Candidate For Treatment Research Articles

Novel Lipid Formulation Increases Absorption of Oral Cannabidiol (CBD)

Background: Cannabidiol (CBD) is an approved treatment for childhood epilepsies and a candidate treatment for several other CNS disorders. However, it has poor oral bioavailability. We investigated the effect of a novel lipid formulation on its absorption in humans and on its tissue distribution in mice. Methods: In a double-blind crossover study in fasting healthy volunteers, we compared the pharmacokinetics of a single dose of 1000 mg of CBD in the lipid formulation and in a powder formulation (ClinicalTrials.gov: NCT05032807). In a second study, male CD1 mice were administered CBD in either the lipid formulation or dissolved in water, via oral gavage (n = 1 per timepoint). The tissue distribution of CBD was assessed using matrix-assisted laser desorption/ionization mass spectrometric imaging. Results: Plasma exposure (AUC0–48) of CBD was nine times greater for the lipid formulation than the powder formulation (611.1 ng·h/mL [coefficient of variation {CV%}: 104.6] and 66.8 ng·h/mL [CV%: 50.7], respectively). With the powder formulation, the AUC0–48 was related to the concentration of specific gastrointestinal bacteria and bile acids. These associations were attenuated with the lipid formulation. In the animal study, after treatment with the lipid formulation, measurable concentrations of CBD were identified in all organs. For the aqueous formulation, tissue concentrations of CBD were below the limit of quantification. Conclusions: Administering oral CBD in a lipid formulation was associated with an increase in its gastrointestinal absorption, as well as an attenuation of the relationship between its absorption and features of the gut microbiome.

Implementation of Simultaneous Village Head Elections

Simultaneous village head elections (PKDS) are a form of democracy implemented in Indonesia, where all villages in a region simultaneously conduct elections for village heads at the same time. This research utilizes a normative juridical approach by referring to the legislation governing PKDS. The analysis shows that the implementation of PKDS is based on the principles of democracy and village autonomy regulated by the applicable laws. Clear and precise regulations regarding the stages, procedures, and mechanisms of PKDS provide a strong foundation for the implementation of this process. However, there are several challenges including coordination among relevant institutions, public awareness, understanding, and participation in the election process, as well as fairness in the treatment of candidates and voters. This study provides recommendations including enhancing socialization and education to emphasize the importance of public participation in village head elections, improving coordination among relevant institutions, and strengthening oversight to ensure fairness and transparency in the election process. The findings of this research are expected to serve as a reference for the government and stakeholders in enhancing the effectiveness and integrity of PKDS in the future.

Pyropheophorbide-α methyl ester-mediated photodynamic therapy triggers pyroptosis in osteosarcoma cells via the ROS/caspase-3/GSDME pathway

BackgroundPyropheophorbide-α methyl ester-mediated photodynamic therapy(MPPa-PDT) is a candidate treatment for solid tumors, including osteosarcoma. Pyroptosis has garnered significant attention in cancer research due to its pro-inflammatory and immunomodulatory nature. This study investigated the mechanism and role of MPPa-PDT-induced pyroptosis in osteosarcoma cells. MethodsWe treated human osteosarcoma 143b and HOS cells with MPPa at concentrations of 0.5 μM and 0.25 μM, respectively, then irradiated the cells with LED light at 630 nm wavelength with an energy density of 4.8 J/cm2. Cell viability and apoptosis ratio were detected using CCK-8 and Annexin V–Propidium Iodide staining, respectively. Intracellular reactive oxygen species (ROS) levels and mitochondrial membrane potential (MtΔψ) were assessed using 2ʹ,7ʹ-Dichlorofluorescin diacetate, and JC-1 staining kits, respectively. Scanning Electron Microscopy (SEM) was utilized to examine cell ultrastructure. The morphological changes of the cells were observed by an inverted microscope. Western blotting analysis was conducted to measure protein levels. To elucidate the mechanism and role, we re-evaluated relevant parameters after pretreating with NAC,Si caspase-3, and Si GSDME. ResultsMPPa-PDT inhibited the activity of osteosarcoma 143b and HOS cells and induced pyroptosis with mitochondrial damage, ROS aggregation, and activation of Caspase-3 and GSDME. The effects of MPPa-PDT on the activity and apoptosis of osteosarcoma cells were partially reversed after pretreating with Si GSDME. After NAC pretreatment, the activation of pyroptosis and Caspase-3 induced by MPPa-PDT was partially reversed. After Si Caspase-3 pretreatment, the pyroptosis induced by MPPa-PDT was partially reversed. ConclusionMPPa-PDT can induce pyroptosis in osteosarcoma cells, which has the effect of enhancing apoptotic processes. Mitochondrial damage and ROS/caspase-3/GSDME pathway are the possible mechanisms of pyroptosis induced by MPPa-PDT.

Dual-Targeted Assembled Nanodrugs for Near-Infrared Photothermal Immunotherapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is known for its poor prognosis and aggressive behavior, being highly prone to recurrence and metastasis, and currently has limited effective treatment options. Photothermal therapy (PTT) is an emerging, minimally invasive, low-drug-resistance, and precisely controllable therapeutic method for cancer treatment, offering hope to break through the bottleneck in TNBC therapy. The antitumor efficiency of PTT is predominantly contingent upon the performance of the photothermal drugs. Therefore, there is an urgent need to develop photothermal drugs that not only have excellent photothermal conversion efficiency but also possess strong tumor-targeting capabilities and good biosafety. Here, we have developed a tumor-targeted photothermal agent with near-infrared (NIR) absorption capability based on the strategy of biomolecular assembly, utilizing biliverdin manganese complexes (MnBV) and amphiphilic phospholipid-polymer conjugates (DSPE-PEG and DSPE-PEG-cKNGRE). This photothermal assembled drug exhibits a uniform size, good stability, and ideal photothermal conversion efficiency. In the 4T1 tumor-bearing mouse model of TNBC, it shows good tumor dual-targeting capabilities and a significant drug enrichment performance. While ablating the primary tumor, PTT further stimulates the maturation of dendritic cells (DCs), enhancing the infiltration of T lymphocytes into the spleen and tumor, thus reshaping the immune microenvironment of TNBC and thereby effectively inhibiting tumor metastasis and recurrence. The developed photothermal assembled drug provides an innovative candidate treatment paradigm for TNBC, offering the potential to advance precise, targeted, and safe therapy for highly invasive and aggressive malignancies.

Cardiac motion in patients with ventricular tachycardia: potential implications for the treatment of patients candidates to stereotactic arrhythmia radio-ablation (STAR)

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has proven to be a valid alternative treatment for refractory ventricular tachycardia (VT) in patients who are unsuitable to undergo standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. There is increased research activity on better understanding the complex and fast motion of the heart and on reducing radiation toxicity. Purpose In the context of an in silico study to evaluate the feasibility of STAR with protons in patients with VT, the initial findings related to cardiac motion on the first 10 patients are here presented. Methods Prior to CA, each patient underwent ECG gated CT scans in expiratory breath-hold, with and without contrast and reconstructed at 30% (systole) and 80% (diastole) of the cardiac R-R cycle. Contouring of the ablation target as a clinical target volume (CTV) for proton treatment planning was performed based on a standard electrophysiological study with 3D eletroanatomical mapping. Two different treatment plans were created: the first with only the diastolic CTV as target (gated treatment), the second including both diastolic and systolic CTVs to create an Internal Target Volume (ITV) in the hypothesis of non-gated treatment. Robust optimization was used to create the Planning Target Volume (PTV). Results The target volumes used for treatment planning are given in Table 1. The median CTV was 10.90 (2.93-36.94) cm3 for diastole and 14.26 (1.73-36.31) cm3 for systole. These volumes are somewhat smaller than those reported in patients treated previously with STAR: this difference may be due to the fact that no respiratory motion was included in the target contour and that the study population includes many patients referred for ventricular ectopic beats without structural heart disease, where the ablation target is expected to be smaller as compared to patients with VT in structural heart disease. Despite a small median difference between the diastolic and systolic CTV of 0.53 (0.03-9.61) cm3, the ITV approach resulted in a median increase in volume compared to the largest of the two CTVs of 29 % (1%-44%). When considering the proton range uncertainty and potential errors in patient positioning (PTV), the target is this time enlarged by a factor 2.9 (1.9-3.9). This data indicates that both cardiac motion and uncertainties in patient positioning before treatment will have a large impact on the treatment volume thus affecting the amount of surrounding tissue exposed to radiation. Conclusion The ablation target contour at systole and diastole are of similar magnitude but their non-overlap results in a large increase in treated volume when radiation delivery is not gated for cardiac motion. Further analysis shall investigate on a case-by-case basis the potential reduction in risk of healthy tissue toxicity with cardiac-gated proton delivery.Table 1

Uncovering ASO-Targetable Deep Intronic AIRE Variants: Insights and Therapeutic Implications.

High-throughput DNA sequencing has accelerated the discovery of disease-causing genetic variants, yet only in 10-40% of cases yield a genetic diagnosis. Increased implementation of genome sequencing has enabled a deeper exploration of the noncoding genome and recognition of noncoding variants as major contributors to disease. In a recent study, we identified a deep intronic variant in the AutoImmune REgulator (AIRE) gene (c.1504-818 G>A) as the cause of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a life-threatening monogenic autoimmune disorder most often caused by biallelic AIRE defects. This deep intronic variant disrupts normal splicing AIRE , causing pseudoexon inclusion and altered protein function. By developing an antisense oligonucleotide (ASO) targeting the pseudoexon sequence, we restored normal AIRE transcript in vitro, thereby revealing a potential genotype-specific candidate treatment. Our study illustrates key aspects of intronic variant detection, validation, and candidate ASO development. Herein, we briefly highlight the growing potential of ASO-based therapies for deep intronic variants, addressing the unmet need of personalized, genotype-specific therapies in diseases lacking curative options.

Bayesian Response Adaptive Randomization for Randomized Clinical Trials With Continuous Outcomes: The Role of Covariate Adjustment.

Study designs incorporate interim analyses to allow for modifications to the trial design. These analyses may aid decisions regarding sample size, futility, and safety. Furthermore, they may provide evidence about potential differences between treatment arms. Bayesian response adaptive randomization (RAR) skews allocation proportions such that fewer participants are assigned to the inferior treatments. However, these allocation changes may introduce covariate imbalances. We discuss two versions of Bayesian RAR (with and without covariate adjustment for a binary covariate) for continuous outcomes analyzed using change scores and repeated measures, while considering either regression or mixed models for interim analysis modeling. Through simulation studies, we show that RAR (both versions) allocates more participants to better treatments compared to equal randomization, while reducing potential covariate imbalances. We also show that dynamic allocation using mixed models for repeated measures yields a smaller allocation proportion variance while having a similar covariate imbalance as regression models. Additionally, covariate imbalance was smallest for methods using covariate-adjusted RAR (CARA) in scenarios with small sample sizes and covariate prevalence less than 0.3. Covariate imbalance did not differ between RAR and CARA in simulations with larger sample sizes and higher covariate prevalence. We thus recommend a CARA approach for small pilot/exploratory studies for the identification of candidate treatments for further confirmatory studies.

Torsion-Induced Traumatic Optic Neuropathy (TITON): A Physiologically Relevant Animal Model of Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) is a common cause of irreversible blindness following head injury. TON is characterized by axon damage in the optic nerve followed by retinal ganglion cell death in the days and weeks following injury. At present, no therapeutic or surgical approach has been found to offer any benefit beyond observation alone. This is due in part to the lack of translational animal models suitable for understanding mechanisms and evaluating candidate treatments. In this study, we developed a rat model of TON in which the eye is rapidly rotated, inflicting mechanical stress on the optic nerve and leading to significant visual deficits. These functional deficits were thoroughly characterized up to one week after injury using electrophysiology and immunohistochemistry. The photopic negative response (PhNR) of the light adapted full field electroretinogram (LA ffERG) was significantly altered following injury. This correlated with increased biomarkers of retinal stress, axon disruption, and ganglion cell death. Together, this evidence suggests the utility of our model for mimicking clinically relevant TON and that the PhNR may be an early diagnostic for TON. We also found indirect evidence that ketamine, which was used for anesthesia, may ameliorate TON. Future studies will utilize this animal model for evaluation of candidate treatments.

313P Validation lab: allowing standardized in vitro and in vivo experiments for candidate treatments for Duchenne muscular dystrophy

313P Validation lab: allowing standardized in vitro and in vivo experiments for candidate treatments for Duchenne muscular dystrophy

Neuroprotective effects of all-trans-retinoic acid are mediated via downregulation of TLR4/NF-κB signaling in a rat model of middle cerebral artery occlusion.

To determine the effects of all-trans-retinoic acid (ATRA) on the post-stroke inflammatory response and elucidate the underlying molecular mechanisms. This animal experiment was conducted at Central Laboratory, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China during 2020-2022. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5h, and treated with ATRA at 2 and 24h after reperfusion. Neurological deficit scores on behavioral tests, and cerebral infarct volume, microglial polarization, and the expression levels of inflammatory cytokines and proteins associated with TLR4/NF-κB signaling were assessed. The ATRA administration reduced cerebral infarct volume and ameliorated neurological deficit scores in MCAO rats. Additionally, ATRA relieved cerebral edema and downregulated the secretion of proinflammatory cytokines after stroke. Finally, ATRA attenuated the polarization of the microglia toward the M1 phenotype and promoted the activation of the beneficial M2 phenotype; the underlying mechanism potentially involved the suppression of the TLR4/NF-κB signaling pathway. The ATRA treatment promoted functional recovery in an experimental model of ischemic stroke by attenuating neural inflammation. ATRA potentially modulated microglia-mediated neuroinflammation via the downregulation of the TLR4/NF-κB signaling pathway, which makes it a candidate treatment for post-stroke neuroinflammation.

Development of novel near-infrared photothermal material for efficient breast cancer therapy

Photothermal therapy (PTT) has become a candidate treatment for breast cancer due to its non-invasive, specific and controllable properties. However, there are few strategies to develop photothermal agents with high photothermal conversion efficiency, adequate tumor accumulation, and the molecular design theory is not perfect. Thus, to obtain the photothermal agent with better comprehensive performance, a novel conjugated polymer PAPQ-Th, comprising quinoxaline derivative 10,11-bis(4-(octyloxy) phenyl)acenaphtho[1,2-b]pyrazino[2,3-g]quinoxaline (PAPQ) as the acceptor and thiophene (Th) as the donor, was designed and synthesized. The PAPQ-Th exhibited the high non-radiative rate of 7.3 × 1011 s−1 and faint fluorescence emission. And PAPQ-Th nanoparticles exhibited strong NIR absorption from 650 nm to 900 nm, negligible ROS generation, and an impressively high photothermal conversion efficiency of 61 % under an 808 nm laser irradiation. Furthermore, PAPQ-Th nanoparticles can be successfully used for both in vitro and in vivo experiments, and exhibited remarkable photothermal antitumor efficacy. After intravenous administration and 808 nm laser irradiation, 4T1 tumor-bearing mice achieve complete tumor remission without recurrence. The results demonstrate that the design of new quinoxaline derivative and construction of novel donor-acceptor conjugated polymer are the effective strategy for the synthesis of efficient photothermal agent.

Chronic Thromboembolic Pulmonary Hypertension

: While the majority of patients have complete resolution of their acute pulmonary embolism (PE) after an adequate course of anticoagulation, some patients remain symptomatic with evidence of chronic PE. Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Chronic Thromboembolic Pulmonary Disease (CTEPD) are terms that describe symptomatic patients with chronic thromboembolic occlusions of the pulmonary arteries with or without pulmonary hypertension, respectively. Here, we review the definitions, epidemiology, pathobiology, diagnosis and management of CTEPH. The chronic PE in CTEPH is essentially a scar in the pulmonary vasculature and is accompanied by a pulmonary arteriolar vasculopathy. Ventilation-perfusion scanning is the most sensitive screening test for CTEPH, and diagnosis must be confirmed by right heart catheterization (RHC). Treatment decisions require a multidisciplinary team and guidance from additional imaging, usually CT or pulmonary angiography. While pulmonary endarterectomy (PEA) to remove the chronic PE surgically is still the first-line treatment for appropriate candidates, there is an expanding role for balloon pulmonary angioplasty (BPA) and medical treatment, as well as multimodality treatment approaches that incorporate all of those options. New imaging modalities and treatment strategies hold the promise to improve our care and management of CTEPH patients in the future.

Extracellular vesicles as the next-generation modulators of pharmacokinetics and pharmacodynamics of medications and their potential as adjuvant therapeutics.

Pharmacokinetics (PK) and pharmacodynamics (PD) are central concepts to guide the dosage and administration of drug therapies and are essential to consider for both healthcare professionals and researchers in therapeutic planning and drug discovery. PK/PD properties of a drug significantly influence variability in response to treatment, including therapeutic failure or excessive medication-related harm. Furthermore, suboptimal PK properties constitute a significant barrier to further development for some candidate treatments in drug discovery. This article describes how extracellular vesicles (EVs) affect different aspects of PK and PD of medications and their potential to modulate PK and PD properties to address problematic PK/PD profiles of drugs. We reviewed EVs' intrinsic effects on cell behaviours and medication responses. We also described how surface and cargo modifications can enhance EV functionalities and enable them as adjuvants to optimise the PK/PD profile of conventional medications. Furthermore, we demonstrated that various bioengineering strategies can be used to modify the properties of EVs, hence enhancing their potential to modulate PK and PD profile of medications. This review uncovers the critical role of EVs in PK and PD modulation and motivates further research and the development of assays to unfold EVs' full potential in solving PK and PD-related problems. However, while we have shown that EVs play a vital role in modulating PK and PD properties of medications, we postulated that it is essential to define the context of use when designing and utilising EVs in pharmaceutical and medical applications. Existing solutions for pharmacokinetics and pharmacodynamics modulation are limited. Extracellular vesicles can optimise pharmacokinetics as a drug delivery vehicle. Biogenesis and administration of extracellular vesicles can signal cell response. The pharmaceutical potential of extracellular vesicles can be enhanced by surface and cargo bioengineering. When using extracellular vesicles as modulators of pharmacokinetics and pharmacodynamics, the 'context of use' must be considered.

Modified Jiaoqi Powder enhances epithelial autophagy against TNF-triggered apoptosis in chronic ulcerative colitis

BackgroundA vicious cycle of dysregulated intestinal epithelial cell death, intestinal barrier defect, and subsequent inflammation response is core to chronic ulcerative colitis (UC). Modified Jiaoqi Powder (MJQP), a traditional Chinese medicine formula, has been clinically applied to treat chronic relapsing type and chronic persistent type of UC . Nevertheless, the underlying mechanism of MJPQ in chronic UC remains unknown. PurposeThe present study aimed to demonstrate the favorable effect and potential molecular mechanism of MJQP in chronic UC. MethodsThe chemical components of MJQP and MJQP drug serum were identified by LC-MS/MS. The curative effect of MJQP was evaluated in a well-established DSS-induced chronic UC mice model by measuring body weight, colon length, disease activity index (DAI) and histological scores . Serum cytokines, including interleukin (IL)-1β, IL-12, IL-13, IL-4, tumor necrosis factor-alpha (TNF-α) and INF-γ were measured using enzyme-linked immunosorbent assay. Western blotting, immunofluorescence, and MTT assay were used to analyze the effects of MJQP on colonic barrier function in chronic UC mice and human epithelial cell lines. TUNEL assay, western blotting, and flow cytometry were used to examine the related apoptosis indicators. An electron microscope was used to observe autophagosomes and autolysosomes, while western blotting and immunofluorescence were used to detect autophagy-associated proteins. Network pharmacology was used to predict potential targets and pathways of MJQP in UC. Finally, the TNF pathway-related proteins were detected by immunohistochemistry and western blotting. ResultsMJQP administration prevented the UC progression with faster weight gain, longer colon length, lower histological scores and DAI, and up/down- regulation of inflammatory factors. The expressions of tight junction proteins ki67 and E-cadherin increased dose-dependently after MJQP intervention. Moreover, MJQP treatment promoted the viability of NCM460 and Caco2 cells in a concentration-dependent manner. MJQP dose-dependently decreased the proportion of TUNEL-positive cells and attenuated the pro-apoptotic proteins cleaved-caspase 8 and cleaved-caspase 3 in colonic tissues. Flow cytometry also showed that MJQP dose-dependently decreased the apoptotic cell population of LPS-induced NCM460 and Caco2 cells. Electron microscopy revealed that autophagosomes and autolysosomes were significantly improved in the MJQP-treated groups. Additionally, autophagy-related proteins were significantly expressed after MJQP treatment. Network pharmacological analysis predicted that MJQP may alleviate chronic UC by affecting TNF-related signaling pathways and promoting intestinal epithelial cell proliferation. As anticipated, the TNF pathway-associated proteins were attenuated dose-dependently in colonic tissues after MJQP treatment. ConclusionThese results provide novel therapeutic strategies, indicating that MJQP may be a promising candidate treatment for chronic UC by promoting epithelial barrier restitution by enhancing epithelial autophagy against TNF–mediated apoptosis.

Long-term outcomes of radiofrequency ablation for intrathoracic goiter up to 5 years: evaluated by computed tomography/magnetic resonance imaging and ultrasound

Objectives This study evaluated the long-term efficacy and safety of radiofrequency ablation (RFA) for intrathoracic goiter (ITG) over a follow-up period exceeding six months. Methods From 2017 to 2022, 22 patients (6 males, 16 females) with 24 ITGs treated with RFA at a single medical center were evaluated. All patients underwent ultrasonography (US), computed tomography (CT), or magnetic resonance imaging (MRI) before RFA. Follow-up CT/MRI was performed six months after the initial RFA and then every 6–12 months. The primary outcomes measured were the degree of extension, goiter volume, volume reduction rate (VRR), tracheal deviation, and tracheal lumen. Additionally, we assessed the outcomes of single-session RFA (n = 16) vs. multiple sessions (n = 8) on goiters and explored the correlation between ITG volume measurements obtained using ultrasonography and CT/MRI. Results The median follow-up period was 12 months (interquartile range: 6–36.8 months). At the last follow-up, the nodule volume measured by CT/MRI had significantly decreased (76.2 vs. 24.6 mL; p < 0.05), with a VRR of 64.6%. Patients who underwent multiple RFA sessions showed a significantly higher VRR than the single-session patients (63.8 vs. 80.1%, p < 0.05). The intraclass correlation between goiter volumes measured using US and CT/MRI was moderate. Conclusion This study affirms the long-term efficacy and safety of RFA for ITG, providing an alternative treatment for nonsurgical candidates. Multiple RFA sessions may be beneficial for achieving better volume reduction. Sole reliance on ultrasonography is inadequate; therefore, integrating CT/MRI is essential for accurate pre-RFA and follow-up assessments.

Effects of home-based EEG neurofeedback training as a non-pharmacological intervention for Parkinson's disease

ObjectivesAberrant movement-related cortical activity has been linked to impaired motor function in Parkinson's disease (PD). Dopaminergic drug treatment can restore these, but dosages and long-term treatment are limited by adverse side-effects. Effective non-pharmacological treatments could help reduce reliance on drugs. This experiment reports the first study of home-based electroencephalographic (EEG) neurofeedback training as a non-pharmacological candidate treatment for PD. Our primary aim was to test the feasibility of our EEG neurofeedback intervention in a home setting. MethodsSixteen people with PD received six home visits comprising symptomology self-reports, a standardised motor assessment, and a precision handgrip force production task while EEG was recorded (visits 1, 2 and 6); and 3 × 1-hr EEG neurofeedback training sessions to supress the EEG mu rhythm before initiating handgrip movements (visits 3 to 5). ResultsParticipants successfully learned to self-regulate mu activity, and this appeared to expedite the initiation of precision movements (i.e., time to reach target handgrip force off-medication pre-intervention = 628 ms, off-medication post-intervention = 564 ms). There was no evidence of wider symptomology reduction (e.g., Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III Motor Examination, off-medication pre-intervention = 29.00, off-medication post intervention = 30.07). Interviews indicated that the intervention was well-received. ConclusionBased on the significant effect of neurofeedback on movement-related cortical activity, positive qualitative reports from participants, and a suggestive benefit to movement initiation, we conclude that home-based neurofeedback for people with PD is a feasible and promising non-pharmacological treatment that warrants further research.

Neural correlates of depression-related smartphone language use in adolescents

Magnetic resonance imaging has provided pathophysiological insights into adolescent depression but is a relatively inaccessible technology. Generating scalable indicators of depression that are informed by neuroscience is therefore critical for providing solutions that allow us to detect and treat this devastating disorder. In this preregistered study, we investigated whether passively acquired smartphone-based language usage represents such an indicator of depression and explored whether the neural correlates of depression mediate or moderate this association. Forty adolescents (ages 14–18 years) with (n = 26) and without (n = 14) depression completed clinical assessments and a resting-state fMRI scan, prior to downloading a passive mobile sensing app to their smartphones. Linguistic features derived from over 1.2 million words (319,364 messages) across all smartphone apps were used to examine word usage patterns. Independent components analysis followed by dual regression was used to derive intrinsic networks commonly associated with depression: central executive network (CEN), default mode network (DMN), and salience network (SN). Depression was associated with more negative emotion word usage and fewer future-focus word usage on a daily basis (all ps < 0.05). Higher depressive symptoms and brain networks DMN and CEN were associated with greater first-person pronoun usage (all ps < 0.04). Accounting for CEN connectivity amplified the positive association between depressive symptoms and first-person pronoun usage. Lower SN–CEN connectivity moderated the association between depression and negative emotion word usage. Depression in adolescents is associated with naturalistic language usage during smartphone activities and may represent neurocognitive biases that are candidate treatment targets for interventions.

Characterisation of colorectal cancer by hierarchical clustering analyses for five stroma-related markers.

Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer-associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF-related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha-smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN-high tumours had a significantly worse 5-year survival rate (57.3% versus 79.0%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCNLowPDPNLow); a PDPN-dominant group (DCNMidPDPNHigh); and a DCN-dominant group (DCNHighPDPNLow), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26-0.96, p = 0.037) as a potential favourable factor compared with the DCN-dominant group. Of note, DCN-dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma-targeting therapies may be candidate treatments for patients with CRC.

Aberrant protein aggregation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal disease. As its pathological mechanisms are not well understood, there are no efficient therapeutics for it at present. While it is highly heterogenous both etiologically and clinically, it has a common salient hallmark, i.e., aberrant protein aggregation (APA). The upstream pathogenesis and the downstream effects of APA in ALS are sophisticated and the investigation of this pathology would be of consequence for understanding ALS. In this paper, the pathomechanism of APA in ALS and the candidate treatment strategies for it are discussed.

A Review of Terlipressin in Hepatorenal Syndrome: Targeting Endothelial Dysfunction and Subsequent Cardiovascular Adverse Events.

Hepatorenal syndrome (HRS) is a serious complication of decompensated liver cirrhosis that results in acute kidney injury (AKI). The mortality rate is high. Endothelial dysfunction secondary to liver cirrhosis is a key driver of the development of portal hypertension, which is eventually complicated by ascites and HRS. Ultimately, splanchnic vasodilation and excess gut lymph production result in ascites, low effective arterial blood volume, and maladaptive compensatory mechanisms that contribute to renal hypoperfusion and injury. While the only curative treatment is liver transplantation, vasoconstrictors and albumin have been the mainstay of treatment for candidates who are ineligible or waiting for transplantation. On September 14, 2022, terlipressin, a V1 vasopressin receptor agonist, was approved by the Food and Drug Administration for the treatment of HRS-AKI. In clinical trials, terlipressin plus albumin have been superior to albumin alone and equivocal to noradrenaline plus albumin in renal function improvement. Terlipressin, however, does not improve survival, is costly, and is associated with severe adverse events-including severe cardiac and vascular complications. The aim of this review is to provide an overview of terlipressin pharmacology, adverse events-with a focus on cardiovascular complications-and comparative randomized controlled trials that resulted in the Food and Drug Administration's approval of terlipressin. New literature since its approval and ongoing clinical trials will also be highlighted.