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.

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.

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.

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

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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.

Localized state effect and exciton dynamics for monolayer WS2.

The two-dimensional transition metal dichalcogenides (TMDCs) have been considered as promising candidates for developing a new generation of optoelectronic devices. Accordingly, investigations of exciton dynamics are of great importance for understanding the physics and the performance of devices based on TMDCs. Herein, after exposure to ambient environment for six months, monolayer tungsten disulfide (WS2) shows formation of localized states. Photoluminescence (PL) and time-resolved PL (TRPL) spectra demonstrate that these localized states have significant impacts on the exciton dynamics, including energy states filling, thermal activation and redistribution, and the decay behavior of excitons. These observations not only enrich the understanding for localized states and correlated exciton dynamics of aged monolayer WS2, but also reveal a possible approach to modulate the optical properties of TMDCs via the aging process.

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.

Integration of transcriptome and cistrome analysis identifies RUNX1-target genes involved in pancreatic cancer proliferation.

The extremely high proliferation rate of tumor cells contributes to pancreatic cancer (PC) progression. Runt-related transcription factor 1(RUNX1), a key factor in hematopoiesis that was correlated with tumor progression. However, the role of RUNX1 in PC proliferation was still unclear. We found that RUNX1 was significantly upregulated in PC tissues and its expression was negatively associated with prognosis of PC patients in a multicenter analysis according to immunohistochemical (IHC). RUNX1 downregulation in PC resulted in a significantly reduced cell proliferation rate, which was consistent with in vivo subcutaneous tumor formation assay results. RNA-seq and ChIP-seq results revealed that a portion of target genes, including HAP1, GPRC5B, PTPN21, VHL and EN2, were regulated by RUNX1, a finding successfully validated by ChIP-qPCR, qRT-PCR and Western blot. Subsequently, IHC and proliferation assays showed these target genes to be dysregulated in PC, affecting tumor growth. Our data suggest that RUNX1 plays an oncogenic role in tumor proliferation and is a potential prognostic biomarker and therapeutic target for PC.

Epitaxial single-crystal rare-earth oxide in horizontal slot waveguide for silicon-based integrated active photonic devices.

We have epitaxially grown high-quality single-crystal rare-earth oxide thin films, including Gd2O3 and erbium-incorporated (ErGd)2O3, on silicon-on-insulator substrate, and investigated their optical properties when embedded in horizontal slot waveguides. (ErGd)2O3 with an erbium concentration in the mid-1021 cm-3 range shows well-resolved Stark-split photoluminescence emission peaks in the telecommunications band and a photoluminescence lifetime-concentration product as large as 2.67×1018 s·cm-3 at room-temperature. Using these materials, horizontal slot waveguides with strong optical confinement in low-refractive-index rare-earth oxide layers, have been fabricated for silicon-based integrated active photonic devices. Thanks to the strong light-matter interaction, a large waveguide modal absorption of 88 dB/cm related to erbium ions is achieved, leading to a large potential optical gain. Intense emissions from the waveguides are also observed, with a radiation efficiency on the order of 10-4. These results indicate that a combination of epitaxial rare-earth oxide thin films and horizontal slot waveguides provides a promising platform for light amplification and generation on silicon.

Long-term survival of an elderly patient with advanced gastric cancer after combination therapy: a case report and literature review.

BACKGROUND: Gastric cancer ranks the fifth most common cancer, and the third leading cause of cancer-related deaths worldwide. Gastric cancer with liver metastasis (GCLM) has devastating prognosis, however, optimal treatment of GCLM, especially in elderly patients, has yet to be clarified. CASE PRESENTATION: A 75-year-old man was diagnosed with advanced gastric cancer (GC), presenting with acute gastrointestinal bleeding and synchronous metastatic lesion in liver. Based on multidisciplinary team (MDT)'s decision, this patient underwent distal palliative gastrectomy with R1 margin. Histopathological diagnosis was stage IV gastric adenocarcinoma (pT3N2M1), HER2 negative. The patient was treated with chemotherapy and argon-helium cryoablation of liver and lung metastases.HER-2 gene amplification was identified in peripheral blood at later stage of therapy. The patient had been followed-up for 39 months, in sharp contrast to a median survival time of 13.8 months for majority of advanced GC. CONCLUSIONS: Palliative distal gastrectomy in combination with chemotherapy and cryoablation significantly prolongs overall survival of an elderly patient with GCLM.

7ß-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues.

With the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7ß-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7ß-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7ß-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7ß-methyl orvinol analogues. Surprisingly, SLL-603, a 7ß-methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7ß-methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations.

Highly n-doped germanium-on-insulator microdisks with circular Bragg gratings.

We demonstrate germanium (Ge) microdisks surrounded by highly reflective circular Bragg gratings on highly n-doped germanium-on-insulator (GOI) substrate. The GOI substrate is fabricated by wafer bonding from Ge grown on Si substrate, and n-type doping concentration of 2.1×1019 cm-3 is achieved by phosphorus diffusion from a spin-on-dopant source. Very sharp Fabry-Perot resonant peaks with high contrast fringes and Q-factors up to 400 are observed near the direct band gap of Ge in photoluminescence spectra. The reflectivity of gratings are enhanced by a factor larger than 3 in a wide wavelength range from 1.57 to 1.82 µm, compared with that of Ge/SiO2 interfaces in normal microdisks without circular Bragg gratings. The surface emission intensity of the devices is found to be increased by the grating period. Our results indicate that GOI microdisk with circular Bragg grating is a promising optical resonator structure suitable for realizing low threshold, compact Ge lasers integrated on Si substrate.

Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective κ opioid receptor agonists.

A novel series of 1-(pyrrolidin-1-ylmethyl)-2-[(3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinoline derivatives maj-3a-maj-3u were synthesized and evaluated in vitro for their binding affinity at κ-opioid receptors. Maj-3c displayed the highest affinity for κ-opioid receptors (Ki = 0.033 nM) among all the compounds evaluated. Furthermore, all four stereoisomers of compound 3c were prepared, and (1S,18S)-3c was identified as the most potent (Ki = 0.0059 nM) κ-opioid receptor agonist among the four stereoisomers. Maj-3c produced significant antinociception (ED50 = 0.000406 mg kg(-1)) compared to U-50,488H and original BRL 52580 in the acetic acid writhing assay, but its strong sedative effect (ED50 = 0.000568 mg kg(-1)) observed in the mouse rotation test reduced its druggability. To minimize the central nervous system side effects, a series of hydroxyl-containing analogs of maj-3c were synthesized, and maj-11a was found to be a potent κ-opioid receptor agonist (Ki = 35.13 nM). More importantly, the dose for the sedative effect (ED50 = 9.29 mg kg(-1)) of maj-11a was significantly higher than its analgesic dose (ED50 = 0.392 mg kg(-1)), which made it a promising peripheral analgesic candidate compound with weak sedative side effects.

Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel µ opioid receptor ligands.

AIM: Tramadol is an atypical opioid analgesic with low potential for tolerance and addiction. However, its opioid activity is much lower than classic opiates such as morphine. To develop novel analgesic and further explore the structure activity relationship (SAR) of tramadol skeleton. METHODS: Based on a three-dimensional (3D) structure superimposition and molecular docking study, we found that M1 (the active metabolite of tramadol) and morphine have common pharmacophore features and similar binding modes at the µ opioid receptor in which the substituents on the nitrogen atom of both compounds faced a common hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. In this study, N-phenethylnormorphine was docked to the µ opioid receptor. It was found that the N-substituted group of N-phenethylnormorphine extended into a hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. This hydrophobic interaction may contribute to the improvement of its opioid activities as compared with morphine. The binding modes of M1, morphine and N-phenethylnormorphine overlapped, indicating that the substituent on the nitrogen atoms of the three compounds may adopt common orientations. A series of N-phenylalkyl derivatives from the tramadol scaffold were designed, synthesized and assayed in order to generate a new type of analgesics. RESULTS: As a result, compound 5b was identified to be an active candidate from these compounds. Furthermore, the binding modes of 5b and morphine derivatives in the µ opioid receptor were comparatively studied. CONCLUSION: Unlike morphine-derived structures in which bulky N-substitution is associated with improved opioid-like activities, there seems to be a different story for tramadol, suggesting the potential difference of SAR between these compounds. A new type of interaction mechanism in tramadol analogue (5b) was discovered, which will help advance potent tramadol-based analgesic design.

Novel κ-opioid receptor agonist MB-1C-OH produces potent analgesia with less depression and sedation.

AIM: To characterize the pharmacological profiles of a novel κ-opioid receptor agonist MB-1C-OH. METHODS: [(3)H]diprenorphine binding and [(35)S]GTPγS binding assays were performed to determine the agonistic properties of MB-1C-OH. Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions. RESULTS: In [(3)H]diprenorphine binding assay, MB-1C-OH did not bind to µ- and δ-opioid receptors at the concentration of 100 µmol/L, but showed a high affinity for κ-opioid receptor (Ki=35 nmol/L). In [(35)S]GTPγS binding assay, the compound had an Emax of 98% and an EC50 of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-1C-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test (ED50=0.39 mg/kg), which was antagonized by pretreatment with a selective κ-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-1C-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase (ED50=0.87 mg/kg). In addition, the sedation or depression actions of MB-1C-OH were about 3-fold weaker than those of the classical κ agonist (-)U50,488H. CONCLUSION: MB-1C-OH is a novel κ-opioid receptor agonist that produces potent antinociception causing less sedation and depression.

Spectroscopic Study on the Interaction between Naphthalimide-Polyamine Conjugates and Bovine Serum Albumin (BSA).

The effect of a naphthalimide pharmacophore coupled with diverse substituents on the interaction between naphthalimide-polyamine conjugates 1-4 and bovine serum albumin (BSA) was studied by UV absorption, fluorescence and circular dichroism (CD) spectroscopy under physiological conditions (pH = 7.4). The observed spectral quenching of BSA by the compounds indicated that they could bind to BSA. Furthermore, caloric fluorescent tests revealed that the quenching mechanisms of compounds 1-3 were basically static type, but that of compound 4 was closer to a classical type. The Ksv values at room temperature for compound-BSA complexes-1-BSA, 2-BSA, 3-BSA and 4-BSA were 1.438 × 104, 3.190 × 104, 5.700 × 104 and 4.745 × 105, respectively, compared with the value of MINS, 2.863 × 104 at Ex = 280 nm. The obtained quenching constant, binding constant and thermodynamic parameter suggested that the binding between compounds 1-4 with BSA protein, significantly affected by the substituted groups on the naphthalene backbone, was formed by hydrogen bonds, and other principle forces mainly consisting of charged and hydrophobic interactions. Based on results from the analysis of synchronous three-dimensional fluorescence and CD spectra, we can conclude that the interaction between compounds 1-4 and BSA protein has little impact on the BSA conformation. Calculated results obtained from in silico molecular simulation showed that compound 1 did not prefer either enzymatic drug sites I or II over the other. However, DSII in BSA was more beneficial than DSI for the binding between compounds 2-4 and BSA protein. The binding between compounds 1-3 and BSA was hydrophobic in nature, compared with the electrostatic interaction between compound 4 and BSA.

Waveguide-integrated microdisk light-emitting diode and photodetector based on Ge quantum dots.

Microdisk integrated with a bus waveguide is fabricated on silicon-on-insulator substrate containing Ge self-assembled quantum dots as active medium. The device is demonstrated to be operated as both light-emitting diode and photodetector. At forward bias, carriers are injected into the microdisk and light emission at 1.45-1.6 µm is extracted through the waveguide via microdisk-waveguide coupling. Sharp resonant peaks with Q-factor as high as 1350 are obtained in the electroluminescence spectra, corresponding to whispering gallery modes of the microdisk. At reverse bias, the device functions as a resonant cavity enhanced photodetector with wavelength-selective photo-response. The photo-current at resonant wavelength of 1533.65 nm is 50 times larger than that at non-resonant wavelength. The dark current density of the photodetector is as low as 0.29 mA/cm2 up to -10 V bias and the peak responsivity is 5.645 mA/W.

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.