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Recent evidence has highlighted the benefits of early detection and treatment for better clinical outcomes in patients with psychosis. Biological markers of the disease have become a focal point of research. This study aimed to identify protein markers detectable in the early stages of psychosis and indicators of progression by comparing them with those of healthy controls (HC) and first episode psychosis (FEP). The participants comprised 28 patients in the clinical high-risk (CHR) group, 49 patients with FEP, and 61 HCs aged 15–35 years. Blood samples were collected and analyzed using multiple reaction monitoring-mass spectrometry to measure the expression of 158 peptide targets. Data were adjusted for age, sex, and use of psychotropic drugs. A total of 18 peptides (17 proteins) differed significantly among the groups. The protein PRDX2 was higher in the FEP group than in the CHR and HC groups and showed increased expression according to disease progression. The levels of six proteins were significantly higher in the FEP group than in the CHR group. Nine proteins differed significantly in the CHR group compared to the other groups. Sixteen proteins were significantly correlated with symptom severity. These proteins are primarily related to the coagulation cascade, inflammatory response, brain structure, and synaptic plasticity. Our findings suggested that peripheral protein markers reflect disease progression in patients with psychosis. Further longitudinal research is needed to confirm these findings and to identify the specific roles of these markers in the pathogenesis of schizophrenia. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect and timing of recombinant human parathyroid hormone analog (PTH) administration for preventing medication-related osteonecrosis of the jaws (MRONJ) using a murine model. After standardized MRONJ induction using zoledronic acid and dexamethasone injections, 48 female Sprague-Dawley rats were divided into four groups according to the timing of PTH administration before or after dental extraction. Rats were euthanized 3 weeks after dental extraction, followed by clinical and histologic analyses. No clinical improvements were observed in the preoperative and postoperative PTH groups, compared to controls (p = 0.638 and 0.496, respectively). However, on histological analysis, the number of empty lacunae reduced significantly, and the number of blood vessels increased in the preoperative PTH group (p = 0.004 and 0.002, respectively). The postoperative PTH group did not show significant differences for empty lacunae and blood vessels compared to controls (p = 0.075 and 0.194, respectively). The reduction in the empty lacunae and the increase in the blood vessels in the preoperative PTH group were significant compared to other groups, suggesting more viable bone tissue in this group. In perspective, preoperative PTH use may represent a better prophylactic regimen for preventing the occurrence of MRONJ after traumatic dental or surgical procedures, especially in patients with a history of long-term bisphosphonate administration or at high risk of developing MRONJ. However, the findings should be proven in further studies on other animals followed by clinical trials. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are key therapeutic agents in the management of metastatic hormone-receptor-positive breast cancer. However, the emergence of drug resistance limits their long-term efficacy. Here, we show that breast cancer cells develop CDK4/6i resistance via a sequential two-step process of E2F activation. This process entails retinoblastoma (Rb)-protein degradation, followed by c-Myc-mediated amplification of E2F transcriptional activity. CDK4/6i treatment halts cell proliferation in an Rb-dependent manner but dramatically reduces Rb-protein levels. However, this reduction in Rb levels insufficiently induces E2F activity. To develop CDK4/6i resistance, upregulation or activating mutations in mitogenic or hormone signaling are required to stabilize c-Myc levels, thereby augmenting E2F activity. Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels. [Display omitted] • Breast cancer cells develop CDK4/6i resistance via sequential E2F activation • Rb-protein degradation and c-Myc-mediated amplification of E2F activity are key mechanisms • c-Myc levels, not Rb levels, predict poor outcomes after CDK4/6i treatment • Proteasome inhibitors restoring Rb levels can potentially overcome CDK4/6i resistance Kim et al. demonstrate that breast cancer cells develop resistance to CDK4/6 inhibitors through a two-step E2F activation process involving Rb-protein degradation and c-Myc-mediated amplification of E2F activity. They suggest that proteasome inhibitors, which restore Rb levels, could potentially overcome this resistance. [ABSTRACT FROM AUTHOR]

The combination of BRAF and MEK inhibitors (BRAFi/MEKi) has shown promising response rates in treating BRAF -mutant melanoma by inhibiting ERK activation. However, treatment efficacy is limited by the emergence of drug-tolerant persister cells (persisters). Here, we show that the magnitude and duration of receptor tyrosine kinase (RTK) activation determine ERK reactivation and persister development. Our single-cell analysis reveals that only a small subset of melanoma cells exhibits effective RTK and ERK activation and develops persisters, despite uniform external stimuli. The kinetics of RTK activation directly influence ERK signaling dynamics and persister development. These initially rare persisters form major resistant clones through effective RTK-mediated ERK activation. Consequently, limiting RTK signaling suppresses ERK activation and cell proliferation in drug-resistant cells. Our findings provide non-genetic mechanistic insights into the role of heterogeneity in RTK activation kinetics in ERK reactivation and BRAFi/MEKi resistance, suggesting potential strategies for overcoming drug resistance in BRAF -mutant melanoma. [Display omitted] • RTK activation causes ERK reactivation and BRAF/MEK-inhibitor-tolerant persister cells • RTK activation kinetics govern ERK signaling dynamics and persister development • Alterations in ERK signaling dynamics are associated with BRAF/MEK-inhibitor resistance • BRAF/MEK-inhibitor resistance can be reversed by limiting RTK signaling Kim et al. show that the strength and duration of receptor tyrosine kinase (RTK) activation regulate ERK reactivation and the development of BRAFi/MEKi-tolerant persister cells in BRAF -mutant melanoma. These persister cells eventually become the dominant population in established resistance. Limiting RTK signaling can reverse the BRAFi/MEKi-resistant state. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study is to investigate whether mismatch negativity (MMN) is associated with functional status or is a state-independent trait for schizophrenia. We assessed MMN in 26 patients with schizophrenia, 20 healthy subjects with high genetic loading, and 48 healthy controls. Repeated measures analysis of variance and Pearson׳s correlations were used to test the hypothesis that MMN is not state-independent. We found a significant main effect of group, indicating differences in the peak amplitudes of the MMN among the three groups. Post-hoc analyses revealed that schizophrenia patients showed a significant reduction in the peak amplitude of MMN, but subjects at high genetic risk and healthy controls did not. Additionally, significant correlations between Global Assessment of Functioning scores and MMN peak amplitude at Fz and Cz were found in patients with schizophrenia. These findings suggest that MMN may reflect current functional status rather than a genetic risk for schizophrenia. [Copyright &y& Elsevier]

Although internet gaming disorder (IGD) is considered an addictive disorder, evidence of the neurobiological underpinnings of IGD as an addictive disorder is currently lacking. We investigated whether attentional bias toward game-related stimuli was altered in IGD patients using an eye-tracking method during an anti-saccade task. Twenty-three IGD patients and 27 healthy control (HC) subjects participated in the anti-saccade task with game-related, neutral, and scrambled images during eye tracking. Participants rated subjective scores of valence, arousal, and craving for each image stimulus after finishing eye tracking. Mixed design analysis of variance was performed to compare the differences between eye movement latency and error rate in the pro-saccade and anti-saccade conditions according to image type across the IGD and HC groups. In the anti-saccade task, the IGD group exhibited higher error rates in the case of game-related images than in neutral or scrambled images. However, ratings on valence, arousal, and craving did not vary among image types. The error rates of the HCs did not vary across image types, but higher arousal/craving and lower valence were reported with respect to the game-related images. Increased error rate during anti-saccade tasks with game-related stimuli in IGD may be due to disabilities in goal-directed behavior or inhibitory control, as observed in other addictive disorders. These findings suggest that attentional bias toward game-related stimuli can be a sensitive biological marker of IGD as an addictive disorder. • Attentional bias has been suggested as one of the core characteristics of addictive disorders. • The IGD group exhibited higher error rates in the case of game-related images in the anti-saccade task. • Attentional bias toward game-related stimuli can be a sensitive biological marker of IGD as an addictive disorder. [ABSTRACT FROM AUTHOR]

Recent studies have indicated that clinical high risk for psychosis (CHR-P) is highly specific for psychotic disorders other than pluripotential to various serious mental illnesses. However, not all CHR-P develop psychotic disorder only, and psychosis can occur in non-psychotic disorders as well. Our prospective cohort study aims to investigate the characteristics and clinical outcomes of a pluripotent high-risk group with the potential to develop a diverse range of psychiatric disorders. The SPRIM study is a prospective naturalistic cohort program that focuses on the early detection of those at risk of developing serious mental illness, including psychosis (CHR-P), bipolar (CHR-B), and depressive disorder (CHR-D), as well as undifferentiated risk participants (UCHR). Our study has a longitudinal design with a baseline assessment and eight follow-up evaluations at 6, 12, 18, 24, 30, 36, 42, and 48 months to determine whether participants have transitioned to psychosis or mood disorders. The SPRIM sample consisted of 90 CHR participants. The total cumulative incidence rate of transition was 53.3% (95% CI 32.5–77.2). CHR-P, CHR-B, CHR-D, and UCHR had cumulative incidence rates of 13.7% (95% CI 3.4–46.4), 52.4% (95% CI 28.1–81.1), 66.7% (95% CI 24.6–98.6) and 54.3% (95% CI 20.5–93.1), respectively. The cumulative incidence of psychosis, bipolar, and depressive disorder among all participants was 3.3% (95% CI 0.8–11.5), 45.7% (95% CI 24.4–73.6), and 11.2% (95% CI 3.1–36.2), respectively. Our study suggests that the concept of pluripotent high-risk for a diverse range of psychiatric disorders is an integrative approach to examining transdiagnostic interactions between illnesses with a high transition rate and minimizing stigma. • Characteristics and clinical outcomes of pluripotent high-risk group; potential for diverse psychiatric disorders. • The total cumulative incidence rate of transition was 53.3% (95% CI 32.5–77.2). • The cummulative incidence of psychosis, bipolar, and depressive disorder among all participants was 3.3%, 45.7%, and 11.2%. [ABSTRACT FROM AUTHOR]

After the existence of a bipolar disorder (BD) prodrome was established, the development of clinical rating instruments has become relevant that are sufficiently brief to be implemented in real-world clinical practice and that are designed to identify individuals at-risk for BD. This study aimed to validate a shorter version of the Bipolar Prodrome Symptom Interview and Scale (BPSS), the BPSS-Abbreviated Prospective (BPSS-AP), for use among clinical populations. Altogether, 104 adults, comprising individuals diagnosed with BD (n = 17, mania: n = 8, hypomania: n = 9), with major depressive disorder (MDD, n = 38, all currently depressed), and healthy controls (HCs, n = 49), underwent BPSS-AP interviews. The psychometric properties of the BPSS-AP were evaluated, including internal consistency, convergent validity, discriminant validity, and factor structure. The median (IQR) age was 29 (23–38), 40 (23–55), and 25 (22–28) years, for the BD, MDD, and HC groups, respectively. The BPSS-AP showed excellent internal consistency (Cronbach's α = 0.95). Convergent validity between the BPSS-AP and Young Mania Rating Scale (YMRS) was high (r > 0.7). The BPSS-AP discriminated patients with BD from those with MDD (P <.001) and from HCs (P <.001). The study design precludes assessment of the predictive validity of the BPSS-AP. This study found that the BPSS-AP, a more concise and feasible version of the semi-structured interview for identifying individuals at risk of developing BD, has satisfactory psychometric properties. There is room for further validation and application of the BPSS-AP in clinical settings to evaluate its utility in research and clinical care. • The BPSS-AP is an 11-item version of clinician-rated scale for bipolar prodromes. • The BPSS-AP is a shorter version for clinical practice and community screening. • We included patients with bipolar disorder (BD) or depression and healthy controls. • The internal consistency and convergent validity of BPSS-AP were excellent. • The BPSS-AP was adequate in discriminating BD from other diagnostic groups. [ABSTRACT FROM AUTHOR]

Depression is a common symptom of many mental disorders, especially major depressive disorder (MDD) and bipolar disorder (BD). Previous studies have reported that these diseases share common pathophysiological pathways; therefore, this study elucidated whether the plasma levels of protein markers related to common depressive symptoms differed between patients with BD and those with MDD. Plasma samples of 71 patients with mood disorders and clinical manifestations were analyzed in this study. After depleting the abundant proteins, liquid chromatography–tandem mass spectrometry and label-free quantification were performed. Five proteins, viz., cholesteryl ester transfer protein (CETP), apolipoprotein D (APOD), mannan-binding lectin serine protease 2 (MASP2), Ig lambda chain V-II region BO (IGLV2-8) and Ig kappa chain V-III region NG9 (IGKV3-20) were negatively associated with the total scores of the Hamilton depression rating scale (HAM-D), after adjusting for the covariates. CETP and APOD also showed significant negative correlations with the anhedonia/retardation and guilt/agitation scores of the HAM-D. Four proteins, namely, Ig kappa chain V-II region TEW (IGKC; IGKV2D-28), Ig lambda variable 5–45 (IGLV5-45), complement factor H (CFH) and attractin (ATRN), showed significant associations with anhedonia/retardation after adjusting for covariates. Proteins that significantly correlated with the symptoms could predict the remission state of depression (area under the curve [AUC], 0.83) and anhedonia/retardation (AUC, 0.80). Bioinformatics analysis revealed that complement activation, immune response, and lipid metabolism were significantly enriched pathways. Although our study design was cross-sectional and no controls were included, protein markers identified in this preliminary study will be further investigated in our subsequent longitudinal study. [ABSTRACT FROM AUTHOR]

Abstract Background Disruption in the thalamus, such as volume, shape, and cortical connectivity, is regarded as an important pathophysiological mechanism in schizophrenia. However, there is little evidence of nuclei-specific structural alterations in the thalamus during early-stage psychosis, mainly because of the methodological limitations of conventional structural imaging in identifying the thalamic nuclei. Methods A total of 37 patients with first-episode psychosis and 36 matched healthy control subjects underwent diffusion tensor imaging, diffusion kurtosis imaging, and T1-weighted magnetic resonance imaging. Connectivity-based segmentation of the thalamus was performed using diffusion tensor imaging, and averages of the diffusion kurtosis values, which represent microstructural complexity, were estimated using diffusion kurtosis imaging and were compared in each thalamic nucleus between the groups. Results The mean kurtosis values in the thalamic regions with strong connections to the orbitofrontal cortex (F 1,70 = 8.40, p <.01) and the lateral temporal cortex (F 1,70 = 8.46, p <.01) were significantly reduced in patients with first-episode psychosis compared with those of the healthy control subjects. The mean kurtosis values in the thalamic region with strong connection to the orbitofrontal cortex showed a significant correlation with spatial working memory accuracy in patients with first-episode psychosis (r =.36, p <.05), whereas no significant correlation between these variables was observed in the healthy control subjects. Conclusions The observed pattern of reduced microstructural complexity in the nuclei not only highlights the involvement of the thalamus but also emphasizes the role of the higher-order nuclei in the pathophysiology beginning in the early stage of schizophrenia. [ABSTRACT FROM AUTHOR]

Summary: Two vascular growth factor families, VEGF and the angiopoietins, play critical and coordinate roles in tumor progression and metastasis. A single inhibitor targeting both VEGF and angiopoietins is not available. Here, we developed a chimeric decoy receptor, namely double anti-angiogenic protein (DAAP), which can simultaneously bind VEGF-A and angiopoietins, blocking their actions. Compared to VEGF-Trap or Tie2-Fc, which block either VEGF-A or angiopoietins alone, we believe DAAP is a highly effective molecule for regressing tumor angiogenesis and metastasis in implanted and spontaneous solid tumors; it can also effectively reduce ascites formation and vascular leakage in an ovarian carcinoma model. Thus, simultaneous blockade of VEGF-A and angiopoietins with DAAP is an effective therapeutic strategy for blocking tumor angiogenesis, metastasis, and vascular leakage. [ABSTRACT FROM AUTHOR]