Neural response during prefrontal theta burst stimulation: Interleaved TMS-fMRI of full iTBS protocols.

BACKGROUND: Left prefrontal intermittent theta-burst stimulation (iTBS) has emerged as a safe and effective transcranial magnetic stimulation (TMS) treatment protocol in depression. Though network effects after iTBS have been widely studied, the deeper mechanistic understanding of target engagement is still at its beginning. Here, we investigate the feasibility of a novel integrated TMS-fMRI setup and accelerated echo planar imaging protocol to directly observe the immediate effects of full iTBS treatment sessions. OBJECTIVE/HYPOTHESIS: In our effort to explore interleaved iTBS-fMRI feasibility, we hypothesize that TMS will induce acute BOLD signal changes in both the stimulated area and interconnected neural regions. METHODS: Concurrent TMS-fMRI with full sessions of neuronavigated iTBS (i.e. 600 pulses) of the left dorsolateral prefrontal cortex (DLPFC) was investigated in 18 healthy participants. In addition, we conducted four TMS-fMRI sessions in a single patient on long-term maintenance iTBS for bipolar depression to test the transfer to clinical cases. RESULTS: Concurrent TMS-fMRI was feasible for iTBS sequences with 600 pulses. During interleaved iTBS-fMRI, an increase of the BOLD signal was observed in a network including bilateral DLPFC regions. In the clinical case, a reduced BOLD response was found in the left DLPFC and the subgenual anterior cingulate cortex, with high variability across individual sessions. CONCLUSIONS: Full iTBS sessions as applied for the treatment of depressive disorders can be established in the interleaved iTBS-fMRI paradigm. In the future, this experimental approach could be valuable in clinical samples, for demonstrating target engagement by iTBS protocols and investigating their mechanisms of therapeutic action.

Factors influencing patient-perceived quality of care in psychiatric hospitals in Taiwan.

Patient-perceived quality of inpatient/outpatient psychiatric care remains under-researched. A cross-sectional survey with purposive sampling comprising 567 inpatients and 549 outpatients was conducted among eight psychiatric care facilities in Taiwan to examine the factors influencing patient-perceived care quality. Inpatients and outpatients perceived moderate quality of care, where "Encounter" was reported as the highest dimension. Inpatients perceived "Secure environment" as the lowest; outpatients rated "Discharge/Referring" as the lowest. Hospital region and customer loyalty were significantly associated with patient-perceived care quality. Other significant factors were also identified: inpatient employment, perceived mental health and treatment effects, understanding diagnosis, previous treatment, and visited by appointment.

Molecular profiling of afatinib-resistant non-small cell lung cancer cells in vivo derived from mice.

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC patients with overexpressed or mutated epidermal growth factor receptor (EGFR) related to disease progression are treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Acquired drug resistance after TKI treatments has been a major focus for development of NSCLC therapies. This study aimed to establish afatinib-resistant cell lines from which afatinib resistance-associated genes are identified and the underlying mechanisms of multiple-TKI resistance in NSCLC can be further investigated. Nude mice bearing subcutaneous NSCLC HCC827 tumors were administered with afatinib at different dose intensities (5-100 mg/kg). We established three HCC827 sublines resistant to afatinib (IC50 > 1 µM) with cross-resistance to gefitinib (IC50 > 5 µM). cDNA microarray revealed several of these sublines shared 27 up- and 13 down-regulated genes. The mRNA expression of selective novel genes - such as transmembrane 4 L six family member 19 (TM4SF19), suppressor of cytokine signaling 2 (SOCS2), and quinolinate phosphoribosyltransferase (QPRT) - are responsive to afatinib treatments only at high concentrations. Furthermore, c-MET amplification and activations of a subset of tyrosine kinase receptors were observed in all three resistant cells. PHA665752, a c-MET inhibitor, remarkably increased the sensitivity of these resistant cells to afatinib (IC50 = 12-123 nM). We established afatinib-resistant lung cancer cell lines and here report genes associated with afatinib resistance in human NSCLC. These cell lines and the identified genes serve as useful investigational tools, prognostic biomarkers of TKI therapies, and promising molecule targets for development of human NSCLC therapeutics.

Aurora kinase inhibitors reveal mechanisms of HURP in nucleation of centrosomal and kinetochore microtubules.

The overexpression of Aurora kinases in multiple tumors makes these kinases appealing targets for the development of anticancer therapies. This study identified two small molecules with a furanopyrimidine core, IBPR001 and IBPR002, that target Aurora kinases and induce a DFG conformation change at the ATP site of Aurora A. Our results demonstrate the high potency of the IBPR compounds in reducing tumorigenesis in a colorectal cancer xenograft model in athymic nude mice. Human hepatoma up-regulated protein (HURP) is a substrate of Aurora kinase A, which plays a crucial role in the stabilization of kinetochore fibers. This study used the IBPR compounds as well as MLN8237, a proven Aurora A inhibitor, as chemical probes to investigate the molecular role of HURP in mitotic spindle formation. These compounds effectively eliminated HURP phosphorylation, thereby revealing the coexistence and continuous cycling of HURP between unphosphorylated and phosphorylated forms that are associated, respectively, with microtubules emanating from centrosomes and kinetochores. Furthermore, these compounds demonstrate a spatial hierarchical preference for HURP in the attachment of microtubules extending from the mother to the daughter centrosome. The finding of inequality in the centrosomal microtubules revealed by these small molecules provides a versatile tool for the discovery of new cell-division molecules for the development of antitumor drugs.

Relationship between nurses' resilience and depression, anxiety and stress during the 2021 COVID-19 outbreak in Taiwan.

AIM: The COVID-19 outbreak in Taiwan had a significant impact on medical services. These changes posed a threat to nurses' mental health. Resilience may protect nurses from the psychological impact of COVID-19. This study aimed to understand nurses' resilience and its relationship with nurses' characteristics (life and work situations) and mental health (depression, anxiety and stress) during the outbreak. DESIGN: A cross-sectional study. METHODS: This study surveyed the nurses at a hospital from 9 August 2021, to 20 August 2021. The content of the questionnaire included nurses' characteristics, resilience and mental health. RESULTS: There was an association between higher resilience and lower mental health problems. We also found that some nurses' characteristics were positively correlated with mental health problems. CONCLUSION: Some nurses' life and work situations predicted high levels of mental health problems during the pandemic. Additionally, higher levels of resilience were associated with lower levels of mental health problems.

Organic ultraviolet filters regulate hyaluronan metabolism in human epidermal keratinocytes through the phosphatidylinositol 3-kinase pathway.

Chronic exposure of skin to ultraviolet (UV) radiation is responsible for skin ageing, which includes degradation of the epidermal and dermal layers. Filtering UV light is key in the sunscreen industry. We studied the effects of organic UV filters on hyaluronan (HA) metabolism and skin hydration in human HaCaT keratinocytes. The gene expression of HA receptors, HA synthase (HAS), hyaluronidase (HYAL), and water channel aquaporin 3 (AQP3) was evaluated by quantitative RT-PCR. The state of oxidative stress was determined by measuring the intracellular levels of reactive oxygen species (ROS). The results showed that five organic UV filters reduced the extracellular contents of HA, and a phosphatidylinositol 3-kinase (PI3K) inhibitor partially restored the decreased HA levels after octinoxate, octocrylene, and oxybenzone treatment. The expression levels of HA receptors, including cluster of differentiation 44 (CD44), receptor for hyaluronic acid-mediated motility (RHAMM), and toll-like receptors (TLRs), were determined. Avobenzone, octinoxate, oxybenzone, and padimate O exerted inhibitory effects on RHAMM expression. Oxybenzone led to a significant increase in CD44 and AQP3 expression. Both octinoxate and octocrylene increased TLR4 expression but decreased ROS accumulation by activating the PI3K pathway. However, the organic UV filters differentially regulated the mRNA expression of HAS and HYAL. Taken together, these results suggest that certain organic UV filters regulate HA metabolism in human keratinocytes in a PI3K pathway-dependent manner.

Concurrent TMS-fMRI: Technical Challenges, Developments, and Overview of Previous Studies.

Transcranial magnetic stimulation (TMS) is a promising treatment modality for psychiatric and neurological disorders. Repetitive TMS (rTMS) is widely used for the treatment of psychiatric and neurological diseases, such as depression, motor stroke, and neuropathic pain. However, the underlying mechanisms of rTMS-mediated neuronal modulation are not fully understood. In this respect, concurrent or simultaneous TMS-fMRI, in which TMS is applied during functional magnetic resonance imaging (fMRI), is a viable tool to gain insights, as it enables an investigation of the immediate effects of TMS. Concurrent application of TMS during neuroimaging usually causes severe artifacts due to magnetic field inhomogeneities induced by TMS. However, by carefully interleaving the TMS pulses with MR signal acquisition in the way that these are far enough apart, we can avoid any image distortions. While the very first feasibility studies date back to the 1990s, recent developments in coil hardware and acquisition techniques have boosted the number of TMS-fMRI applications. As such, a concurrent application requires expertise in both TMS and MRI mechanisms and sequencing, and the hurdle of initial technical set up and maintenance remains high. This review gives a comprehensive overview of concurrent TMS-fMRI techniques by collecting (1) basic information, (2) technical challenges and developments, (3) an overview of findings reported so far using concurrent TMS-fMRI, and (4) current limitations and our suggestions for improvement. By sharing this review, we hope to attract the interest of researchers from various backgrounds and create an educational knowledge base.

BPR0C261 is a novel orally active antitumor agent with antimitotic and anti-angiogenic activities.

BPR0C261 is a synthetic small molecule compound cytotoxic against human cancer cells and active prolonging the lifespan of leukemia mice. In the present study, we further investigated the mechanisms of its anticancer action and found that BPR0C261 inhibited microtubule polymerization through interacting with the colchicine binding sites on tubulins, disrupted microtubule arrangement and caused cell cycle arrest at G(2)/M phase in cancer cells. BPR0C261 also inhibited the clonogenic growths of cancer cells and showed cytotoxicity against human cervical cancer cells of multidrug-resistant phenotype. In addition, BPR0C261 concentration-dependently inhibited the proliferation and migration of HUVECs and disrupted the endothelial capillary-like tube formations in HUVEC and rat aorta ring cultures. Given orally, BPR0C261 inhibited angiogenesis in s.c. implanted Matrigel plugs in mice. Notably, its IC(50) values against the endothelial cell growths were approximately 10-fold lower than those against the cancer cells. It was found orally absorbable in mice and showed a good oral bioavailability (43%) in dogs. BPR0C261 permeated through the human intestinal Caco-2 cell monolayer, suggesting oral availability in humans. Orally absorbed BPR0C261 distributed readily into the s.c. xenografted tumors in nude mice in which the tumor tissue levels of BPR0C261 were found oral dose-dependent. BPR0C261 showed in vivo activities against human colorectal, gastric, and nasopharyngeal tumors in nude mice. Most interestingly, the combination of BPR0C261 plus cisplatin synergistically prolonged the lifespans of mice inoculated with murine leukemia cells. Thus, BPR0C261 is a novel orally active tubulin-binding antitumor agent with antimitotic, apoptosis-inducing, and vasculature disrupting activities.

Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine Aurora kinase inhibitor.

Ligand efficiency (LE) and lipophilic efficiency (LipE) are two important indicators of "drug-likeness", which are dependent on the molecule's activity and physicochemical properties. We recently reported a furano-pyrimidine Aurora kinase inhibitor 4 (LE = 0.25; LipE = 1.75), with potent activity in vitro; however, 4 was inactive in vivo. On the basis of insights obtained from the X-ray co-crystal structure of the lead 4, various solubilizing functional groups were introduced to optimize both the activity and physicochemical properties. Emphasis was placed on identifying potential leads with improved activity as well as better LE and LipE by exercising tight control over the molecular weight and lipophilicity of the molecules. Rational optimization has led to the identification of Aurora kinase inhibitor 27 (IBPR001; LE = 0.26; LipE = 4.78), with improved in vitro potency and physicochemical properties, resulting in an in vivo active (HCT-116 colon cancer xenograft mouse model) anticancer agent.