Conversion therapy for advanced hepatocellular carcinoma in the era of precision medicine: Current status, challenges and opportunities.

Hepatocellular carcinoma (HCC), the most prevalent malignancy of the digestive tract, is characterized by a high mortality rate and poor prognosis, primarily due to its initial diagnosis at an advanced stage that precludes any surgical intervention. Recent advancements in systemic therapies have significantly improved oncological outcomes for intermediate and advanced-stage HCC, and the combination of locoregional and systemic therapies further facilitates tumor downstaging and increases the likelihood of surgical resectability for initially unresectable cases following conversion therapies. This shift toward high conversion rates with novel, multimodal treatment approaches has become a principal pathway for prolonged survival in patients with advanced HCC. However, the field of conversion therapy for HCC is marked by controversies, including the selection of potential surgical candidates, formulation of conversion therapy regimens, determination of optimal surgical timing, and application of adjuvant therapy post-surgery. Addressing these challenges and refining clinical protocols and research in HCC conversion therapy is essential for setting the groundwork for future advancements in treatment strategies and clinical research. This narrative review comprehensively summarizes the current strategies and clinical experiences in conversion therapy for advanced-stage HCC, emphasizing the unresolved issues and the path forward in the context of precision medicine. This work not only provides a comprehensive overview of the evolving landscape of treatment modalities for conversion therapy but also paves the way for future studies and innovations in this field.

α-Alkylation and Asymmetric Transfer Hydrogenation of Tetralone via Hydrogen Borrowing and Dynamic Kinetic Resolution Strategy Using a Single Iridium(III) Complex.

Here we present a novel strategy for the synthesis of enantiomerically enriched tetrahydronaphthalen-1-ols. The reaction proceeds via an alkylation (via hydrogen borrowing) and ammonium formate-mediated asymmetric transfer hydrogenation (via dynamic kinetic resolution), giving alkylated tetralols in high yields and good enantio- and diastereoselectivity across a diverse range of both alcohol and tetralone substrates. Additionally, these products were successfully derivatized to several complex molecules, demonstrating the utility of the tetrahydronaphthalen-1-ol.

Case Report: A rare case of intramedullary spinal cord abscess with brain abscess caused by Klebsiella pneumoniae underwent surgical intervention.

Background: Intramedullary Spinal Cord Abscess (ISCA) is an uncommon infectious disease of the central nervous system. Since its first report in 1830, there have been very few documented cases associated with it. Here, we present a case of ISCA with cerebral abscess caused by Klebsiella pneumoniae. Case presentation: A 55-year-old male patient presented with head and neck pain, fever, and left limb weakness for 5 days. The diagnosis of ISCA with brain abscess caused by Klebsiella pneumoniae was confirmed through sputum culture, cerebrospinal fluid gene test, pus culture, and magnetic resonance imaging (MRI) as well as computerized tomography (CT) scan. The patient had a history of pulmonary tuberculosis and old tuberculous foci were observed in the lung. Initially considering tuberculosis as the cause due to unclear etiology at that time, anti-tuberculosis treatment was administered. However, due to rapid deterioration in the patient's condition and severe neurological dysfunction within a short period of time after admission, surgical intervention including incision and drainage for intramedullary abscess along with removal of brain abscess was performed. Subsequent postoperative follow-up showed improvement in both symptoms and imaging findings. Conclusion: Early diagnosis of central nervous system (CNS) abscess coupled with prompt surgical intervention and administration of appropriate antibiotics are crucial factors in preventing disease progression and reducing mortality rates.

Observation of Acoustically Induced Dressed States of Rare-Earth Ions.

Acoustically induced dressed states of long-lived erbium ions in a crystal are demonstrated. These states are formed by rapid modulation of two-level systems via strain induced by surface acoustic waves whose frequencies exceed the optical linewidth of the ion ensemble. Multiple sidebands and the reduction of their intensities appearing near the surface are evidence of a strong interaction between the acoustic waves and the ions. This development allows for on-chip control of long-lived ions and paves the way to highly coherent hybrid quantum systems with telecom photons, acoustic phonons, and electrons.

Visual Color Change During Spin-coating Guiding the Quality of Cu2 ZnSn(S,Se)4 Films.

Solution method provides a low-cost and environmentally friendly route for the fabrication of Cu2 ZnSn(S,Se)4 (CZTSSe) thin-film solar cells. However, uncontrollable quality of the CZTSSe absorber layer will severely limit the device's performance. In this study, it is find that the thickness and the quality of the formed precursor is not stable because of the variation of the viscosity of the precursor solution. Combined by different characterization methods, the results disclose that such change is strongly related to the reflected color of the first coating layer during precursor growth. Further studies disclose that only by maintaining the appropriate reflected color can a well-crystallized CZTSSe film be prepared, thereby obtaining good solar cell efficiency. This semi-empirical pattern is confirmed by thin-film interference theory. Under the guidance of this method, CZTSSe absorbers with high quality are obtained easily, and the highly efficient CZTSSe solar cell can be fabricated easily. This study provides a feasible and effective strategy to obtain the optimal structure and composition of CZTSSe film toward the production of highly efficient kesterite solar cells, which can also be widely applied to the preparation of other films by solution-based method.

Research on the detection model of mental illness of online forum users based on convolutional network.

Recently, there will be more than 4.62 billion social media users worldwide. A large number of users tend to publish personal emotional dynamics or express opinions on social media. These massive user data provide data support for the development of mental illness detection research and have achieved good results. However, it is difficult for current mental illness detection models to accurately identify key emotional features from a large number of posts issued by users to detect problem users. In view of the fact that the existing models cannot more accurately extract the words with high emotional contribution in the content of user posts, this paper proposes two hierarchical user post feature representation models, named Single-Gated LeakReLU-CNN (SGL-CNN) and Multi-Gated LeakyReLU-CNN (MGL-CNN). We leverage these 2 models to identify users with mental illness in online forums. For all posts published by each user within a certain time span, the model proposed in this paper can identify key emotional features in them and filter out other unimportant information as much as possible. In addition, the addition of gating units in this paper can significantly improve the performance of emotion detection tasks. The experimental results based on the task of RSDD dataset prove that the performance of the model proposed in this paper is superior to that of the existing methods.

Changes in the cis-trans isomer selectivity of a reversed-phase liquid chromatography column during use with acidic mobile phase conditions.

Reversed-phase liquid chromatography (RPLC) is the analytical tool of choice for monitoring process-related organic impurities and degradants in pharmaceutical materials. Its popularity is due to its general ease-of-use, high performance, and reproducibility in most cases, all of which have improved as the technique has matured over the past few decades. Nevertheless, in our work we still occasionally observe situations where RPLC methods are not as robust as we would like them to be in practice due to variations in stationary phase chemistry between manufactured batches (i.e., lot-to-lot variability), and changes in stationary phase chemistry over time. Over the last three decades several models of RPLC selectivity have been developed and used to quantify and rationalize the effects of numerous parameters (e.g., effect of bonded phase density) on separation selectivity. The Hydrophobic Subtraction Model (HSM) of RPLC selectivity has been used extensively for these purposes; currently the publicly available database of column parameters contains data for 750 columns. In this work we explored the possibility that the HSM could be used to better understand the chemical basis of observed differences in stationary phase selectivity when they occur - for example, lot-to-lot variations or changes in selectivity during column use. We focused our attention on differences and changes in the observed selectivity for a pair of cis-trans isomers of a pharmaceutical intermediate. Although this is admittedly a challenging case, we find that the observed changes in selectivity are not strongly correlated with HSM column parameters, suggesting that there is a gap in the information provided by the HSM with respect to cis-trans isomer selectivity specifically. Further work with additional probe molecules showed that larger changes in cis-trans isomer selectivity were observed for pairs of molecules with greater molecular complexity, compared to the selectivity changes observed for simpler molecules. These results do not provide definitive answers to questions about the chemical basis of changes in stationary phase chemistry that lead to observed differences in cis-trans isomer selectivity. However, the results do provide important insights about the critical importance of molecular complexity when choosing probe compounds and indicate opportunities to develop improved selectivity models with increased sensitivity for cis-trans isomer selectivity.

A target-based discovery from a parasitic helminth as a novel therapeutic approach for autoimmune diseases.

BACKGROUND: Regulatory T cells (Tregs) can alleviate the development of autoimmune and inflammatory diseases, thereby proposing their role as a new therapeutic strategy. Parasitic helminths have co-evolved with hosts to generate immunological privilege and immune tolerance through inducing Tregs. Thus, constructing a "Tregs-induction"-based discovery pipeline from parasitic helminth is a promising strategy to control autoimmune and inflammatory diseases. METHODS: The gel filtration chromatography and reverse-phase high-performance liquid chromatography (RP-HPLC) were used to isolate immunomodulatory components from the egg extracts of Schistosoma japonicum. The extracted peptides were evaluated for their effects on Tregs suppressive functions using flow cytometry, ELISA and T cell suppression assay. Finally, we carried out colitis and psoriasis models to evaluate the function of Tregs induced by helminth-derived peptide in vivo. FINDINGS: Here, based on target-driven discovery strategy, we successfully identified a small 3 kDa peptide (SjDX5-53) from egg extracts of schistosome, which promoted both human and murine Tregs production. SjDX5-53 presented immunosuppressive function by arresting dendritic cells (DCs) at an immature state and augmenting the proportion and suppressive capacity of Tregs. In mouse models, SjDX5-53 protected mice against autoimmune-related colitis and psoriasis through inducing Tregs and inhibiting inflammatory T-helper (Th) 1 and Th17 responses. INTERPRETATION: SjDX5-53 exhibited the promising therapeutic effects in alleviating the phenotype of immune-related colitis and psoriasis. This study displayed a screening and validation pipeline of the inducer of Tregs from helminth eggs, highlighting the discovery of new biologics inspired by co-evolution of hosts and their parasites. FUNDING: This study was supported by the Natural Science Foundation of China (82272368) and Natural Science Foundation of Jiangsu Province (BK20211586).

Clinical implications and molecular features of tertiary lymphoid structures in stage I lung adenocarcinoma.

AIMS: We investigated the clinical implications and molecular features of TLS in stage I lung adenocarcinoma (LUAD). METHODS: We retrospectively reviewed the clinicopathological characteristics of 540 patients with p-stage I LUAD. Logistic regression analysis was applied to determining the relationships between clinicopathological features and the presence of TLS. TLS-associated immune infiltration pattern and signature genes were characterized using the transcriptomic profiles of 511 LUADs from The Cancer Genome Atlas (TCGA) database. RESULTS: The presence of TLS was associated with a higher pT stage, low- and middle-grade patterns, and the absence of tumor spreading through air spaces (STAS) and subsolid nodules. Multivariate Cox regression analysis identified that the presence of TLS was associated with favorable overall survival (OS) (p < 0.001) and recurrence-free survival (RFS) (p < 0.001). Subgroup analysis showed that the most favorable OS (p < 0.001) and RFS (p < 0.001) favored the TLS + PD-1- subgroup. The presence of TLS was characterized by abundance in antitumor immunocytes including activated CD8+ T and B cells as well as dentritic cells in TCGA cohort. CONCLUSION: The presence of TLS was an independent favorable factor for patients with stage I LUAD. The presence TLS was featured by special immune profiles which might aid oncologists in determining personalized adjuvant treatment.

Toward High Efficient Cu2 ZnSn(Sx ,Se1- x )4 Solar Cells: Break the Limitations of VOC and FF.

Increasing the fill factor (FF) and the open-circuit voltage (VOC ) simultaneously together with non-decreased short-circuit current density (JSC ) are a challenge for highly efficient Cu2 ZnSn(S,Se)4 (CZTSSe) solar cells. Aimed at such target in CZTSSe solar cells, a synergistic strategy to tailor the recombination in the bulk and at the heterojunction interface has been developed, consisting of atomic-layer deposited aluminum oxide (ALD-Al2 O3 ) and (NH4 )2 S treatment. With this strategy, deep-level CuZn defects are converted into shallower VCu defects and improved crystallinity, while the surface of the absorber is optimized by removing Zn- and Sn-related impurities and incorporating S. Consequently, the defects responsible for recombination in the bulk and at the heterojunction interface are effectively passivated, thereby prolonging the minority carrier lifetime and increasing the depletion region width, which promote carrier collection and reduce charge loss. As a consequence, the VOC deficit decreases from 0.607 to 0.547 V, and the average FF increases from 64.2% to 69.7%, especially, JSC does not decrease. Thus, the CZTSSe solar cell with the remarkable efficiency of 13.0% is fabricated. This study highlights the increased FF together with VOC simultaneously to promote the efficiency of CZTSSe solar cells, which could also be applied to other photoelectronic devices.

Spatially resolved multimode excitation for smooth supercontinuum generation in a SiN waveguide.

We propose a method of supercontinuum light generation enhanced by multimode excitation in a precisely dispersion-engineered deuterated SiN (SiN:D) waveguide. Although a regularly designed SiN-based nonlinear optical waveguide exhibits anomalous dispersion with the fundamental and first-order multimode operation, the center-symmetric light pumping at the input edge has so far inhibited the full potential of the nonlinearity of SiN-based materials. On the basis of numerical analysis and simulation for the SiN:D waveguide, we intentionally applied spatial position offsets to excite the fundamental and higher-order modes to realize bandwidth broadening with flatness. Using this method, we achieved an SNR improvement of up to 18 dB at a wavelength of 0.6 µm with an offset of about 1 µm in the Y-axis direction and found that the contribution was related to the presence of dispersive waves due to the excitation of TE10, and TE01 modes.

Endothelial function and arterial stiffness indexes in subjects with carotid plaque and carotid plaque length: A subgroup analysis showing the relationship with hypertension and diabetes.

BACKGROUND: Stroke is a leading cause of death and disability globally. A large proportion of ischemic strokes are caused by carotid atherosclerotic plaques. However, the relationship between vascular health status (arterial stiffness and endothelial dysfunction) and carotid plaque remains unclear. OUR STRATEGY: Here, we recruited 991 subjects with carotid plaques and 1170 subjects without carotid plaques to measure arterial stiffness and endothelial dysfunction, using a logistic regression model and multiple linear regression models to predict the relationship between them and carotid plaques. MAIN RESULTS: The data revealed that patients with carotid plaques presented a significantly higher mean of cf-PWV and lower mean RHI values. Age, male gender, diabetes, hypertension, and smoking contributed to plaque formation. Carotid plaques and their lengths were negatively associated with RHI values and positively associated with cf-PWV values; diabetes combined with hypertension showed a cumulative effect on arteriosclerosis. CONCLUSION: RHI combined with cf-PWV could improve the efficacy of predicting the presence of carotid plaques and their lengths.

Identification and Characterization of Antigenic Properties of Schistosoma japonicum Heat Shock Protein 90α Derived Peptides.

It is known that schistosome-derived antigens induce innate and adaptive immune responses that are essential for the formation of hepatic immunopathology. Here, we screened and synthesized four peptides derived from Schistosoma japonicum (S. japonicum) heat shock protein 90α (Sjp90α-1, -2, -3, and -4), which is widely expressed in adults and eggs of the genus S. japonicum and induces remarkable immune reactions. To define the antigenicity of these peptides, we stimulated splenocytes with peptides, and the results showed that only the Sjp90α-1 peptide could predominately induce the activation of dendritic cells (DCs) and macrophages as well as alter the proportion of follicular helper T (Tfh) cells. Next, CD4+ T cells were purified and cocultured with mouse bone-marrow-derived DCs (BMDCs) with or without Sjp90α-1 peptide stimulation in vitro, and the results showed that Sjp90α-1-stimulated BMDCs can significantly induce CD4+ T-cell differentiation into Tfh cells, while the direct stimulation of CD4+ T cells with Sjp90α-1 did not induce Tfh cells, indicating that the Sjp90α-1 peptide promotes Tfh cell differentiation depending on the presence of DCs. Furthermore, we selected and prepared an Sjp90α-1-peptide-based antibody and illustrated that it has excellent reactivity with the immunizing peptide and detects a single band of 29 kDa corresponding to the Sjp90α protein. The immunolocalization results showed that the protein recognized by this Sjp90α-1-peptide-based antibody is present in the mature eggs and the tegument of adults, implying that the parasite-derived peptide has a potential interaction with the host immune system. Finally, we evaluated antipeptide IgG antibodies and revealed a significantly higher level of anti-Sjp90α-1 peptide IgG antibodies in mice 3 weeks after S. japonicum infection. In conclusion, we illustrate that these synthetic peptides warrant further investigation by evaluating their antigen-specific immune response and their ability to efficiently induce Tfh cells. Moreover, they may constitute a potentially helpful method for the laboratory diagnosis of schistosomiasis japonica.

Persistent Hemodynamic Depression After Carotid Artery Stenting: A Review and Update.

According to the American Heart Association, ischemic stroke is the second leading cause of death globally and is responsible for approximately 11% of deaths. Carotid endarterectomy (CEA) is the standard treatment for moderate or severe extracranial internal carotid artery (ICA) stenoses. With the development of materials and technology in neurointervention, the Centers for Medicare and Medicaid Services (CMS) have proposed that carotid artery stenting (CAS) can serve as an alternative treatment for CEA. As CAS is widely used worldwide, comorbidities, especially persistent hemodynamic depression (PHD) and stroke, have attracted public attention. In this review, we summarized the current advances in PHD after CAS. A better understanding of CAS-related PHD may inspire the design of potential prognostic and therapeutic tools.

Direct f-3f self-referencing using an integrated silicon-nitride waveguide.

We have achieved the simultaneous generation of a 2.6-octave-wide supercontinuum (SC) spectrum over 400-2500 nm and third-harmonic light solely by a dispersion-controlled silicon-nitride waveguide (SiNW). To increase the visible intensity of the SC light component, we fabricated low-loss 5-mm-long deuterated SiNWs with spot-size converters by low-temperature deposition. We succeeded in measuring the carrier-envelope-offset (CEO) signal with a 34-dB signal-to-noise ratio because this short deuterated SiNW provides a large temporal overlap between the f and 3f components. In addition, we have demonstrated this method of CEO locking at telecommunications wavelengths with f-3f self-referencing generated solely by the SiNW without the use of highly nonlinear fiber and an additional nonlinear crystal. Compared with the method of CEO locking with a highly nonlinear fiber and a standard f-2f self-referencing interferometer, this method is not only simple and compact but also stable.

Dual Antiplatelet Therapy Plus Argatroban Prevents Early Neurological Deterioration in Branch Atherosclerosis Disease.

[Figure: see text].

Helminth-induced CD9+ B-cell subset alleviates obesity-associated inflammation via IL-10 production.

It has been shown that helminth infection can protect against obesity and improve insulin sensitivity to a certain extent, based on epidemiological investigations and animal experiments. Meanwhile, helminths induce a network of regulatory immune cells, including regulatory B cells (Bregs). However, the molecule characteristics and function of these Bregs in improving whole-body metabolic homeostasis remains largely unclear. We established a mouse model with chronic Schistosoma japonicum infection, and compared the differences in B10 cells (CD19+CD5+CD1dhi) and B10- cells (CD19+CD5-CD1d-) from splenic B cells of infected mice using RNA-seq. A unique Breg population was identified. Furthermore, these Bregs were evaluated for their ability to produce inhibitory cytokines in vitro and suppress obesity when adoptively transferred into mice on a high-fat diet. We found that schistosome infection could expand Breg cell populations in mice. CD9 was demonstrated to be a key surface marker for most murine IL-10+ B cells in spleen. CD19+CD9+ B cells produced more IL-10 than conventional B10 cells. Adoptive transfer of CD9+ B cells had the capacity to alleviate obesity-associated inflammation via promoting Tregs, Th2 cells and decreasing Th1, Th17 cells in high-fat diet mice. In conclusion, schistosome infection can induce regulatory CD9+ B cell production, which plays a critical role in the regulation of metabolic disorders through IL-10 production.

Abnormal temperature-dependent photoluminescence characteristics of ReS2nanowalls.

Two samples with [001] orientated rhenium disulfide (ReS2) nanowalls (NWs) grown above and in front of precursor (NH4ReO4) by chemical vapor deposition were investigated. The temperature-dependent photoluminescence (PL) indicated that the PL peak exhibited linear blue-shift at a rate of ∼0.24 meV K-1with increasing the temperature from 10 to 300 K, while the linewidth monotonically increased due to the exciton-phonon interaction. This abnormal blue-shift of PL emission energy, which is explained by a competition between the band gap shrinkage and the energy level degeneracy with respect to the increase of temperature and lattice constant, enables ReS2NWs to possess great potential for development of thermal sensors. In addition, exciton localization effect in the ReS2NWs from abundant edges and weak interlayer interaction was also observed to be related to the height and density of ReS2NWs. These results not only enrich the understanding for exciton dynamics in ReS2NWs, but also help to exploit ReS2NWs for device applications.

Gold-Catalyzed One-Pot Synthesis of Polyfluoroalkylated Oxazoles from N-Propargylamides Under Visible-Light Irradiation.

A gold-catalyzed synthesis of polyfluoroalkylated oxazoles from N-propargylamides under visible-light irradiation has been developed. These reactions display excellent compatibility of radicals and gold catalysts under visible-light irradiation. Mechanistic experiments indicate that polyfluoroalkyl iodides play a dual role in enhanced compatibility of radicals and gold catalysts through assisted protodeauration of vinyl gold and reactivated the gold catalyst. In addition, PPh3 AuNTf2 not only activates N-propargylamide to generate vinyl gold intermediate, but also greatly promotes homolysis of polyfluoroalkyl iodides under blue light irradiation.