with a DAR 6 MMAE ADC serving as reference. The observed cell cytotoxicity is target-dependent since no impact on cell viability was observed for low Her2-expressing MDA-MB468 cells. Particularly the DAR 3 ADC in THIOMAB format exhibiting desirable biophysical properties and high potency emerged as a promising candidate for further in vivo investigations., (© 2024 The Author(s). ChemBioChem published by Wiley-VCH GmbH.)

Homologous recombination (HR)-related gene alterations are present in a significant subset of prostate, breast, ovarian, pancreatic, lung, and colon cancers rendering these tumors as potential responders to specific DNA damaging agents. A small molecule acylfulvene prodrug, LP-184, metabolizes to an active compound by the oxidoreductase activity of enzyme prostaglandin reductase 1 (PTGR1), which is frequently elevated in multiple solid tumor types. Prior work demonstrated that cancer cell lines deficient in a spectrum of DNA damage repair (DDR) pathway genes show increased susceptibility to LP-184. Here, we investigated the potential of LP-184 in targeting multiple tumors with impaired HR function and its mechanism of action as a DNA damaging agent. LP-184 induced elevated DNA double-strand breaks in HR deficient (HRD) cancer cells. Depletion of key HR components BRCA2 or ataxia telangiectasia mutated (ATM) in cancer cells conferred up to 12-fold increased sensitivity to the LP-184. LP-184 showed nanomolar potency in a diverse range of HRD cancer models, including prostate cancer organoids, leiomyosarcoma cell lines, and patient-derived tumor graft models of lung, pancreatic, and prostate cancers. LP-184 demonstrated complete, durable tumor regression in 10 patient-derived xenograft (PDX) models of HRD triple-negative breast cancer (TNBC) including those resistant to PARP inhibitors (PARPi). LP-184 further displayed strong synergy with PARPi in ovarian and prostate cancer cell lines as well as in TNBC PDX models. These preclinical findings illustrate the potential of LP-184 as a pan-HRD cancer therapeutic. Taken together, our results support continued clinical evaluation of LP-184 in a large subset of HRD solid tumors., Significance: New agents with activity against DDR-deficient solid tumors refractory to standard-of-care therapies are needed. We report multiple findings supporting the potential for LP-184, a novel alkylating agent with three FDA orphan drug designations, to fill this void clinically: strong nanomolar potency; sustained, durable regression of solid tumor xenografts; synthetic lethality with HR defects. LP-184 adult phase IA trial to assess safety in advanced solid tumors is ongoing., (© 2024 The Authors; Published by the American Association for Cancer Research.)

The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways. Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared with DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1, and BRCA2. Depletion of PTGR1, however, completely abrogates the antitumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy. Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184., (©2023 American Association for Cancer Research.)

More than 40% of non-small cell lung cancer (NSCLC) patients lack actionable targets and require non-targeted chemotherapeutics. Many become refractory to drugs due to underlying resistance-associated mutations. KEAP1 mutant NSCLCs further activate NRF2 and upregulate its client PTGR1. LP-184, a novel alkylating agent belonging to the acylfulvene class is a prodrug dependent upon PTGR1. We hypothesized that NSCLC with KEAP1 mutations would continue to remain sensitive to LP-184. LP-184 demonstrated highly potent anticancer activity both in primary NSCLC cell lines and in those originating from brain metastases of primary lung cancers. LP-184 activity correlated with PTGR1 transcript levels but was independent of mutations in key oncogenes (KRAS and KEAP1) and tumor suppressors (TP53 and STK11). LP-184 was orders of magnitude more potent in vitro than cisplatin and pemetrexed. Correlative analyses of sensitivity with cell line gene expression patterns indicated that alterations in NRF2, MET, EGFR and BRAF consistently modulated LP-184 sensitivity. These correlations were then extended to TCGA analysis of 517 lung adenocarcinoma patients, out of which 35% showed elevated PTGR1, and 40% of those further displayed statistically significant co-occurrence of KEAP1 mutations. The gene correlates of LP-184 sensitivity allow additional personalization of therapeutic options for future treatment of NSCLC., Competing Interests: CONFLICTS OF INTEREST A.K., J.R.M., U.K., P.S. and K.B. are or have been salaried employees of or consultants to the pharmaceutical company Lantern Pharma Inc. A.K., U.K., P.S., and K.B. hold options to purchase common stock of Lantern Pharma Inc. and are also included as inventors on patent applications filed by Lantern Pharma Inc. J.-P.R. and R.M. are employees of REPROCELL USA, Inc., a commercial contract research organization providing services to Lantern Pharma Inc., (Copyright: © 2021 Kulkarni et al.)