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Objectives: Contrast enhanced ultrasound (CEUS) now joins the ranks of CT and MRI for noninvasive diagnosis of hepatocellular carcinoma (HCC). CEUS LI-RADS provides greater than 95% specificity for diagnosis within LR-5. Unlike CT/MRI, CEUS is nodule based. Currently, LI-RADS does not recommend CEUS of nodules occult or invisible on pre-contrast ultrasound except by experts. This study addresses our ability to find occult nodules using CEUS and to characterize them with CEUS LI-RADS., Methods: 100 patients at risk for HCC, 81 with cirrhosis, with occult lesions were retrospectively identified from our archived patient logs. All patients had CEUS examination. Three specialized CEUS techniques (blindshot injection, portal venous (PVP) sweep of the liver, and on-top injection) are used to evaluate nodules., Results: There were 114 occult lesions in 100 patients. The origin of 78(68%) lesions was an MRI (n = 69) or CT scan (n = 9) with an observation of abnormal enhancement, generally arterial phase hyperenhancement (APHE). All these patients had blindshot CEUS injection looking for a correlate with APHE. The remainder of occult lesions (n = 36)(32%) were first detected during CEUS, generally as washout foci on PVP sweeps or incidental APHE or washout nearby other targets. All washout areas had subsequent on-top injection to assess for APHE. Application of CEUS LI-RADS algorithm categorized 26 LR-5, 34 LR-4, and 5 LR-M. CEUS upgraded LI-RADS category of 24/50(48%) occult lesions reported on CT/MRI. 29(25%) occult lesions were offered treatment and from categories LR-5 and LR-M, 5 had biopsy confirmation and 15 were treated. From both sources, MR/CT and CEUS, there were 12 occult lesions scanned for treatment response, categorized as 7 LR-TR viable, 1 LR-TR nonviable, and 4 LR-TR equivocal on CEUS., Conclusion: Our study shows we can find and characterize occult nodules using CEUS techniques and CEUS LI-RADS algorithm, with positive impact on clinical management., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Understanding the origin and evolution of the mineralized skeleton is crucial for unravelling vertebrate history. However, several limitations hamper our progress. The first obstacle is the lack of uniformity and clarity in the literature for the definition of the tissues of concern, especially of enameloid(s) and enamel(s), resulting in ambiguous terminology and inconsistencies among studies. Moreover, the identification criteria currently employed to characterize hypermineralized tissues in extinct taxa, such as the presence or absence of tubules for enameloids, may lead to unsupported conclusions. We suggest that comparative developmental studies may be key to unambiguous terminology, truly diagnostic identification criteria and developmentally informed evolutionary hypotheses. We exemplify this approach by: (i) introducing a new conceptual framework for enameloid(s) and enamel(s), with clear terminologies, definitions and interactions between concepts; (ii) suggesting more rigorous ways to identify tissues, based on the observation of defining or additional properties, as well as on the comparison of developmental scenarios when possible; (iii) constructing a clear phylogenetic framework to discuss their homologies and highlighting possible transitions between these tissues; and by (iv) proposing developmental models that explain both enamel and enameloid formation, and suggest possible transitions between them., (© 2024 The Author(s). Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.)

Background and Aim: There is no gold standard for making the diagnosis of autoimmune hepatitis (AIH), and the diagnosis of acute onset AIH (A-AIH) is most challenging. A-AIH sometimes develops into acute liver failure with poor prognosis if the diagnosis is delayed. Therefore, it is most important for the better prognosis to diagnose non-severe A-AIH early and treat appropriately. However, features in the early stage of A-AIH are unclear. We examined initial characteristics of non-severe A-AIH in detail and tried to find novel clinical features for the early diagnosis., Methods: Clinical, biochemical, immunological, radiological, and histological features of 71 patients (54 women, mean age 57.9 ± 14.3 years) with non-severe A-AIH admitted to community hospitals between 2001 and 2022 were analyzed retrospectively., Result: Forty-six had no symptom on onset and liver injuries were discovered by regular medical checkups. The mean duration from onset to consultation was 25.0 ± 29.3 days. Liver histology showed acute hepatitis in 59% and chronic hepatitis in 41%. Patients with symptoms revealed more male sex (P = 0.039), higher alanine aminotransferase (P < 0.001), higher total bilirubin (P < 0.001), and higher rate of histological acute hepatitis (P = 0.0013) than those without symptoms significantly. Male sex, presence of symptoms on onset, occurrence of jaundice in the course, and histological acute hepatitis were correlated., Conclusions: Sixty-five percent of non-severe A-AIH patients were asymptomatic on onset, suggesting that A-AIH would develop insidiously and present a longer clinical course than that reported. Male patients more often revealed true acute hepatitis clinically, biochemically, and histologically than female ones., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: The recognition of arterial phase hyperenhancement (APHE) and washout during the late phase is key for correct diagnosis of hepatocellular carcinoma (HCC) with contrast-enhanced ultrasound (CEUS). This meta-analysis was conducted to compare SonoVue®-enhanced and Sonazoid®-enhanced ultrasound in the assessment of HCC enhancement and diagnosis., Methods: Studies were included in the analysis if they reported data for HCC enhancement in the arterial phase and late phase for SonoVue® or in the arterial phase and Kupffer phase (KP) for Sonazoid®. Forty-two studies (7502 patients) with use of SonoVue® and 30 studies (2391 patients) with use of Sonazoid® were identified. In a pooled analysis, the comparison between SonoVue® and Sonazoid® CEUS was performed using chi-square test. An inverse variance weighted random-effect model was used to estimate proportion, sensitivity, and specificity along with 95% confidence interval (CI)., Results: In the meta-analysis, the proportion of HCC showing APHE with SonoVue®, 93% (95% CI 91-95%), was significantly higher than the proportion of HCC showing APHE with Sonazoid®, 77% (71-83%) (p < 0.0001); similarly, the proportion of HCC showing washout at late phase/KP was significantly higher with SonoVue®, 86% (83-89%), than with Sonazoid®, 76% (70-82%) (p < 0.0001). The sensitivity and specificity for the detection of APHE plus late-phase/KP washout detection in HCC were also higher with SonoVue® than with Sonazoid® (sensitivity 80% vs 52%; specificity 80% vs 73% in studies within unselected patient populations)., Conclusion: APHE and late washout in HCC are more frequently observed with SonoVue® than with Sonazoid®. This may affect the diagnostic performance of CEUS in the diagnosis of HCCs., Clinical Relevance Statement: Meta-analysis data show the presence of key enhancement features for diagnosis of hepatocellular carcinoma is different between ultrasound contrast agents, and arterial hyperenhancement and late washout are more frequently observed at contrast-enhanced ultrasound with SonoVue® than with Sonazoid®., Key Points: • Dynamic enhancement features are key for imaging-based diagnosis of HCC. • Arterial hyperenhancement and late washout are more often observed in HCCs using SonoVue®-enhanced US than with Sonazoid®. • The existing evidence for contrast-enhanced US may need to be considered being specific to the individual contrast agent., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Lowering barometric pressure (LP) can exacerbate neuropathic pain. However, animal studies in this field are limited to a few conditions. Furthermore, although sympathetic involvement has been reported as a possible mechanism, whether the sympathetic nervous system is involved in the hypothalamic-pituitary-adrenal (HPA) axis remains unknown. To address these issues, we investigated LP-induced hyperalgesia by focusing on the cumulative effect of LP and measuring plasma corticosterone levels as a marker of HPA axis activation in mice. Methods: Mice with chronic constriction injury (CCI) were used in this study. For behavioral tests, two types of LP stimulation were adopted: a single LP at 20 hPa (Single LP) and three consecutive LPs at 20 hPa (3LPs). Twelve mice were used for each protocol. The no-pressure-change protocol was used as the control. The mechanical sensitivity was tested before and after LP stimulation using von Frey filaments (vF). For corticosterone measurements, six CCI and six intact mice were exposed to 3LPs (CCI-3LPs and INT-3LPs), and another six CCI and six intact mice were exposed to the no-pressure-change protocol (CCI-NP and INT-NP). Blood samples were collected immediately after exposure. Plasma corticosterone levels were measured by ELISA. Results: The number of paw elevations by vF before and after LP stimulation did not differ significantly in either the Single LP or the no-pressure-change protocol. For the 3LPs, the number of paw elevations after LP stimulation was significantly greater than before stimulation. Plasma corticosterone levels in the CCI-3LPs were significantly higher than those in CCI-NPs. In intact mice, there was no significant difference in plasma corticosterone levels between the INT-3LPs and INT-NPs. Conclusions: LP has a cumulative effect on neuropathic pain. Hypothalamic-pituitary-adrenal axis activation may have an important relationship with LP-induced pain in mice. [ABSTRACT FROM AUTHOR]

Simple Summary: In this phase II trial, patients with advanced hepatocellular carcinoma (HCC) previously treated with lenvatinib were enrolled to receive atezolizumab and bevacizumab every 3 weeks. The primary endpoint was progression-free survival. A total of 26 eligible patients were enrolled. The median progression-free survival from the start of treatment was 9.70 [90% confidence interval, 5.10–14.24] months, with the lower limit above the predefined threshold. The median overall survival was 17.23 [90% confidence interval, 13.18–27.85] months and the objective response rate was 34.6%. Sixteen patients (61.5%) received subsequent therapies. Severe adverse events, adverse events leading to treatment delays, and adverse events leading to treatment discontinuation occurred in eight (30.8%), fourteen (53.8%), and five (19.2%) patients, respectively, and no treatment-related death occurred. This combination therapy is suggested to be effective and safely administered for patients with advanced HCC previously treated with lenvatinib. Background/Objectives: Atezolizumab and bevacizumab combination therapy has been established as a standard of care for first-line treatment; however, its efficacy and safety have not been fully evaluated for patients previously treated with systemic therapy. Methods: In this phase II trial, patients with advanced hepatocellular carcinoma previously treated with lenvatinib were enrolled to receive a dose of 1,200 mg of atezolizumab and 15 mg/kg of bevacizumab every 3 weeks. The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, disease control rate, subsequent therapy, and frequency of adverse events. The threshold and expected progression-free survival were 3 and 6.8 months, respectively. Considering a one-sided significance level of 0.05 and a statistical power of 80%, the minimum required sample size was 26 patients. Results: The median progression-free survival from the start of treatment was 9.70 [90% confidence interval, 5.10–14.24] months, and the lower limit of the 90% CI was above the predefined threshold. The objective response and disease control rates were 34.6% and 73.1%, respectively. Sixteen patients (61.5%) received subsequent therapies, and the median overall survival was 17.23 [90% confidence interval, 13.18–27.85] months. Severe adverse events, adverse events leading to treatment delays, and adverse events leading to treatment discontinuation occurred in eight (30.8%), fourteen (53.8%), and five (19.2%) patients, respectively, and no treatment-related deaths occurred. Conclusions: Atezolizumab and bevacizumab combination therapy is effective and can safely be administered to patients with advanced HCC previously treated with lenvatinib. [ABSTRACT FROM AUTHOR]

Simple Summary: Unlike RECIST (version 1.1), which is the standard for assessing the treatment efficacy for solid tumors, tumor necrosis is considered a marker of the treatment effect in HCC. mRECIST, which considers tumor necrosis, and the Liver Cancer Treatment Direct Effectiveness Criteria (RECICL) are widely used. There are notable differences between one-dimensional and two-dimensional measurements in mRECIST and RECICL, and their practicality and usefulness are controversial. After fully understanding the characteristics and problems of each method, diagnostic imaging physicians must focus on the imaging modality and criteria that should be used to determine the effectiveness of the method. Furthermore, the inclusion of LI-RADS provides a standardized framework for evaluating HCC and supports consistent diagnostic and therapeutic decision-making. Given the availability of several drugs, predicting the efficacy of systemic chemotherapy for HCC is currently a clinical topic. However, the role of CT is limited. Recently, attempts have been made to detect Wnt/β-catenin mutation/activation in HCC using Gd-EOB-DTPA enhanced MRI (EOB-MRI), and future developments are expected in terms of predicting efficacy. For instance, regorafenib has demonstrated survival benefits in patients previously treated with sorafenib, as highlighted in a recent systematic review and meta-analysis. Additionally, atezolizumab combined with bevacizumab has emerged as a first-line treatment for unresectable hepatocellular carcinoma. The liver is supplied by a dual blood flow system consisting of the portal vein and hepatic artery. Imaging techniques for diagnosing hepatocellular carcinoma (HCC) have been developed along with blood flow imaging, which visualizes the amount of arterial and portal blood flow. The diagnosis of HCC differentiation is important for early-stage liver cancer screening and determination of treatment strategies. Dynamic computed tomography/magnetic resonance imaging (MRI) includes blood flow imaging and MRI with contrast-enhanced ultrasound and liver-specific contrast agents are used in combination. In addition, unlike the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1), which is the standard for determining treatment efficacy for solid tumors in general, tumor necrosis is generally considered a treatment effect in HCC, and the modified RECIST and Liver Cancer Direct Effectiveness Criteria (RECICL) are widely used. Familiarity with the definitions, criteria, and potential challenges of the mRECIST and RECICL is essential for their effective application in clinical practice. This review integrates the latest advancements in systemic treatments and imaging techniques, including the role of LI-RADS and updates on molecular-targeted therapies such as regorafenib, supported by some systematic review and meta-analysis. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite recent advances, glioblastoma remains incurable, with a poor prognosis. The REGOMA trial compared regorafenib with lomustine as second-line treatments for recurrent glioblastoma. Regorafenib resulted in better overall survival than lomustine, leading to its inclusion in current guidelines. Currently, bevacizumab, lomustine, and regorafenib are recommended treatment options for recurrent glioblastoma. Bevacizumab is a vascular endothelial growth factor receptor-A inhibitor and prevents angiogenesis. However, the optimal treatment for patients whose conditions progress after bevacizumab-based therapy in the third-line setting remains unclear. We assessed the efficacy and safety of regorafenib as a third-line treatment after bevacizumab and aimed to evaluate the potential benefit of continued vascular endothelial growth factor receptor inhibition. Regorafenib appears to be a good option regarding efficacy and safety for patients who progress after bevacizumab-based therapy. However, further studies are required to better define the role of regorafenib in recurrent glioblastoma. Background/Objectives: In the REGOMA trial, regorafenib demonstrated an overall survival advantage over lomustine, and it has become a recommended treatment for recurrent glioblastoma in guidelines. This study aimed to evaluate the effectiveness and safety of regorafenib as a third-line treatment for patients with recurrent glioblastoma who progressed while taking bevacizumab-based therapy. Methods: This retrospective, multicenter study in Turkey included 65 patients treated between 2021 and 2023 across 19 oncology centers. The main inclusion criteria were histologically confirmed isocitrate dehydrogenase (IDH)-wildtype glioblastoma, progression after second-line bevacizumab-based treatment, and an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2. Patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. Results: The median age of the patients was 53 years (18–67 years), with a median progression-free survival of 2.5 months (95% Confidence Interval: 2.23–2.75) and a median overall survival of 4.1 months (95% CI: 3.52–4.68). The median overall survival was improved in patients who received subsequent therapy after regorafenib treatment compared with those who did not (p = 0.022). Progression-free survival was longer in patients with ECOG 0–1 than in those with ECOG 2 (p = 0.042). The safety profile was consistent with that of the REGOMA trial, with no drug-related deaths observed. Conclusions: Regorafenib shows good efficacy and safety as a third-line treatment for recurrent glioblastoma after bevacizumab-based therapy. This study supports the use of regorafenib and emphasizes the need for further randomized studies to validate its role and optimize treatment strategies. [ABSTRACT FROM AUTHOR]

Background/Objectives: Hepatocellular carcinoma (HCC) remains a significant global health concern, primarily due to the limited efficacy of targeted therapies, which are often compromised by drug resistance and adverse side effects. Methods: In this study, we utilized a Tandem Mass Tag (TMT)-based quantitative proteomic approach to analyze global protein expression and serine/threonine/tyrosine (S/T/Y) phosphorylation modifications in HepG2 cells following treatment with three clinically relevant hepatocellular carcinoma-targeted agents: apatinib, regorafenib, and lenvatinib. Results: Utilizing KEGG pathway enrichment analysis, biological process enrichment analysis, and protein interaction network analysis, we elucidated the common and specific metabolic pathways, biological processes, and protein interaction regulatory networks influenced by three liver cancer therapeutics. The study additionally proposed potential combinational treatment strategies, highlighting a possible synergistic interaction between HCC-targeted drugs and the DNA methyltransferase inhibitor. Furthermore, through the integration of clinical phosphorylation site data, we identified several phosphorylation sites that exhibited higher abundance in tumor tissues compared to adjacent non-tumor tissues. These sites were associated with poor prognosis and elevated functional scores. Conclusions: In summary, this study conducted an in-depth analysis of the molecular alterations in proteins and phosphorylation modifications induced by clinical HCC-targeted drugs, predicting drug combination strategies and therapeutic targets. [ABSTRACT FROM AUTHOR]

Two new 2-arylbenzo[b]furans (1-2) and ten known compounds (3-12) were identified from the 95% EtOH extract of the branches and leaves of Itea indochinensis for the first time. Their structures were determined mainly based on extensive analyses of UV, IR, 1D/2D NMR and HRMS spectra. The results of MTT assays demonstrated the anti-tumor potential of compound 1 with good selectivity, which displayed moderate inhibitory effects on proliferation of SK-hep-1 cells with IC50 value of 22.3 μM, while weak inhibitory effect on proliferation of HepG2 cells with an inhibition rate of 25% at 20 μM, and no obviously inhibitory effect on proliferation of A549 cells at 20 μM. In addition, compound 1 exhibited its significant scavenging capacity on ABTS·+ free radical with an IC50 value of 0.11 mg/mL, while weak scavenging effects on DPPH and O2·- radicals with scavenging ratios of 32.93% and 21.49% at 1 mg/mL, respectively. [ABSTRACT FROM AUTHOR]

The genus Galanthus (Amaryllidaceae) currently contains 25 plant species naturally occurring in Europe and the Middle East region. These perennial bulbous plants possess well-known medicinal and ornamental qualities. Alkaloid diversity is their most distinctive phytochemical feature. A total of 127 compounds (≈20% of all known Amaryllidaceae alkaloids) grouped in 16 structural types have been previously found in Galanthus extracts. Some structural types like galanthindole, graciline and plicamine were first discovered in Galanthus plants. Nine Galanthus species, however, remain unstudied regarding their alkaloid patterns. Intraspecific variability has only been studied in G. nivalis and G. elwesii. Amaryllidaceae alkaloids are molecules with anticholinesterase, antibacterial, antifungal, antiviral and anticancer properties. Galanthamine, isolated for the first time from Galanthus woronowii Losinsk., stands out as an acetylcholinesterase inhibitor approved for medical use by the FDA for the treatment of symptoms of Alzheimer's disease. Lycorine, narciclasine and pancratistatin are noteworthy cytotoxic and antitumor alkaloids. Structural types like galanthamine, homolycorine and haemanthamine are fairly well studied in anticancer research, but little to no information is available on galanthindole, graciline and other types. This review aims to present an update on the alkaloid diversity of Galanthus spp. and highlight the need for further research on the antitumor potential of these molecules. [ABSTRACT FROM AUTHOR]

Systemic therapy for unresectable hepatocellular carcinoma (HCC) has progressed with the development of multiple kinases, such as vascular endothelial growth factor (VEGF) signaling, targeting cancer growth and angiogenesis. Additionally, the efficacy of sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has been demonstrated in various clinical trials, and they are now widely used in clinical practice. Furthermore, the development of effective immune checkpoint inhibitors has progressed in systemic therapy for unresectable HCC, and atezolizumab + bevacizumab (atezo/bev) therapy and durvalumab + tremelimumab therapy are now recommended as first-line treatment. Atezo/bev therapy, which combines an anti-programmed cell death 1 ligand 1 antibody with an anti-VEGF antibody, is the first cancer immunotherapy to demonstrate efficacy against unresectable HCC. With the increasing popularity of these treatments, VEGF inhibition is attracting attention from the perspective of its anti-angiogenic effects and impact on the cancer-immune cycle. In this review, we outline the role of VEGF in the tumor immune microenvironment and cancer immune cycle in HCC and outline the potential immune regulatory mechanisms of VEGF. Furthermore, we consider the potential significance of the dual inhibition of angiogenesis and immune-related molecules by VEGF, and ultimately aim to clarify the latest treatment strategies that maximizes efficacy. [ABSTRACT FROM AUTHOR]

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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. FGFR4 has been implicated in HCC progression, making it a promising therapeutic target. We introduce an approach for identifying novel FGFR4 inhibitors by sequentially adding fragments to a common warhead unit. This strategy resulted in the discovery of a potent inhibitor, 4c, with an IC50 of 33 nM and high selectivity among members of the FGFR family. Although further optimisation is required, our approach demonstrated the potential for discovering potent FGFR4 inhibitors for HCC treatment, and provides a useful method for obtaining hit compounds from small fragments. [ABSTRACT FROM AUTHOR]

In Asia–Pacific region, hepatocellular carcinoma is a serious health threat attributing to over 600,000 deaths each year and account for over 70% of global cases. Clinically, the major unmet needs are recurrence after curative-intent surgery, liver transplantation or local ablation and disease progression in those with hepatocellular carcinoma not eligible for resection or failed locoregional therapy. In the recent few years, new targeted therapy and immune-checkpoint inhibitors have been registered as systemic therapy to address these issues. Notably, new forms of systemic therapy, either as first-line or second-line therapy for unresectable hepatocellular or those not eligible for locoregional therapy, are now available. New data is also emerging with the use of systemic therapy to prevent hepatocellular carcinoma recurrence after curative-intent resection or local ablation therapy and to retard disease progression after locoregional therapy. In the future, further implementation of immune-checkpoint inhibitors and other forms of immunotherapy are expected to bring a new paradigm to the management of hepatocellular carcinoma. New insight related to immune-related adverse events with the use of immunotherapy has allso enabled optimization of the therapeutic approach to patients with hepatocellular carcinoma. The purpose of this clinical practice guideline is to provide an up-to-date recommendation based on clinical evidence and experience from expert Asia–Pacific key opinion leaders in the field of hepatocellular carcinoma. Three key questions will be addressed, namely: (1) Which patients with hepatocellular carcinoma should be considered for systemic therapy? (2) Which systemic therapy should be used? (3) How should a patient planned for immune checkpoint-based systemic therapy be managed and monitored? [ABSTRACT FROM AUTHOR]

Adonis tianschanica is a lesser-known plant species belonging to the genus Adonis that grows in Kazakhstan. The aim of this study was to characterize the composition of the ethanolic, water, and hydroethanolic extracts from the aerial parts of A. tianschanica by HPLC-ESI-QTOF-MS/MS to isolate the major compound isoquercitrin by HSCCC (High-Speed Counter-Current Chromatography) and to determine the cytotoxicity and anti-inflammatory potential of the extracts produced with this plant. Fingerprinting of the analyzed extracts showed the presence of a multitude of metabolites comprising polyphenols, organic acids, and coumarins, and only trace quantities of cardiac glycosides in the analyzed samples. Flavonoids were certainly the best-represented group, with kaempferol, quercetin, and their derivatives as the major components of the extracts. Key findings in this paper were that the ethanol: water (50:50 v/v) extract of A. tianschanica and its major compound isoquercitrin were able to reduce the production of NO induced by LPS, in addition to demonstrating anti-inflammatory effects by reducing cytokines such as IL-6, TNF-α, and IL-1β. [ABSTRACT FROM AUTHOR]

Simple Summary: In heavily pretreated melanoma patients with progressive melanoma brain metastases (MBM) there are no life prolonging treatments available to date. In this retrospective, single-center, case series, we show that combining the multi-kinase inhibitor regorafenib with standard-of-care BRAF/MEK inhibitors can have meaningful anti-tumor activity in melanoma patients with progressive MBM with an acceptable safety profile. These findings warrant further prospective investigations. Background: There are no active treatment options for patients with progressive melanoma brain metastases (MBM) failing immune checkpoint blockade (ICB) and BRAF/MEK inhibitors (BRAF/MEKi). Regorafenib (REGO), an oral multi-kinase inhibitor (incl. RAF-dimer inhibition), can overcome adaptive resistance to BRAF/MEKi in preclinical models. Methods: This is a single-center retrospective case series of patients with refractory MBM treated with REGO plus BRAF/MEKi (compassionate use). Results: A total of 22 patients were identified (18 BRAF-mutant, 4 NRASQ61-mutant; 19 with progressive MBM; 11 on corticosteroids). Thirteen BRAFV600-mutant patients were progressing on BRAF/MEKi at the time of REGO association. BRAF-mutant patients received REGO (40–80 mg once daily) combined with BRAF/MEKi, NRAS-mutant patients were treated with REGO + MEKi (+low-dose BRAFi to mitigate skin-toxicity). Grade 3 TRAE included arterial hypertension (n = 4) and maculopapular rash (n = 3). There were no G4/5 TRAE. In BRAF-mutant patients, overall and intracranial objective response rates (overall ORR and IC-ORR) were 11 and 29%, and overall and intracranial disease control rates (overall DCR and IC-DCR) were 44 and 59%, respectively. In NRAS-mutant patients overall ORR and IC-ORR were 0 and 25% and overall DCR and IC-DCR were 25 and 50%, respectively. The median PFS and OS were, respectively, 7.1 and 16.4 weeks in BRAF-mutant and 8.6 and 10.1 weeks in NRAS-mutant patients. Conclusions: In heavily pretreated patients with refractory MBM, REGO combined with BRAF/MEKi demonstrated promising anti-tumor activity with an acceptable safety profile. In BRAFV600-mutant melanoma patients, responses cannot solely be attributed to BRAF/MEKi rechallenge. Further investigation in a prospective trial is ongoing to increase understanding of the efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HHC) remains a severe threat to world health due to its delayed detection, complicated treatment, and rapid, asymptomatic progression. The high recurrence rates for surgical resections compel researchers to investigate more effective treatment methods. Clinical trials showed promising results in targeted therapy, minimally invasive procedures, and immunotherapy, leading to an increase in overall survival and progression-free survival in HCC patients. For those who do not qualify for surgery, minimally invasive treatments like transarterial therapies and local ablative therapies provide possibilities. Systemic therapies, including targeted therapies and immunotherapy, are essential for advanced HCC. Moreover, the evaluation of combination therapy is a major point for recent clinical trials. An overview of the current approaches to treating HCC is provided in this review. Hepatocellular carcinoma (HCC) is a prevalent malignant tumour worldwide. Depending on the stage of the tumour and liver function, a variety of treatment options are indicated. Traditional radiotherapy and chemotherapy are ineffective against HCC; however, the U.S. Food and Drug Administration (FDA) has approved radiofrequency ablation (RFA), surgical resection, and transarterial chemoembolization (TACE) for advanced HCC. On the other hand, liver transplantation is recommended in the early stages of the disease. Tyrosine kinase inhibitors (TKIs) like lenvatinib and sorafenib, immunotherapy and anti-angiogenesis therapy, including pembrolizumab, bevacizumab, tremelimumab, durvalumab, camrelizumab, and atezolizumab, are other treatment options for advanced HCC. Moreover, to maximize outcomes for patients with HCC, the combination of immune checkpoint inhibitors (ICIs) along with targeted therapies or local ablative therapy is being investigated. This review elaborates on the current status of HCC treatment, outlining the most recent clinical study results and novel approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC), the primary liver cancer arising from hepatocytes, the predominant cell constituting the liver, accounts for ~90% of all liver cancers. HCC is characterized by activation of receptors on tumor cell surface which regulates tumor cell proliferation and spread to distant organs (metastasis). The class of drugs which predominantly inhibits these receptors are collectively known as tyrosine kinase inhibitors (TKIs). Among them sorafenib, lenvatinib, regorafenib, and cabozantinib have been approved either as the first or as the second line of treatment for advanced HCC. In general, ~30% of HCC patients respond to TKIs, and those that respond invariably develop resistance in ~6 months. This review paper addresses the potential molecular mechanisms by which resistance to TKIs develop and enumerates potential strategies to overcome them thereby providing prolonged survival benefit to HCC patients. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and the development of effective treatment strategies remains a significant challenge in the management of advanced HCC patients. The emergence of tyrosine kinase inhibitors (TKIs) has been a significant advancement in the treatment of HCC, as these targeted therapies have shown promise in prolonging the survival of patients with advanced disease. Although immunotherapy is currently considered as the first line of treatment for advanced HCC patients, many such patients do not meet the clinical criteria to be eligible for immunotherapy, and in many parts of the world there is still lack of accessibility to immunotherapy. As such, TKIs still serve as the first line of treatment and play a major role in the treatment repertoire for advanced HCC patients. However, the development of resistance to these agents is a major obstacle that must be overcome. In this review, we explore the underlying mechanisms of resistance to TKIs in HCC, the clinical implications of this resistance, and the potential strategies to overcome or prevent the emergence of resistance. [ABSTRACT FROM AUTHOR]

The African bichir (Polypterus senegalus) is a living representative of Polypteriformes. P. senegalus possesses teeth composed of dentin covered by an enameloid cap and a layer of collar enamel on the tooth shaft, as in lepisosteids. A thin layer of enamel matrix can also be found covering the cap enameloid after its maturation and during the collar enamel formation. Teleosts fish do not possess enamel; teeth are protected by cap and collar enameloid, and inversely in sarcopterygians, where teeth are only covered by enamel, with the exception of the cap enameloid in teeth of larval urodeles. The presence of enameloid and enamel in the teeth of the same organism is an opportunity to solve the evolutionary history of the presence of enamel/enameloid in basal actinopterygians. In silico analyses of the jaw transcriptome of a juvenile bichir provided twenty SCPP transcripts. They included enamel, dentin, and bone-specific SCPPs known in sarcopterygians and several actinopterygian-specific SCPPs. The expression of these 20 genes was investigated by in situ hybridizations on jaw sections during tooth and dentary bone formation. A spatiotemporal expression patterns were established and compared with previous studies of SCPP gene expression during enamel/enameloid and bone formation. Similarities and differences were highlighted, and several SCPP transcripts were found specifically expressed during tooth or bone formation suggesting either conserved or new functions of these SCPPs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Heat shock protein 90 (HSP90) is a pivotal molecular chaperone with multifaceted roles in cellular health and disease. Herein, we explore how HSP90 orchestrates cellular stress responses, particularly through its partnership with heat shock factor 1 (HSF-1). PU-H71, a selective inhibitor of HSP90, demonstrates significant potential in cancer therapy by targeting a wide array of oncogenic pathways. By inducing the degradation of multiple client proteins, PU-H71 disrupts critical signaling pathways such as MAPK, PI3K/Akt, JAK/STAT, EGFR, and mTOR, which are essential for cancer cell survival, proliferation, and metastasis. We examined its impact on combating triple-negative breast cancer and enhancing the effectiveness of carbon-ion beam therapy, offering new avenues for cancer treatment. Furthermore, the dual inhibition of HSP90A and HSP90B1 by PU-H71 proves highly effective in the context of myeloma, providing fresh hope for patients with this challenging malignancy. We delve into its potential to induce apoptosis in B-cell lymphomas that rely on Bcl6 for survival, highlighting its relevance in the realm of hematologic cancers. Shifting our focus to hepatocellular carcinoma, we explore innovative approaches to chemotherapy. Moreover, the current review elucidates the potential capacity of PU-H71 to suppress glial cell activation paving the way for developing novel therapeutic strategies for neuroinflammatory disorders. Additionally, the present report also suggests the promising role of PU-H71 in JAK2-dependent myeloproliferative neoplasms. Eventually, our report sheds more light on the multiple functions of HSP90 protein as well as the potential therapeutic benefit of its selective inhibitor PU-H71 in the context of an array of diseases, laying the foundations for the development of novel therapeutic approaches that could achieve better treatment outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver cancer can sometimes come back after a liver transplant, which creates serious health challenges for patients. In this study, two medicines, sorafenib and regorafenib, were used to treat patients with this type of recurring cancer. Patients started with sorafenib, and if this medicine stopped working or caused too many side effects, they switched to regorafenib. The results showed that using these medicines one after the other could help patients live longer. However, these treatments can also lead to strong side effects, so patients need careful monitoring. This study highlights the importance of personalized care for people facing a return of liver cancer after a transplant. Background and Aims: During liver transplantation, hepatocellular carcinoma (HCC) recurrence remains a critical challenge for patient survival. Targeted therapies, such as sorafenib and regorafenib, have been utilized to manage relapsed HCC in this unique setting. This study aimed to assess the efficacy of Sorafenib and Regorafenib in patients with HCC who experienced recurrence after liver transplantation. We focused on survival outcomes, treatment responses, and the management of side effects in this patient group. Methods: We conducted a retrospective analysis of 73 patients who experienced HCC recurrence post-liver transplantation between 2012 and 2022 across 11 oncology centers in Turkey. Patients were categorized according to Child–Pugh classification and treated with sorafenib as first-line therapy and Regorafenib in case of progression. Survival rates were analyzed using the Kaplan–Meier method, and risk factors were evaluated using Cox regression analysis. Results: Of the 73 patients included in the study, 62 were male (84.9%), and 11 were female (15.1%), with a mean age of 61.5 ± 10.9 years. All patients received sorafenib as first-line treatment. Among patients who experienced progression with sorafenib or discontinued treatment due to toxicity, 45.2% (n = 33) continued treatment with regorafenib. The median progression-free survival (PFS1) time with sorafenib was 5.6 months, and the one-year survival rate was 24.3%. The median progression-free survival (PFS2) time with regorafenib, which was administered as second-line treatment, was also calculated as 5.9 months. Overall survival (OS) duration was determined as 35.9 months. The most common side effects associated with both drugs included fatigue, hand and foot syndrome, and hypertension. Significantly better survival outcomes were shown in the Child–Pugh A group compared to other patients. Conclusions: These results suggest that Sorafenib and Regorafenib treatments offer a survival advantage in patients with relapsed HCC post-transplantation. However, individualized treatment strategies and close follow-up are crucial for optimizing outcomes. Further studies are needed to refine therapeutic protocols and enhance the care of this specific patient group. [ABSTRACT FROM AUTHOR]

Portal vein thrombosis (PVT) is one of the common complications of cirrhosis. The incidence of PVT correlates with liver disease severity—higher incidence in patients with Child–Turcotte–Pugh (CTP) C, large spontaneous portosystemic shunts, hepatofugal portal flow, and in the presence of hepatocellular carcinoma. PVT may worsen ascites, increase the risk and poor control of variceal bleeding. The occurrence of PVT may increase morbidity and lower survival after a liver transplant. Using statins prevents the occurrence of PVT, whereas beta-blockers may aggravate its occurrence. Cross-sectional imaging is mandatory for the precise diagnosis and classification of PVT. Symptomatic, occlusive PVT and candidacy for liver transplantation are the main indications for anticoagulation. Vitamin K antagonists, low-molecular-weight heparin, and newer anticoagulants are effective and safe in cirrhosis. Direct-acting oral anticoagulants are agents of choice in early cirrhosis (CTP A, B). The duration of anticoagulant therapy, predictors of response, and management of complications of cirrhosis while on therapy require in-depth knowledge and individualized treatment. Transjugular intrahepatic porto-systemic shunt can be considered in nonresponsive cases or when anticoagulants are contraindicated. This manuscript reviews the latest updated knowledge about managing PVT in cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) accounts for approximately 90% of liver cancer cases. Sorafenib, the first drug to demonstrate survival benefits for advanced HCC, was validated through the SHARP randomized clinical trial (RCT). While RCTs are essential for assessing new therapies, real-world studies provide additional insights into their effectiveness in routine clinical practice. This study aimed to evaluate sorafenib's real-world effectiveness by analyzing overall survival (OS) and the time to radiological and symptomatic progression. Methods: Data from 368 patients treated with sorafenib at a Brazilian Cancer Center between 2009 and 2020 were retrospectively reviewed. Results: The median OS was 9.6 months, and the time to radiological progression was 5.3 months, similar to the SHARP trial. However, the time to symptomatic progression was shorter (2.3 months) than the SHARP study (4.1 months). In terms of safety, 27.4% of patients presented clinically relevant toxicities, and 24.5% needed to discontinue treatment due to toxicity. Conclusions: Overall, sorafenib demonstrated effectiveness in the studied population, with OS and radiological progression times comparable to SHARP study results. The difference in symptomatic progression may be due to the study's retrospective nature and limitations. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explored the factors associated with treatment efficacy, treatment duration, and overall survival (OS) in 58 patients with advanced hepatocellular carcinoma undergoing atezolizumab + bevacizumab therapy. Better baseline cognitive and physical function scores and absence of severe (grade ≥ 2) hypoalbuminemia were associated with an improved objective response rate, longer treatment duration, and better OS. These findings highlight the importance of monitoring and managing treatment-related adverse events and maintaining health-related quality of life through multidisciplinary care. Background/Objectives: Health-related quality of life (HRQoL) is critical in patients with hepatocellular carcinoma (HCC). It has become a key endpoint in the evaluation of new therapies, including atezolizumab + bevacizumab (Atezo + Bev) therapy. Methods: This study explored the factors associated with treatment efficacy, treatment duration, and overall survival (OS) in patients with advanced HCC undergoing Atezo + Bev therapy. We included 58 consecutive patients with HCC receiving Atezo + Bev from 19 November 2020, to 28 December 2023, who were followed up until the end of the study or death. We analyzed the relationships between baseline characteristics, adverse events (AEs), and HRQoL and efficacy, OS, and treatment duration. Results: The demographic (older men) and baseline characteristics (Child–Pugh score of 5, Barcelona Clinic Liver Cancer Stage C) were consistent with those of previous studies. The treatment demonstrated promising efficacy with a disease control rate of 71.2%, but HRQoL scores in five functional domains and seven symptoms worsened significantly within the first 3 months. Notably, better baseline cognitive and physical function scores and absence of severe (grade ≥ 2) hypoalbuminemia were associated with an improved objective response rate, longer treatment duration, and better OS. Conclusions: These findings underscore the importance of monitoring and managing treatment-related AEs and maintaining the HRQoL. They also highlight the crucial and reassuring role of multidisciplinary care in enhancing treatment outcomes in this cohort. [ABSTRACT FROM AUTHOR]

Background and Aims: Skeletal muscle loss has been identified as a prognostic factor in patients with unresectable hepatocellular carcinoma (uHCC) undergoing treatment with lenvatinib (LEN). While atezolizumab plus bevacizumab (ATZ-BEV) is recommended as first-line therapy for uHCC, the impact of skeletal muscle loss in these patients remains unclear. Methods: We enrolled 97 patients treated with either LEN or ATZ-BEV as their first-line therapy and divided them into two groups based on the presence or absence of a low psoas muscle index (low PMI) before treatment. We compared patient characteristics and overall survival (OS) between the groups. Additionally, we investigated the transition of the PMI during drug therapy, specifically before treatment, at the initial evaluation, and after the end of treatment. Results: Seventy percent of patients in the LEN group and seventy-one percent in the ATZ-BEV group had a low PMI. Multivariate analysis across all patients revealed a low PMI (hazard ratio [HR] 3.25, p = 0.0004) as a prognostic factor for OS. The PMI decreased more in the LEN group compared to the ATZ-BEV group. In the Barcelona Clinic Liver Cancer—C group, the OS of ATZ-BEV therapy was significantly better than that of LEN therapy when a low PMI was present (p = 0.046). Conclusions: A low PMI emerges as a significant prognostic factor in uHCC patients undergoing drug therapy, not only in LEN therapy but also in ATZ-BEV therapy. Additionally, ATZ-BEV therapy may be more favorable for sarcopenic patients with advanced HCC stages. [ABSTRACT FROM AUTHOR]

Background: Several fusion oncogenes showing a higher incidence in pediatric acute myeloid leukemia (AML) are associated with heterogeneous megakaryoblastic and other myeloid features. Here we addressed how developmental mechanisms influence human leukemogenesis by ETO2::GLIS2, associated with dismal prognosis. Methods: We created novel ETO2::GLIS2 models of leukemogenesis through lentiviral transduction and CRISPR-Cas9 gene editing of human fetal and post-natal hematopoietic stem/progenitor cells (HSPCs), performed in-depth characterization of ETO2::GLIS2 transformed cells through multiple omics and compared them to patient samples. This led to a preclinical assay using patient-derived-xenograft models to test a combination of two clinically-relevant molecules. Results: We showed that ETO2::GLIS2 expression in primary human fetal CD34+ hematopoietic cells led to more efficient in vivo leukemia development than expression in post-natal cells. Moreover, cord blood-derived leukemogenesis has a major dependency on the presence of human cytokines, including IL3 and SCF. Single cell transcriptomes revealed that this cytokine environment controlled two ETO2::GLIS2-transformed states that were also observed in primary patient cells. Importantly, this cytokine sensitivity may be therapeutically-exploited as combined MEK and BCL2 inhibition showed higher efficiency than individual molecules to reduce leukemia progression in vivo. Conclusions: Our study uncovers an interplay between the cytokine milieu and transcriptional programs that extends a developmental window of permissiveness to transformation by the ETO2::GLIS2 AML fusion oncogene, controls the intratumoral cellular heterogeneity, and offers a ground-breaking therapeutical opportunity by a targeted combination strategy. [ABSTRACT FROM AUTHOR]

Simple Summary: The most common adverse events (AEs) that occurred in response to targeted therapy for hepatocellular carcinoma were appetite loss (adverse event grade 0/1/2/3 = 97/23/55/12), general fatigue (102/31/44/6), hypertension (120/6/40/17), hand-foot syndrome (HFS) (135/21/24/3), proteinuria (140/13/16/14), and hypothyroidism (148/12/23/0). Among these, appetite loss and general fatigue negatively affect overall survival (OS) and progression-free survival (PFS). Increasing AE grades of hypertension, proteinuria, and hypothyroidism were associated with better OS, whereas hypertension, HFS, and hypothyroidism were associated with better PFS. To assess the impact of adverse event (AE) severity, caused by targeted therapy, on overall survival (OS) and progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (HCC), a total of 183 patients with HCC treated with atezolizumab plus bevacizumab (40), lenvatinib (57), sorafenib (79), cabozantinib (3), ramucirumab (3), and regorafenib (1) were included in this study. Age-, AFP-, and ALBI score-adjusted hazard ratios (HRs) of AE grades 1 to 3 versus grade 0 for OS and PFS were calculated using Cox proportional hazards models. The linear trend of the HRs was assessed by calculating the p values for this trend. The most common AEs were appetite loss (AE grade 0/1/2/3 = 97/23/55/12), general fatigue (102/31/44/6), hypertension (120/6/40/17), hand-foot syndrome (HFS) (135/21/24/3), proteinuria (140/13/16/14), and hypothyroidism (148/12/23/0). The adjusted HRs for OS of these AEs were 0.532–1.450–2.361 (p for trend 0.037), 1.057–1.691–3.364 (p for trend 0.004), 1.176–0.686–0.281 (p for trend 0.002), 0.639–0.759–1.820 (p for trend 0.462), 1.030–0.959–0.147 (p for trend 0.011), and 0.697–0.609 (p for trend 0.119), respectively. Those for PFS of the corresponding AEs were 0.592–1.073–2.811 (p for trend 0.255), 1.161–1.282–4.324 (p for trend 0.03), 0.965–0.781–0.655 (p for trend 0.095), 0.737–0.623–2.147 (p for trend 0.153), 1.061–0.832–0.800 (p for trend 0.391), and 1.412–0.560 (p for trend 0.081), respectively. Appetite loss and general fatigue negatively affected clinical outcomes, whereas hypertension, HFS, proteinuria, and hypothyroidism had positive effects. [ABSTRACT FROM AUTHOR]

Background: Transarterial chemoembolisation (TACE) and radioembolisation (TARE) can lead to the deterioration of liver function, especially in cases of a high tumour burden, potentially lessening the benefits of subsequent systemic treatments. We aimed to verify whether a high number of previous transarterial treatments modified the outcomes of patients who received sorafenib as a frontline systemic treatment. Methods: A retrospective analysis of a large multicenter dataset containing prospectively collected data of sorafenib-treated patients was conducted. Results: Data from 696 patients were analysed, with 139 patients having received >two transarterial procedures before starting sorafenib. A propensity score matched 139 identified pairs of patients. Having received >two locoregional treatments was independently associated with a shorter survival (hazard ratio 1.325, 95% confidence interval 1.018–1.725, p = 0.039). This pattern was confirmed amongst responders to sorafenib, but not in progressors. A trend toward a higher rate of the permanent discontinuation of sorafenib due to liver failure (18.7 vs. 10.8%, p = 0.089) and a lower rate of eligibility for second-line treatments (24.5 vs. 17.3%, p = 0.184) was observed in patients who had received >two transarterial procedures. Conclusions: Repeated endovascular treatments negatively impacted the survival of HCC patients, especially sorafenib-responders. An early switch to systemic therapies should be considered in cases that are unlikely to respond. [ABSTRACT FROM AUTHOR]

In our previous study, we found that small ubiquitin‐related modifier (SUMO)‐activating enzyme ubiquitin‐associated‐2 domain (UBA2) was upregulated in hepatocellular carcinoma (HCC) patients who were insensitive to chemoembolization. In this study, we aimed to investigate the role of UBA2 in HCC progression. Three cohorts were used to evaluate the efficacy of UBA2 as a prognostic factor for HCC. Our results indicated that UBA2 was associated with aggressive clinical behaviors and was a strong indicator of poor prognosis in HCC. In vitro experiments demonstrated that UBA2 accelerated cell growth, invasion, and migration. These results were further supported by in vivo experiments. RNA‐sequencing analysis indicated NQO1 as a target of UBA2, with its levels altering following UBA2 manipulation. The results were verified by western blotting (WB) and quantitative PCR. The SUMOplot Analysis Program predicted lysine residue K240 as a modification target of UBA2, which was confirmed by immunoprecipitation (IP) assays. Subsequent mutation of NQO1 at K240 in HCC cell lines and functional assays revealed the significance of this modification. In addition, the oncogenic effect of UBA2 could be reversed by the SUMO inhibitor ML792 in vivo and in vitro. In conclusion, our study elucidated the regulatory mechanism of UBA2 in HCC and suggested that the SUMO inhibitor ML792 may be an effective combinatory treatment for patients with aberrant UBA2 expression. [ABSTRACT FROM AUTHOR]

Background: Our research endeavored to develop a robust predictive signature grounded in super-enhancer-related genes (SERGs), with the dual objectives of forecasting survival outcomes and evaluating the tumor immune microenvironment (TiME) in hepatocellular carcinoma (HCC). Methods: HCC RNA-sequencing data were retrieved from The Cancer Genome Atlas (TCGA), and 365 patients were randomly assigned to training or testing sets in 1:1 ratio. SERGs of HCC were downloaded from Super-Enhancer Database (SEdb). On the basis of training set, a SERGs signature was identified, and its prognostic value was confirmed by internal and external validation (GSE14520) sets. We subsequently examined the model for potential functional enrichment and the degree of tumor immune infiltration. Additionally, we carried out in vitro experiments to delve into the biological functions of CBX2 gene. Results: An SE-related prognostic model including CBX2, TPX2, EFNA3, DNASE1L3 and SOCS2 was established and validated. According to this risk model, patients in the high-risk group had a significantly worse prognosis, and their immune cell infiltration was significantly different from that of low-risk group. Moreover, the high-risk group exhibited a significant enrichment of tumor-associated pathological pathways. The SERGs signature can generally be utilized to screen HCC patients who are likely to respond to immunotherapy, as there is a positive correlation between the risk score and the Tumor Immune Dysfunction and Exclusion (TIDE) score. Furthermore, the downregulation of the CBX2 gene expression was found to inhibit HCC cell viability, migration, and cell cycle progression, while simultaneously promoting apoptosis. Conclusions: We developed a novel HCC prognostic model utilizing SERGs, indicating that patients with high-risk score not only face a poorer prognosis but also may exhibit a diminished therapeutic response to immune checkpoint inhibitors (ICIs). This model is designed to tailor personalized treatment strategies to the individual needs of each patient, thereby improving the overall clinical outcomes for HCC patients. Furthermore, CBX2 is a promising candidate for therapeutic intervention in HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Tyrosine kinase inhibitors (TKIs) have demonstrated effectiveness in a variety of malignancies. As is the case for many different classes of drugs, tyrosine kinase inhibitors induce autophagy in various tumor cell models. Autophagy is a cellular degradative machinery that can be protective or cytotoxic to the cells, and in some cases, autophagy has no detectable influence on cell sensitivity to chemotherapy. This review demonstrates that cytoprotective and cytotoxic autophagy are the main forms induced by TKIs and that targeting or modulating autophagy can potentially enhance the tumor cell response to tyrosine kinase inhibitors. Tyrosine kinase inhibitors (TKIs) represent a relatively large class of small-molecule inhibitors that compete with ATP for the catalytic binding site of tyrosine kinase proteins. While TKIs have demonstrated effectiveness in the treatment of multiple malignancies, including chronic myelogenous leukemia, gastrointestinal tumors, non-small cell lung cancers, and HER2-overexpressing breast cancers, as is almost always the case with anti-neoplastic agents, the development of resistance often imposes a limit on drug efficacy. One common survival response utilized by tumor cells to ensure their survival in response to different stressors, including anti-neoplastic drugs, is that of autophagy. The autophagic machinery in response to TKIs in multiple tumor models has largely been shown to be cytoprotective in nature, although there are a number of cases where autophagy has demonstrated a cytotoxic function. In this review, we provide an overview of the literature examining the role that autophagy plays in response to TKIs in different preclinical tumor model systems in an effort to determine whether autophagy suppression or modulation could be an effective adjuvant strategy to increase efficiency and/or overcome resistance to TKIs. [ABSTRACT FROM AUTHOR]

Despite advances in the treatment of hepatocellular carcinoma (HCC) over the last few decades, treatment opportunities for patients with HCC remain limited. HCC is the most common form of liver cancer, accounting for approximately 90% of all cases worldwide. Moreover, apart from the current pharmacological interventions, hepatic resection and liver transplantation are the mainstay curative approaches for patients with HCC. This systematic review included phase I, II, III, and IV clinical trials (CTs) and randomized controlled trials (RCTs) on current treatments for patients with HCC in Asian populations (2013–2023). A total of 427 articles were screened, and 184 non-duplicate publications were identified. After screening the titles and abstracts, 96 publications were excluded, and another 28 were excluded after full-text screening. The remaining 60 eligible RCTs/CTs were finally included. A total of 60 clinical trials fulfilled our inclusion criteria with 36 drugs used as monotherapy or combination therapy for HCC. Most studies used sorafenib alone or in combination with any of the treatment regimens. Lenvatinib or atezolizumab with bevacizumab was used for HCC after initial sorafenib treatment. Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicates that sorafenib, used alone or in combination with atezolizumab and bevacizumab, has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in Asian populations. [ABSTRACT FROM AUTHOR]

Autoimmune hepatitis is a common cause of acute liver failure. Treatment includes steroids for acute liver injury and liver transplantation in those who fail to respond or develop acute liver failure. The aim of this study is to further characterize acute liver failure secondary to autoimmune hepatitis and identify variables that predict 21-day transplant-free survival. This study included adults hospitalized with acute liver failure enrolled in the Acute Liver Failure Study Group Registry between 1998 and 2019 from 32 centers within the US. The etiology of all cases was reviewed by the Adjudication Committee, and all cases identified as autoimmune hepatitis were included. Acute liver injury was defined as an INR ≥2.0 without encephalopathy and acute liver failure as INR ≥ 1.5 with encephalopathy. Laboratory and clinical data were reviewed. Variables significantly associated with 21-day transplant-free survival were used to develop a multivariable logistic regression model.  A total of 193 cases of acute liver failure secondary to autoimmune hepatitis were identified and reviewed. There were 161 patients (83.4%) diagnosed with acute liver failure on enrollment, and 32 (16.6%) developed acute liver failure during hospitalization. At 21 days, 115 (59.6%) underwent liver transplantation, 28 (14.5%) had transplant-free survival, and 46 (23.8%) died before liver transplantation. Higher admission values of bilirubin, INR, and coma grade were associated with worse outcomes. A prognostic index incorporating bilirubin, INR, coma grade, and platelet count had a concordance statistic of 0.84. Acute liver failure secondary to autoimmune hepatitis is associated with a high short-term mortality. We developed a model specifically for autoimmune hepatitis that may be helpful in predicting 21-day transplant-free survival and early identification of patients in need of expedited liver transplant evaluation., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Aim: The prognosis of patients with acute liver failure has improved dramatically in the past three decades due to advances in medical critical care and use of liver transplantation (LT) in Western countries, where the etiology of acute liver failure is different from that in Japan. We analyzed patients with fulminant hepatitis (FH) and late-onset hepatic failure (LOHF) admitted to our unit over a 32-year period to clarify the nature of Japanese patients with FH and LOHF., Methods: A total of 137 Japanese patients with FH and LOHF between 1986 and 2017 were analyzed for etiologies, disease types, treatment protocols, and outcome., Results: Of 137 patients, 124 were FH (53 acute type and 71 subacute type) and 13 LOHF. The major etiology was due to viral infections in 48% of patients. A total of 23.4% of patients recovered without LT, 7.3% received LT, and 69.3% died without LT. The number of patients showed rise and fall without an evident decrease during the period. Patients with autoimmune hepatitis increased after the establishment of autoimmune hepatitis criteria in 1999 (p < 0.001), and that with indeterminate cause decreased (p < 0.01). The mean age was older in the last decade than in the first decade (p = 0.036). Spontaneous and overall survival rates were not different during the period., Conclusions: The prognosis of our patients with FH and LOHF has not improved, probably because of aging and the increasing proportion of etiologies with poor prognosis and difficult-to-treat patients without response to medications regardless of advancement of clinical management, including artificial liver support devices and LT., (© 2022 Japan Society of Hepatology.)

Liver cancer has been reported to be one of the most malignant diseases in the world. It is late diagnosis consequently leads to a difficult treatment, as the cancer reached an advanced stage. Hepatocellular carcinoma (HCC) is the primary type of cancer diagnosed in the liver, with deadly characteristics and a poor prognosis. The first‐in‐line treatment for advanced HCC is sorafenib. Sorafenib acts by inhibiting cell proliferation and by inducing apoptosis as well as blocks receptors associated with these mechanisms. Due to its constant use, sorafenib resistance has been described, especially to proteins of the Bcl‐2 family, and their overexpression of Bcl‐XL and Mcl‐1. This review focuses on the role of the Bcl‐2 proteins in relation to sorafenib resistance as a consequence of first‐in‐line treatment in HCC. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence implicates the gut microbiota, metabolites, circulating cytokines and growth factors, and plasma proteins as potential susceptibility factors for intracranial aneurysm (IA). However, due to their complexity, the causal relationship between these factors and IA remains unclear. Our goal was to determine whether these factors are causally associated with IA, UIA, and SAH and provide suggestions for the prevention and treatment of these cerebrovascular diseases. Methods: Utilizing data from genome‐wide association studies (GWAS), we conducted a large‐scale Mendelian randomization (MR) analysis between these factors and diseases using five different models (Wald ratio, IVW, MR‐Egger, weighted median, and MRPRESSO). Several sensitivity analyses were also applied to ensure the robustness of the results. Results: Our MR analysis revealed several significant causal relationships between 18 gut microbiota taxa (genus.Bilophila‐SAH, beta[95%CI] = −1.08[−1.61 ~ −0.54]), 55 blood metabolites (7‐alpha‐hydroxy‐3‐oxo‐4‐cholestenoate‐IA, beta[95%CI] = −2.78[−4.47 ~ −1.08]), 2 cytokines (IL‐6‐UIA, beta[95%CI] = 0.73[0.34 ~ 1.39]), 45 plasma proteins (RELT‐UIA, beta[95%CI] = −0.8[−1.22 ~ −0.38]), and IA, UIA, and SAH. Many of these were reported for the first time. Conclusions: In conclusion, our study provides reference of the potential causal effects of gut microbiota, blood metabolites, cytokines, and plasma proteins on IA, UIA, and SAH. These findings may contribute to a better understanding of the pathogenesis and potential therapeutic targets for these cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

The global burden of hepatitis B virus (HBV) infection remains high, with chronic hepatitis B (CHB) patients facing a significantly increased risk of developing cirrhosis and hepatocellular carcinoma (HCC). The ultimate objective of antiviral therapy is to achieve a sterilizing cure for HBV. This necessitates the elimination of intrahepatic covalently closed circular DNA (cccDNA) and the complete eradication of integrated HBV DNA. This review aims to summarize the oncogenetic role of HBV integration and the significance of clearing HBV integration in sterilizing cure. It specifically focuses on the molecular mechanisms through which HBV integration leads to HCC, including modulation of the expression of proto-oncogenes and tumor suppressor genes, induction of chromosomal instability, and expression of truncated mutant HBV proteins. The review also highlights the impact of antiviral therapy in reducing HBV integration and preventing HBV-related HCC. Additionally, the review offers insights into future objectives for the treatment of CHB. Current strategies for HBV DNA integration inhibition and elimination include mainly antiviral therapies, RNA interference and gene editing technologies. Overall, HBV integration deserves further investigation and can potentially serve as a biomarker for CHB and HBV-related HCC. [ABSTRACT FROM AUTHOR]

Portal vein thrombosis (PVT) is a challenging and controversial complication of cirrhosis. Experimental models that reproduce cirrhotic PVT and effective pharmacological therapies are limited. We aimed to investigate the nature course and mechanisms of PVT in cirrhosis. A novel PVT model was developed via two-step total portal vein ligation in healthy and thioacetamide (TAA)-cirrhotic rats. Circulating and liver-infiltrating neutrophils were isolated from individuals with cirrhosis to examine neutrophil extracellular traps (NETs) and explore their unique characteristics and implications in PVT-associated fibrosis in cirrhosis. We further validated macrophage–myofibroblast transition (MMT) via multiplex immunofluorescence and single-cell sequencing. In the experimental model, cirrhosis promoted PVT development and portal vein intimal thickening. Interestingly, cirrhosis promoted spontaneous resolution of PVT due to instability of thrombus structure, along with pulmonary and intrahepatic clots. NETs-MMT mediate cirrhotic PVT and PVT-associated fibrosis, including fibrotic thrombus remodeling and increased hepatic collagen deposition. Mechanistically, caspase-4-dependent activation of neutrophils and GSDMD mediated the formation of NETs. The extracellular DNA of NETs promoted TGF-β1/Smad3-driven MMT. Inhibiting GSDMD with disulfiram suppressed cirrhotic PVT and prevented associated fibrosis. The cirrhotic PVT model reflected the following three main characteristics of cirrhotic PVT: spontaneous resolution, immunothrombosis, and intimal fibrosis. Targeting NETs with GSDMD inhibitors may serve as a new therapeutic concept to treat cirrhotic PVT. [ABSTRACT FROM AUTHOR]

Gnetum formosum Markgr., a member of the Gnetaceae family, is distributed in Vietnam. This plant remains a botanical enigma with an unexplored diversity of chemical constituents and pharmacological effects. In this study, two new steroidal saponins, namely gnetumosides A (1) and B (2), were isolated from the aerial parts of G. formosum. Their chemical structures were elucidated using spectroscopic techniques, including high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) and NMR, along with chemical hydrolysis and comparison with the reported literature. The potential anti-inflammatory effects of the isolated compounds were evaluated by measuring lipopolysaccharide-stimulated nitric oxide (NO) production in murine macrophage cells. Notably, compound 1 exhibited the most potent inhibitory activity (IC50 = 14.10 ± 0.75 µM), comparable to dexamethasone. Additionally, the mechanisms underlying the observed anti-inflammatory effects were investigated through molecular docking and molecular dynamics simulations on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins. This study is the first to investigate the chemical constituents and pharmacological effects of G. formosum. [ABSTRACT FROM AUTHOR]

Hypoxia is a hallmark of solid tumors, including hepatocellular carcinoma (HCC). Hypoxia has proven to be involved in multiple tumor biological processes and associated with malignant progression and resistance to therapy. Transarterial chemoembolization (TACE) is a well-established locoregional therapy for patients with unresectable HCC. However, TACE-induced hypoxia regulates tumor angiogenesis, energy metabolism, epithelial-mesenchymal transition (EMT), and immune processes through hypoxia-inducible factor 1 (HIF-1), which may have adverse effects on the therapeutic efficacy of TACE. Hypoxia has emerged as a promising target for combination with TACE in the treatment of HCC. This review summarizes the impact of hypoxia on HCC tumor biology and the adverse effects of TACE-induced hypoxia on its therapeutic efficacy, highlighting the therapeutic potential of hypoxia-targeted therapy in combination with TACE for HCC. [ABSTRACT FROM AUTHOR]

[2,3-diamino-N-(4-(benzo[d]thiazol-2-yl)phenyl)propanamide], named as ETN101, is a novel therapeutic agent for hepatocellular carcinoma. In vitro studies examined ETN101 metabolites in human, mouse, rat, dog, and monkey hepatocytes and identified the drug-metabolizing enzymes involved using cDNA-expressed human recombinant cytochrome P450s (CYPs), carboxylesterases (CESs), N-acetyltransferase (NAT) 1, and human liver cytosol. ETN101 showed similar metabolic stability across hepatocytes from five species, with particularly comparable stability in humans, rats, and monkeys. Its half-life was 75.0 min in humans, 68.9 in rats, 73.1 in monkeys, 120.4 in mice, and 112.7 in dogs. Thirty-four ETN101 metabolites, including the major metabolite M1, were identified using liquid chromatography–high-resolution mass spectrometry. ETN101 was primarily metabolized to M1 and CYP1A2 is exclusively responsible for M1 metabolism. Both NAT1 and NAT2 were responsible for the N-acetylation of M1 to M2. ETN101 remained stable in human CESs. In conclusion, this study provides comprehensive insights into the metabolic characteristics of ETN101, valuable for its toxicological and clinical development. [ABSTRACT FROM AUTHOR]

Ocimum gratissimum (O. gratissimum), a medicinal herb with antifungal and antiviral activities, has been found to prevent liver injury and liver fibrosis and induce apoptosis in hepatocellular carcinoma (HCC) cells. In this study, we evaluated the effect of aqueous extracts of O. gratissimum (OGE) on improving the efficacy of chemotherapeutic drugs in HCC cells. Proteomic identification and functional assays were used to uncover the critical molecules responsible for OGE-induced sensitization mechanisms. The antitumor activity of OGE in combination with a chemotherapeutic drug was evaluated in a mouse orthotopic tumor model, and serum biochemical tests were further utilized to validate liver function. OGE sensitized HCC cells to the chemotherapeutic drug cisplatin. Proteomic analysis and Western blotting validation revealed the sensitization effect of OGE, likely achieved through the inhibition of breast cancer type 1 susceptibility protein (BRCA1). Mechanically, OGE treatment resulted in BRCA1 protein instability and increased proteasomal degradation, thereby synergistically increasing cisplatin-induced DNA damage. Moreover, OGE effectively inhibited cell migration and invasion, modulated epithelial-to-mesenchymal transition (EMT), and impaired stemness properties in HCC cells. The combinatorial use of OGE enhanced the efficacy of cisplatin and potentially restored liver function in a mouse orthotopic tumor model. Our findings may provide an alternate approach to improving chemotherapy efficacy in HCC. [ABSTRACT FROM AUTHOR]

Dental microwear analysis is a well-established technique that provides valuable information about the diets of extant and extinct taxa. It has been used effectively in most major groups of vertebrates. However, in chondrichthyans, these methods have been implemented only recently in the form of dental microwear texture analysis, with conflicting results. Causes intrinsic to chondrichthyan biology, such as limited food-to-tooth contact, low diversity in terms of trophic categories or fast tooth replacement, have been suggested to reduce diet-related wear on individual teeth, hindering the use of this approach for reliable dietary reconstruction. Here, we explored the relationship between diet and dental microwear in chondrichthyans by using 2D analysis, which can provide finer-scale identification and accurate definition of scratch morphology from tooth surfaces a priori. Scratches were counted and measured on the teeth of 34 extant elasmobranchs grouped into three categories (piscivorous, durophagous and generalist) according to dietary preferences. Our results revealed specific patterns of tooth microwear as a function of dietary abrasiveness, enabling the discrimination of trophic groups and thus establishing a useful comparative framework for inferring aspects of trophic ecology in fossils. We then used this information to study dental microwear in six fossil species from the same locality and stratigraphic levels. First, analyses of the enameloid surfaces of the fossil show that post-mortem alterations are distinguishable, allowing reliable quantification of diet-related ante-mortem microwear signatures. Discriminant analysis allowed the recognition of microwear patterns comparable to those of living sharks and linked them to specific trophic groups with high probability levels (> 90%). Thus, microwear features developing on chondrichthyan teeth during feeding are intense enough to retain information regarding diet preferences. 2D microwear analysis can track this information, proving to be a useful tool for providing significant information not only about diet but also about oral processing mechanisms in extinct chondrichthyans. [ABSTRACT FROM AUTHOR]