Nitrile gloves have become a significant environmental pollutant after the COVID-19 pandemic due to their single-use design. This study examines the capability of P. aeruginosa to use nitrile gloves as its sole carbon energy source. Biodegradation was determined by P. aeruginosa adapting to increasing nitrile glove concentrations at 1%, 3%, and 5% (w/v). The growth kinetics of P. aeruginosa were evaluated, as well as the polymer weight loss. Topographic changes on the glove surfaces were examined using SEM, and FT-IR was used to evaluate the biodegradation products of the nitrile gloves. Following the establishment of a biofilm on the glove surface, the nitrile toxicity was minimized via biodegradation. The result of the average weight loss of nitrile gloves was 2.25%. FT-IR analysis revealed the presence of aldehydes and aliphatic amines associated with biodegradation. SEM showed P. aeruginosa immersed in the EPS matrix, causing the formation of cracks, scales, protrusions, and the presence of semi-spherical particles. We conclude that P. aeruginosa has the capability to use nitrile gloves as its sole carbon source, even up to 5%, through biofilm formation, demonstrating the potential of P. aeruginosa for the degradation of nitrile gloves. Full article

The use of seawater and sea sand as replacements for fresh water and river sand in the preparation of seawater and sea sand concrete can effectively address issues such as high transportation costs, extended construction periods, and resource wastage. Nevertheless, in northern coastal areas, the problem of concrete durability in the complex and changing marine environment is more prominent. Research on the durability of seawater sea sand concrete is beneficial to the widening of its application range. To investigate the impact of glass fiber (GF) and polyvinyl alcohol fiber (PVA) with different blending methods on the seawater freeze–thaw resistance of seawater sea sand concrete (SSC), corresponding specimens were prepared, and seawater freeze–thaw cycling tests were conducted. By adopting the slow-freezing method and combining macro-structure and micro-morphology, the damage mechanism and the deterioration law of fiber-reinforced SSC under seawater freezing and thawing were investigated. The results indicate that, macroscopically, the incorporation of GF and PVA can effectively mitigate the damage to the matrix and reduce the effects of external erosive substances on the rate of strength loss, the rate of mass loss, and the relative dynamic elastic modulus. After 75 cycles, the SSC with a total volume doping of 0.3% and a blending ratio of 1:1 showed a 41.23% and 27.55% reduction in mass loss and strength loss, respectively, and a 29.9% improvement in relative dynamic elastic modulus compared with the basic group. Microscopic analysis reveals that the combined effect of freezing and expansion forces, the expansive substances generated by seawater intrusion into the interior of the matrix, and salt crystallization all weaken the bond between aggregate and mortar, leading to accelerated deterioration of the concrete. The incorporation of fibers enables the matrix to become denser and improves its crack-resistant properties, resulting in a better durability than that of the basic group. The damage prediction model established by the NSGM(1,N) model of gray system theory exhibits high accuracy and is suitable for long-term prediction, accurately predicting the damage of seawater sea sand concrete under seawater freeze–thaw coupling. Full article

In this work, we consider the physical basis of deformation and fracture in layered composite nanocrystalline/amorphous material–low-melting crystalline alloy in a wide temperature range. Deformation and fracture at the crack tip on the boundary of such materials as nanocrystalline alloy of the trademark 5BDSR, amorphous alloy of the trademark 82K3XSR and low-melting crystalline alloy were experimentally investigated. The crack was initiated by uniaxial stretching in a temperature range of 77–293 K. A theoretical description of the processes of deformation and fracture at the crack tip is proposed, with the assumption that these processes lead to local heating and ensure the plastic character of crack growth at liquid nitrogen temperatures. The obtained results improve the theoretical understanding of the physics of fracture at the boundary of nanocrystalline and crystalline alloys in a wide temperature range. The possibility of preserving the plastic nature of fracture in a thin boundary layer of crystalline–nanocrystalline material at cryogenic temperatures has been experimentally shown. Full article

Background: Gaucher disease (GD) is caused by glucocerebrosidase (GCase) enzyme deficiency, leading to glycosylceramide (Gb-1) and glucosylsphingosine (Lyso-Gb-1) accumulation. The pathological hallmark for GD is an accumulation of large macrophages called Gaucher cells (GCs) in the liver, spleen, and bone marrow, which are associated with chronic organ enlargement, bone manifestations, and inflammation. Tartrate-resistant acid phosphatase type 5 (TRAP5 protein, ACP5 gene) has long been a nonspecific biomarker of macrophage/GCs activation; however, the discovery of two isoforms of TRAP5 has expanded its significance. The discovery of TRAP5′s two isoforms revealed that it is more than just a biomarker of macrophage activity. While TRAP5a is highly expressed in macrophages, TRAP5b is secreted by osteoclasts. Recently, we have shown that the elevation of TRAP5b in plasma is associated with osteoporosis in GD. However, the role of TRAP isoforms in GD and how the accumulation of Gb-1 and Lyso-Gb-1 affects TRAP expression is unknown. Methods: 39 patients with GD were categorized into cohorts based on bone mineral density (BMD). TRAP5a and TRAP5b plasma levels were quantified by ELISA. ACP5 mRNA was estimated using RT-PCR. Results: An increase in TRAP5b was associated with reduced BMD and correlated with Lyso-Gb-1 and immune activator chemokine ligand 18 (CCL18). In contrast, the elevation of TRAP5a correlated with chitotriosidase activity in GD. Lyso-Gb-1 and plasma seemed to influence the expression of ACP5 in macrophages. Conclusions: As an early indicator of BMD alteration, measurement of circulating TRAP5b is a valuable tool for assessing osteopenia–osteoporosis in GD, while TRAP5a serves as a biomarker of macrophage activation in GD. Understanding the distinct expression pattern of TRAP5 isoforms offers valuable insight into both bone disease and the broader implications for immune system activation in GD. Full article

Coatomer Protein Complex-II (COPII) mediates anterograde vesicle transport from the endoplasmic reticulum (ER) to the Golgi apparatus. Here, we report that the COPII coatomer complex is constructed dependent on a small GTPase, Sar1, in spermatocytes before and during Drosophila male meiosis. COPII-containing foci co-localized with transitional endoplasmic reticulum (tER)-Golgi units. They showed dynamic distribution along astral microtubules and accumulated around the spindle pole, but they were not localized on the cleavage furrow (CF) sites. The depletion of the four COPII coatomer subunits, Sec16, or Sar1 that regulate COPII assembly resulted in multinucleated cell production after meiosis, suggesting that cytokinesis failed in both or either of the meiotic divisions. Although contractile actomyosin and anilloseptin rings were formed once plasma membrane ingression was initiated, they were frequently removed from the plasma membrane during furrowing. We explored the factors conveyed toward the CF sites in the membrane via COPII-mediated vesicles. DE-cadherin-containing vesicles were formed depending on Sar1 and were accumulated in the cleavage sites. Furthermore, COPII depletion inhibited de novo plasma membrane insertion. These findings suggest that COPII vesicles supply the factors essential for the anchoring and/or constriction of the contractile rings at cleavage sites during male meiosis in Drosophila. Full article

Certain microalgal species can grow with different trophic strategies depending on the availability of nutrient resources. They can use the energy from light or an organic substrate, or both, and can therefore be called autotrophs, heterotrophs, or mixotrophs. We recently isolated a microalgal strain from the microplastic biofilm, which was identified as Auxenochlorella protothecoides, AS-1. Strain AS-1 grew rapidly in bacterial culture media and exhibited different growth rates and cell sizes under different trophic conditions. We compared the growth performance of AS-1 under the three different trophic modes. AS-1 reached a high biomass (>4 g/L) in 6 days under mixotrophic growth conditions with a few organic carbons as a substrate. In contrast, poor autotrophic growth was observed for AS-1. Different cell sizes, including daughter and mother cells, were observed under the different growth modes. We applied a Coulter Counter to measure the size distribution patterns of AS-1 under different trophic modes. We showed that the cell size distribution of AS-1 was affected by different growth modes. Compared to the auto-, hetero- and mixotrophic modes, AS-1 achieved higher biomass productivity by increasing cell number and cell size in the presence of organic substrate. The mechanisms and advantages of having more mother cells with organic substrates are still unclear and warrant further investigations. The work here provides the growth information of a newly isolated A. protothecoides AS-1 which will be beneficial to future downstream applications. Full article

Membrane proteins constitute about 20% of the human proteome and play crucial roles in cellular functions. However, a complete understanding of their structure and function is limited by their hydrophobic nature, which poses significant challenges in purification and stabilization. Detergents, essential in the isolation process, risk destabilizing or altering the proteins’ native conformations, thus affecting stability and functionality. This study leverages single-particle cryo-electron microscopy to elucidate the structural nuances of membrane proteins, focusing on the SLAC1 bacterial homolog from Haemophilus influenzae (HiTehA) purified with diverse detergents, including n-dodecyl β-D-maltopyranoside (DDM), glycodiosgenin (GDN), β-D-octyl-glucoside (OG), and lauryl maltose neopentyl glycol (LMNG). This research not only contributes to the understanding of membrane protein structures but also addresses detergent effects on protein purification. By showcasing that the overall structural integrity of the channel is preserved, our study underscores the intricate interplay between proteins and detergents, offering insightful implications for drug design and membrane biology. Full article

The environmental impacts of excessive phosphorus emissions (PE) have been widely discussed in recent years. This study aims to calculate and evaluate the phosphorus footprint (PF) of food thrown away in Chinese universities. Based on a nationwide survey involving 9192 university students from 29 provinces and 29 universities in China, the result reveals that the PF generated by food waste in Chinese university canteens was 3.209 Kt in 2018. Furthermore, it is found that meal satisfaction, gender, regional economic level, dietary culture, and years of education all have significant impacts on lost food PF. Our findings emphasize the importance of reducing food waste in university canteens, which plays a crucial role in ensuring food security and environmental protection. Full article

Background: Chronic lateral epicondylitis challenges the therapeutical approach; underlying mechanisms are incompletely understood; neuropathic pain and central and peripheral sensitization may explain the fact that botulinum toxin has been found to play a role in pain and function management. Methods: We searched the literature for MeSH terms: lateral epicondylitis or synonyms and botulinum toxin. Results: We found 14 papers containing trials on botulinum toxin injection into the tendon or into the extensor muscles (specifically, extensor carpi radialis brevis and extensor communis digitorum). We followed the administration pathways, doses, timing, and side effects. Conclusions: With a chronic course, the focus of the therapy shifts from the afflicted tendon to the inserting muscles, as muscle contracture may create a vicious loop to perpetuate and aggravate the disease. Doses, timing, and side effects are discussed. Full article

Antithrombotics have been widely used to treat and prevent COVID-19-related thrombosis; however, studies on their use at population levels are limited. We aimed to describe antithrombotic use patterns during the pandemic in Spanish primary care and hospital-admitted patients with COVID-19. Methods: A real-world data study was performed. Data were obtained from BIFAP’s electronic health records. We investigated the antithrombotic prescriptions made within ±14 days after diagnosis between March 2020 and February 2022, divided their use into prior and new/naive groups, and reported their post-discharge use. Results: We included 882,540 individuals (53.4% women), of whom 78,499 were hospitalized. The median age was 44.7 (IQR 39–59). Antithrombotics were prescribed in 37,183 (4.6%) primary care subjects and 42,041 (53.6%) hospital-admitted patients, of whom 7505 (20.2%) and 20,300 (48.3%), respectively, were naive users. Prior users were older and had more comorbidities than new users. Enoxaparin was the most prescribed antithrombotic in hospitals, with higher prescription rates in new than prior users (2348.2, IQR 2390–3123.1 vs. 1378, IQR 1162–1751.6 prescriptions per 10,000 cases, p = 0.002). In primary care, acetylsalicylic acid was the most used antithrombotic, with higher use rates in prior than in naïve users. Post-discharge use occurred in 6686 (15.9%) subjects (median use = 10 days, IQR 9-30). Conclusions: Our study identified a consensus on prescribing antithrombotics in COVID-19 patients, but with low use rates in hospitals. Full article

The functionality and reliability of nanoscale multilayer devices and components are influenced by changes in stress and microstructure throughout fabrication, processing, and operation. NiV/B₄C multilayers with a d-spacing of 3 nm were prepared by magnetron sputtering, and two groups of annealing experiments were performed. The stress, microstructure, and interface changes in NiV/B₄C after annealing were investigated by grazing-incidence X-ray reflectometry (GIXR), grazing-incidence X-ray diffraction (GIXRD), X-ray diffuse scattering, and grazing-incidence small-angle X-ray scattering (GISAXS). The temperature dependence experiments revealed a gradual shift in the multilayer stress from compression to tension during annealing from 70 °C to 340 °C, with the stress approaching near-zero levels between 70 °C and 140 °C. The time-dependent experiments indicated that most of the stress changes occurred within the initial 10 min, which showed that prolonged annealing was unnecessary. Combining the X-ray diffraction and X-ray scattering measurements, it was found that the changes in the thickness, interface roughness, and lateral correlation length, primarily due to crystallization, drove the changes in stress and microstructure. Full article

Lotus japonicus, is an important perennial model legume, has been widely used for studying biological processes such as symbiotic nitrogen fixation, proanthocyanidin (PA) biosynthesis, and abiotic stress response. High-quality L. japonicus genomes have been reported recently; however, the genetic basis of genes associated with specific characters including proanthocyanidin distribution in most tissues and tolerance to stress has not been systematically explored yet. Here, based on our previous high-quality L. japonicus genome assembly and annotation, we compared the L. japonicus MG-20 genome with those of other legume species. We revealed the expansive and specific gene families enriched in secondary metabolite biosynthesis and the detection of external stimuli. We suggested that increased copy numbers and transcription of PA-related genes contribute to PA accumulation in the stem, petiole, flower, pod, and seed coat of L. japonicus. Meanwhile, According to shared and unique transcription factors responding to five abiotic stresses, we revealed that MYB and AP2/ERF play more crucial roles in abiotic stresses. Our study provides new insights into the key agricultural traits of L. japonicus including PA biosynthesis and response to abiotic stress. This may provide valuable gene resources for legume forage abiotic stress resistance and nutrient improvement. Full article

In today’s investment landscape, the integration of environmental, social, and governance (ESG) factors with data-driven strategies is pivotal. This study delves into this fusion, employing sophisticated statistical techniques and Python programming to unveil insights often overlooked by traditional approaches. By analyzing extensive datasets, including S&P500 financial indicators from 2012 to 2021 and 2021 ESG metrics, investors can enhance portfolio performance. Emphasizing ESG integration for sustainable investing, the study underscores the potential for alpha generation. Time series analysis further elucidates market dynamics, empowering investors to align with both financial objectives and ethical values. Notably, the research uncovers a positive correlation between ESG risk and total risk, suggesting that companies with lower ESG risk tend to outperform those with higher ESG risk. Moreover, employing a long–short ESG risk strategy yields abnormal returns of approximately 4.37%. This integration of ESG factors not only mitigates risks associated with environmental, social, and governance issues but also capitalizes on opportunities for sustainable growth, fostering responsible investing practices and ensuring long-term financial returns, resilience, and value creation. Full article

Insect recognition, crucial for agriculture and ecology studies, benefits from advancements in RGB image-based deep learning, yet still confronts accuracy challenges. To address this gap, the HI30 dataset is introduced, comprising 2115 hyperspectral images across 30 insect categories, which offers richer information than RGB data for enhancing classification accuracy. To effectively harness this dataset, this study presents the Two-Branch Self-Correlation Network (TBSCN), a novel approach that combines spectrum correlation and random patch correlation branches to exploit both spectral and spatial information. The effectiveness of the HI30 and TBSCN is demonstrated through comprehensive testing. Notably, while ImageNet-pre-trained networks adapted to hyperspectral data achieved an 81.32% accuracy, models developed from scratch with the HI30 dataset saw a substantial 9% increase in performance. Furthermore, applying TBSCN to hyperspectral data raised the accuracy to 93.96%. Extensive testing confirms the superiority of hyperspectral data and validates TBSCN’s efficacy and robustness, significantly advancing insect classification and demonstrating these tools’ potential to enhance precision and reliability. Full article

Pelagic Sargassum landings (hereby referred to as sargasso) increased dramatically in 2011 throughout the equatorial tropical Atlantic due to the formation of the Great Atlantic Sargassum Belt (GASB). Despite increasing reports, understanding of local abundances and vegetative characteristics, especially in South Florida, remains limited. From 2018 to 2021, sargasso was collected at two South Florida beaches, with additional sampling at a third beach to assess nutrient and heavy metal concentrations. Biomass landings varied greatly, with S. fluitans III predominant during the “peak season” (May to July) and S. natans I predominant in the “off season”, while S. natans VIII was consistently least abundant. This suggests that South Florida may receive sargasso from the Sargasso Sea during the low season and from the GASB during the peak sargasso season. Across all three morphotypes, mean nitrogen (N) and phosphorus (P) contents were 0.97% and 0.04% (dry weight), respectively. Out of the 16 heavy metals detected, our values were similar to those reported across the Caribbean. Arsenic was the most prevalent heavy metal, with sargasso containing epibionts having higher arsenic concentrations. These results provide comprehensive information to better understand the characteristics and potential origin of sargasso landings in South Florida. Full article

The edible brown seaweed, Ecklonia cava, is highly valued for its bioactive compounds, and is widely used in food supplements and functional foods. The increasing demand for this seaweed in the food industry emphasizes the necessity for sustainable cultivation practices. This study focused on inducing callus in the meristem and stipe of E. cava using different culture media: Provasoli’s enriched seawater medium (PESI), enriched artificial seawater medium (ESAW), artificial enriched seawater medium (ASP2), or Von Stosch’s enriched seawater medium (VS). Various abiotic stress factors (photoperiod, agar concentration, and temperature), growth regulators, carbon sources, polyamines, and plasma treatments were explored for their impact on callus induction. Both stipe and meristem explants developed callus within three to six weeks across all media except ASP2. Callus development was favored at temperatures between 8 to 13 °C and in the absence of light. Stipe explants showed a higher callus induction rate (up to 65.59 ± 6.24%) compared to meristem (up to 57.53 ± 8.32%). Meristem explants showed optimal callus induction in PESI medium with a low concentration of indole-3-acetic acid (IAA; 40.93 ± 8.65%). However, higher concentrations of IAA and 1-naphthaleneacetic acid (NAA) reduced meristem callus induction. Stipe showed high induced-callus (up to 50.37 ± 5.17%) in PESI medium with low concentrations of IAA, NAA, and 6-benzylaminopurine (BAP). Both stipe and meristem explants induced largest callus at 2% sucrose, but higher carbon source concentrations reduced callus induction. Spermine (Spm) at 1 µM resulted in high induced calluses; however, increasing Spm concentrations decreased callus induction. This tissue culture technique not only supports mass cultivation of E. cava, but also holds potential for extending to other seaweed species, contributing to the sustainability of seaweed stocks for the food industry. Full article

Early evidence suggests a strong impact of tumour-infiltrating lymphocytes (TILs) on both the prognosis and clinical behaviour of ovarian cancer. Proven associations, however, have not yet translated to successful immunotherapies and further work in the field is urgently needed. We aimed to analyse the tumour microenvironment of a well-characterised cohort of ovarian cancer samples. Tumour markers were selected owing to their comparative underrepresentation in the current literature. Paraffin-embedded, formalin-fixed tumour tissue blocks of 138 patients representative of the population and including early stage disease were identified, stained for CD3, CD20, CD68 and CD163 and analysed for both the stromal and intertumoral components. Data were statistically analysed in relation to clinical details, histological subtype, borderline vs. malignant status, survival and management received. Mean stromal CD3, total CD3 count, mean stromal CD20 and total CD20 count all correlated negatively with survival. Malignant ovarian tumours consistently demonstrated significantly higher infiltration of all analysed immune cells than borderline tumours. Assessment of the stromal compartment produced a considerably higher proportion of significant results when compared to the intra-tumoural infiltrates. Customary assessment of solely intra-tumoural cells in advanced stage disease patients undergoing primary debulking surgery should be challenged, with recommendations for future scoring systems provided. Full article

The performance of oat flake flour and pumpkin seed protein powder in gluten-free dough and bread based on rice flours was assessed in this study. After studying the thermo-mechanical properties of the rice and oat flake flours at different water absorption capacities, two composite flours obtained by mixing the rice and oat flake flours with and without pumpkin seed protein powder were investigated. Regardless of the sample subjected to thermo-mechanical behavior analysis, the increase in the water adsorption level when preparing the dough caused a decrease in protein weakening, as well as starch retrogradation. The dough with added oat flake flour had a higher resistance to kneading compared to the control prepared with rice flour. Additionally, the substitution of rice flour with oat flake flour produced important changes in the gelatinization temperature, which decreases from 84–86 °C to 76 °C. The addition of pumpkin seed protein powder increased the maximum torque during kneading at 30 °C and decreased breakdown and starch retrogradation compared to the composite flour based on rice flour and oat flake flour. The higher amount of water used for preparing the dough improved the specific volume and crumb firmness of the bread prepared with the pumpkin seed protein-enriched composite flours. Full article

This retrospective study aimed to analyze the return to running of non-professional runners after experiencing asymptomatic or mild COVID-19. Participants aged 18–55 years who maintained a training load of ≥10 km/week for at least three months prior to diagnosis and utilized Garmin/Polar apps were included. From these devices, parameters such as pace, distance, total running time, cadence, and heart rate were collected at three intervals: pre-COVID, immediately post-COVID, and three months after diagnosis. The Wilcoxon signed rank test was used for analysis (significance was set at ≤0.05). Twenty-one participants (57.1% male; mean age 35.0 ± 9.8 years) were included. The results revealed a significant decrease in running duration and distance two weeks after diagnosis, without significant changes in other parameters. Three months after infection, no differences were observed compared to pre-infection data, indicating a return to the pre-disease training load. These findings underscore the transient impact of COVID-19 on training performance among non-professional runners with mild or asymptomatic symptoms, highlighting the importance of tailored strategies for resuming running after infection. Full article

The fibroblast growth factor receptor 2 (FGFR2) gene is one of the most extensively studied genes with many known mutations implicated in several human disorders, including oncogenic ones. Most FGFR2 disease-associated gene mutations are missense mutations that result in constitutive activation of the FGFR2 protein and downstream molecular pathways. Many tertiary structures of the FGFR2 kinase domain are publicly available in the wildtype and mutated forms and in the inactive and activated state of the receptor. The current literature suggests a molecular brake inhibiting the ATP-binding A loop from adopting the activated state. Mutations relieve this brake, triggering allosteric changes between active and inactive states. However, the existing analysis relies on static structures and fails to account for the intrinsic structural dynamics. In this study, we utilize experimentally resolved structures of the FGFR2 tyrosine kinase domain and machine learning to capture the intrinsic structural dynamics, correlate it with functional regions and disease types, and enrich it with predicted structures of variants with currently no experimentally resolved structures. Our findings demonstrate the value of machine learning-enabled characterizations of structure dynamics in revealing the impact of mutations on (dys)function and disorder in FGFR2. Full article

Ergot alkaloids (EAs) formed by Claviceps fungi are one of the most common food contaminants worldwide, affecting cereals such as rye, wheat, and barley. To accurately determine the level of contamination and to monitor EAs maximum levels set by the European Union, the six most common EAs (so-called priority EAs) and their corresponding epimers are quantified using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). The quantification of EAs in complex food matrices without appropriate internal standards is challenging but currently carried out in the standard method EN 17425:2021 due to their commercial unavailability. To address the need for isotopically labeled EAs, we focus on two semi-synthetic approaches for the synthesis of these reference standards. Therefore, we investigate the feasibility of the N⁶-demethylation of native ergotamine to yield norergotamine, which can subsequently be remethylated with an isotopically labeled methylating reagent, such as iodomethane (¹³CD₃-I), to yield isotopically labeled ergotamine and its C⁸-epimer ergotaminine. Testing the isotopically labeled ergotamine/-inine against native ergotamine/-inine with HPLC coupled to high-resolution HR-MS/MS proved the structure of ergotamine-¹³CD₃ and ergotaminine-¹³CD₃. Thus, for the first time, we can describe their synthesis from unlabeled, native ergotamine. Furthermore, this approach is promising as a universal way to synthesize other isotopically labeled EAs. Full article

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for ~90% of liver neoplasms. It is the second leading cause of cancer-related deaths and the seventh most common cancer worldwide. Although there have been rapid developments in the treatment of HCC over the past decade, the incidence and mortality rates of HCC remain a challenge. With the widespread use of the hepatitis B vaccine and antiviral therapy, the etiology of HCC is shifting more toward metabolic-associated steatohepatitis (MASH). Early-stage HCC can be treated with potentially curative strategies such as surgical resection, liver transplantation, and radiofrequency ablation, improving long-term survival. However, most HCC patients, when diagnosed, are already in the intermediate or advanced stages. Molecular targeted therapy, followed by immune checkpoint inhibitor immunotherapy, has been a revolution in HCC systemic treatment. Systemic treatment of HCC especially for patients with compromised liver function is still a challenge due to a significant resistance to immune checkpoint blockade, tumor heterogeneity, lack of oncogenic addiction, and lack of effective predictive and therapeutic biomarkers. Full article