Effect of cytokines on advanced hepatocellular carcinoma prognosis receiving radiotherapy and tislelizumab plus anlotinib: a single-center phase II clinical trial.

The purpose of this study was to investigate the relationship between circulating cytokines and liver function and prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with radiotherapy combined with tislelizumab and anlotinib. The liver function indexes and pre-treatment levels of cytokines in 47 patients were measured by chemical method and flow cytometry. The median follow-up was 23.1 months. The objective response and the disease control rates were 46.8% and 68.1%, while overall survival (OS) and progression-free survival (PFS) were 12.6 and 11.4 months, respectively. Adverse events (2.1%) were grade 3-4. In addition to stage, intrahepatic metastasis and Child-Pugh score, pre-treatment interleukin-6 (IL-6) was the main cytokine affecting OS and PFS (p < 0.05). The OS (14.63 pg/mL as cutoff value) and PFS (9.85 pg/mL as cutoff value) of patients with low IL-6 levels exceeded those with high levels (21.0 and 6.9, 15.8 and 10.0 months, respectively). The risks of death and disease progression were reduced by 63.0% (HR = 0.37, 95% CI: 0.19-0.72) and 43.0% (HR = 0.57, 95% CI: 0.22-1.47), respectively. Pre-treatment IL-6 levels may be a simple and effective prognostic indicator for patients with advanced HCC treated with radiotherapy combined with immunotargeted therapy.

Xerostomia: An easily ignored symptom induced by induction chemotherapy in patients with nasopharyngeal carcinoma.

BACKGROUND: To investigate the prevalence and predictive factors of xerostomia during induction chemotherapy (IC) in patients with nasopharyngeal carcinoma (NPC). METHODS: We prospectively enrolled NPC patients who received IC between October 2020 and October 2021. The Visual Analogue Scale (VAS) and Xerostomia Inventory (XI) were used to evaluate the condition of xerostomia. The volume of the submandibular gland (SMG) was also calculated before and after IC. RESULTS: Fifty-two patients were enrolled in this study. Of these patients, 32.7% (n = 17) experienced xerostomia before IC. There were 32 (61.5%) patients suffered from xerostomia after IC, including 21 (40.4%) patients with newly diagnosed xerostomia after IC and 11 (21.1%) patients complained their xerostomia aggravated in those with xerostomia before IC. The median XI scores increased from 11 (standard deviation [SD], 2.930) to 18 (SD 3.995), 16 (SD 3.605), and 17 (SD 4.331) after the first, second, and third cycles of IC, respectively. The median score of VAS also increased from 0 to 4 during the following three cycles of IC. In those with IC-related xerostomia, the SMG volume after IC was significantly decreased compared with those without IC-related xerostomia (P = 0.001). The reduction of the SMG volume after IC was the independent risk factor for xerostomia (P = 0.002). CONCLUSION: Approximately two-thirds of NPC patients suffered from IC-related xerostomia and patients with a reduction of SMG volume after IC had a higher risk of xerostomia.

Triplet-triplet annihilation upconversion in LAPONITE®/PVP nanocomposites: absolute quantum yields of up to 23.8% in the solid state and application to anti-counterfeiting.

The low quantum efficiency in the solid phase and the highly efficient quenching by oxygen are two major weaknesses limiting the practical applications of triplet-triplet annihilation (TTA) upconversion (UC). Herein, we report an organic-inorganic hybrid nanocomposites fabricated by self-assembly of LAPONITE® clay and poly(N-vinyl-2-pyrrolidone) (PVP), which serves as excellent matrix for solid-state TTA-UC even in air. In the hybrid hydrogel doped by TTA-UC components, the anionic acceptors are arranged in an ordered manner at the nano-disk edge through electrostatic attraction, which avoids haphazard accumulation of the acceptors and allows for highly efficient inter-acceptor triplet energy migration. Moreover, the entangled PVP could not only protect the triplet excitons from oxygen quenching but even proactively eliminate oxygen by photoirradiation. Significantly, the dried gel prepared by completely removing water from the hydrogel gave absolute UC quantum efficiencies of up to 23.8% (out of a 50% maximum), which is the highest TTA-UC efficiency obtained in the solid state. The dried gels are readily made into powder by grinding with maintained UC emissions, making them convenient for application to information encryption and anti-counterfeiting security by virtue of the high UC quantum efficiency and insensitivity to oxygen.

Synthesis of cyclodextrin derivatives for enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate.

Photochemical methods are increasingly being used in organic synthesis. They are especially useful for preparing many compounds that are not readily accessible through thermal or enzymatic reactions. The supramolecular strategy has proved highly promising in recent years for manipulating the stereochemical outcome of chiral photoreactions through relatively strong and long-lasting noncovalent interactions in both ground and excited states. Among the numerous chiral photochemical reactions, photocyclodimerization of 2-anthracenecarboxylate (AC) is the most comprehensively studied supramolecular chiral photoreaction and has essentially become a benchmark reaction for evaluating supramolecular photochirogenesis. Cyclodextrin (CD) derivatives were the earliest and are the most widely applied chiral host for mediating photoreactions. Herein, we use CD-mediated photocyclodimerization of AC as an example to introduce the operation process of supramolecular chiral photoreactions. The protocol includes the following contents: (i) the preparation, purification and characterization of ß-CD derivatives; (ii) methods for investigating the host-guest inclusion behavior between AC and ß-CD derivatives; (iii) the photochemical reaction operation flow under different solvent and temperature conditions; (iv) chiral high-performance liquid chromatography (HPLC) analyses of the product distribution and enantioselectivity. The protocol is introduced by using representative examples of the synthesis of ß-CD derivatives and the manipulation of environmental factors that give excellent regio- and enantioselectivities in the photocyclodimerization of AC. The synthesis and purification of ß-CD derivatives require 3-5 d of work. The photoirradiation of AC with ß-CD derivatives can be done within 1 h. The product analysis requires 5 h.

Causes of Death in Long-Term Nasopharyngeal Carcinoma Survivors.

Purpose: To assess the causes of death (COD) and long-term survival after nasopharyngeal carcinoma (NPC) diagnosis. Methods: Using linked data from the Surveillance, Epidemiology, and End Results program, patients with NPC diagnosed from 1990 to 2010 and followed up >5 years were identified. Chi-squared test, the Kaplan-Meier method, and the Cox proportional hazard model were used for analyses. Results: Among the 3,036 long-term NPC survivors, 1,432 survived for >5-10 years and 1,604 survived for >10 years. The most common COD was primary NPC (36.9%), followed by other causes (28.7%), other cancers (15.3%), cardiac disease (12.9%), and non-malignant pulmonary disease (6.2%). With a median follow-up of 125 months, deaths from NPC decreased with increasing time from diagnosis, while death because of cardiac disease and other causes increased. In those aged <50 years, death due to NPC remained the main COD over time, while cardiopulmonary disease-related death was the leading COD in patients aged ≥50 years. In White patients, death due to NPC decreased, and death due to cardiac disease increased over time. Death from NPC remained significant in Black and Asian patients even 15 years after the diagnosis of NPC, while death due to cardiac disease significantly increased after 9 years of diagnosis in Black patients. Multivariate analyses showed that the independent factors associated with inferior NPC-specific survival were older age, Asians, American Indian/Alaska Native, regional stage, distant stage, and diagnosis in the early years. Conclusions: The probability of death from primary NPC remains significant even 15 years after the NPC diagnosis. Our study advocates continued surveillance for NPC survivors beyond the traditional 5 years. Individualized follow-up strategies are required for patients with NPC of different ages and races.

Catalytic Chiral Photochemistry Sensitized by Chiral Hosts-Grafted Upconverted Nanoparticles.

Singlet chiral photocatalysis is highly challenging. Herein, we report fluorescence resonance energy transfer (FRET)-based chiral photocatalysis with γ-cyclodextrin (CD)-grafted lanthanide-doped upconverted nanoparticles (UCNP). The CD-modified UCNP strongly emits in the UV wavelength region upon excitation with a 980 nm laser, which selectively sensitizes the photosubstrates complexed by CD on the surface of UCNP through FRET. Therefore, enantiodifferentiating photocyclodimerization of anthracene or naphthalene derivatives sensitized by the CD-modified UCNP gives photoproducts in good enantioselectivity even in the presence of a catalytic amount of CD-modified UCNP. Moreover, the photocatalysts are readily separated and could be reused for at least six cycles without decreasing the enantioselectivity.

Association of thyroid hormones and thyroid-stimulating hormone with mortality in adults admitted to the intensive care unit: A systematic review and meta-analysis.

BACKGROUND: Thyroid hormones (THs) and thyroid-stimulating hormone (TSH) seem to show high potential in predicting the clinical death outcome of patients admitted to the intensive care unit (ICU). However, diverse studies on this topic are conflicting. METHODS: A search was conducted by two investigators involved in this research in the PubMed, Embase, and Cochrane databases (all last launched on July 12, 2021). The quality of the included studies was evaluated using the Newcastle-Ottawa Quality Assessment Scale (NOS). Subgroup analyses were performed to determine the sources of heterogeneity. Sensitivity and publication bias analyses were also assessed. RESULTS: A total of 27 studies (4970 participants) were included based on the eligibility criteria. Compared with survivors, nonsurvivors were found to have lower levels of THs (T3, T4, fT3, and fT4), whereas no significant difference was found in TSH levels (13 studies for T3: standardized mean differences [SMD], -0.78; 95% CI, -1.36 to -0.20; I2 = 96%; p = 0.008; 11 studies for T4: SMD = -0.79; 95% CI, -1.31 to -0.28; I2 =95%; p = 0.0002; 14 studies for fT3: SMD = -0.76; 95% CI, -1.21 to -0.32; I2 = 95%; p = 0.0008; 17 studies for fT4: SMD = -0.60; 95% CI, -0.99 to -0.22; I2 = 95%; p = 0.002; 20 studies for TSH: SMD = 0.00; 93% CI, -0.29 to 0.29; I2 = 93%; p = 0.98). CONCLUSION: Nonsurvivors were associated with lower levels of THs (T3, T4, fT3, and fT4) than survivors. THs show great application potential in predicting ICU patients' death outcomes and improving already widely used prognostic scores in the ICU (ie, Acute Physiological and Chronic Health Evaluation [APACHE] II and Therapeutic Intervention Scoring System).

Supramolecular Enantiodifferentiating Photocyclodimerization of 2-Anthracenecarboxylic Acid Mediated by Bridged ß-Cyclodextrins: Critical Effects of the Host Structure, pH and Co-Solvents.

Several sulfoxide- and sulfone-bridged ß-cyclodextrin (CD) dimers were synthesized for mediating the enantiodifferentiating [4+4] photocyclodimerization of 2-anthracenecarboxylic acid (AC). The complexation behavior of these chiral hosts with AC was investigated by UV-vis, circular dichroism, fluorescence, and NMR spectroscopies and certified the formation of 1 : 1 and 1 : 2 host-guest complexes. The product distribution and enantioselectivity of the photoreaction turned out to be a critical function of the chemical structure of bridged CDs. Comparing to the sulfur-bridged 2AX -3GX ß-CD dimer 7, the conversion of the photolyzes with sulfoxide-bridged was significantly improved, and the ee of cyclodimer 2 was remarkably increased from -82.8% with 7 to -96.7% with the sulfoxide-bridged 2AX -3GX ß-CD dimer 8. The relative yields and ee values of the slipped cyclodimers 5 and 6 were greatly enhanced in the presence of 6 M CsCl. The reaction selectivity is susceptible to the pH variation of the aqueous buffer solution, demonstrating that the supramolecular photochirogenesis is controlled by multidimensional factors, including the chemical structure of the chiral host, solvent, and pH conditions.

pH-Controlled Chirality Inversion in Enantiodifferentiating Photocyclodimerization of 2-Antharacenecarboxylic Acid Mediated by γ-Cyclodextrin Derivatives.

Several γ-cyclodextrin (γ-CDx) derivatives were used as chiral hosts for the photocyclodimerization of 2-anthracenecarboxylic acid (AC). The effect of pH on photoreactivity and stereochemical outcome of photoproducts was investigated. Upon changing the solution pH, the stereochemical outcome of HH cyclodimer 3 was inverted from 25.2% to -64.4% and 41.2% to -76.2%, respectively, in the photocyclodimerization of AC mediated by bis-quinoline-modified γ-CDx 7 and its N-methylated derivative 8.

Synergetic effects in the enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylic acid mediated by ß-cyclodextrin-pillar[5]arene-hybridized hosts.

Tri-cavity hosts consisting of one pillar[5]arene (P5) sandwiched by two ß-cyclodextrins (CDs) were synthesized, and their diastereoseparation was successfully accomplished. Photocyclodimerization of 2-anthracenecarboxylate with these hybrid hosts demonstrated the critical dependence of stereoselectivity on the absolute configuration of the central P5 and the conjugating positions on the ß-CD, and gave the non-classical HT photodimers in up to 87% ee.

Author Correction: piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Three-Dimensional Nanoscale Flexible Memristor Networks with Ultralow Power for Information Transmission and Processing Application.

To construct an artificial intelligence system with high efficient information integration and computing capability like the human brain, it is necessary to realize the biological neurotransmission and information processing in artificial neural network (ANN), rather than a single electronic synapse as most reports. Because the power consumption of single synaptic event is ∼10 fJ in biology, designing an intelligent memristors-based 3D ANN with energy consumption lower than femtojoule-level (e.g., attojoule-level) and faster operating speed than millisecond-level makes it possible for constructing a higher energy efficient and higher speed computing system than the human brain. In this paper, a flexible 3D crossbar memristor array is presented, exhibiting the multilevel information transmission functionality with the power consumption of 4.28 aJ and the response speed of 50 ns per synaptic event. This work is a significant step toward the development of an ultrahigh efficient and ultrahigh-speed wearable 3D neuromorphic computing system.

piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis.

Piwi proteins are normally restricted in germ cells to suppress transposons through associations with Piwi-interacting RNAs (piRNAs), but they are also frequently activated in many types of human cancers. A great puzzle is the lack of significant induction of corresponding piRNAs in cancer cells, as we document here in human pancreatic ductal adenocarcinomas (PDACs), which implies that such germline-specific proteins are somehow hijacked to promote tumorigenesis through a different mode of action. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. This is in contrast to piRNA-dependent PIWIL1 ubiquitination and removal by APC/C during late spermiogenesis. These findings unveil a piRNA-dependent mechanism to switch PIWIL1 from a substrate in spermatids to a co-activator of APC/C in human cancer cells.

A Quinoline-Appended Cyclodextrin Derivative as a Highly Selective Receptor and Colorimetric Probe for Nucleotides.

The design and development of specific recognition and sensing systems for biologically important anionic species has received growing attention in recent years, as they play significant roles in biology, pharmacy, and environmental sciences. Herein, a new supramolecular sensing probe L1 was developed for highly selective differentiation of nucleotides. L1 displayed extremely marked absorption and emission differentiation upon binding with nucleotide homologs of AMP, ADP, and ATP, due to the divergent spatial orientations of guests upon binding, which allowed for a naked-eye colorimetric differentiation for nucleotides. A differentiating mechanism was unambiguously rationalized by using various spectroscopic studies and theoretical calculations. Furthermore, we successfully demonstrated that L1 can be applied to the real-time monitoring of the enzyme-catalyzed phosphorylation/dephosphorylation processes and thus demonstrated an unprecedented visualizable strategy for selectively differentiating the structurally similar nucleotides and real-time monitoring of biological processes via fluorescent and colorimetric changes.

DYRK1A inhibition suppresses STAT3/EGFR/Met signalling and sensitizes EGFR wild-type NSCLC cells to AZD9291.

DYRK1A is considered a potential cancer therapeutic target, but the role of DYRK1A in NSCLC oncogenesis and treatment requires further investigation. In our study, high DYRK1A expression was observed in tumour samples from patients with lung cancer compared with normal lung tissues, and the high levels of DYRK1A were related to a reduced survival time in patients with lung cancer. Meanwhile, the DYRK1A inhibitor harmine could suppress the proliferation of NSCLC cells compared to that of the control. As DYRK1A suppression might be effective in treating NSCLC, we next explored the possible specific molecular mechanisms that were involved. We showed that DYRK1A suppression by siRNA could suppress the levels of EGFR and Met in NSCLC cells. Furthermore, DYRK1A siRNA could inhibit the expression and nuclear translocation of STAT3. Meanwhile, harmine could also regulate the STAT3/EGFR/Met signalling pathway in human NSCLC cells. AZD9291 is effective to treat NSCLC patients with EGFR-sensitivity mutation and T790 M resistance mutation, but the clinical efficacy in patients with wild-type EGFR remains modest. We showed that DYRK1A repression could enhance the anti-cancer effect of AZD9291 by inducing apoptosis and suppressing cell proliferation in EGFR wild-type NSCLC cells. In addition, harmine could enhance the anti-NSCLC activity of AZD9291 by modulating STAT3 pathway. Finally, harmine could enhance the anti-cancer activity of AZD9291 in primary NSCLC cells. Collectively, targeting DYRK1A might be an attractive target for AZD9291 sensitization in EGFR wild-type NSCLC patients.

Efficient Triplet-Triplet Annihilation Upconversion with an Anti-Stokes Shift of 1.08 eV Achieved by Chemically Tuning Sensitizers.

A series of Pt(II)-Schiff base complexes were synthesized as triplet sensitizers for the purpose of tuning the singlet and triplet energy levels so as to minimize energy loss during triplet-triplet annihilation (TTA) upconversion (UC). A deep-red to blue TTA-UC was achieved with an unprecedentedly large anti-Stokes shift of 1.08 eV. UC quantum yields of up to 21% (with a theoretical maximum efficiency of 50%) were observed in solution. The complexes also showed efficient UC emission in air-saturated hydrogels with a UC quantum yield up to 14.8%, which is much higher than the highest previously reported value. The low threshold excitation intensity provided by the present system offers promising potential for application in terrestrial solar energy conversion.

A cell line resistant to avian leukosis virus subgroup B infection.

The expression of env proteins that bind to viral cell receptors on avian leukosis virus (ALV)-susceptible cells can block ALV infection. In this study, we constructed a cell line (DF-1/B) by expressing the ALV-B env protein in DF-1 cells. PCR, immune fluorescence assay, Western blot, and immune electron microscopy results showed that the env gene can be stably expressed in DF-1cells and the env protein could be detected on the DF-1 cell membrane. An antiviral experiment concluded that the DF-1/B cell line could be resistant to 1 × 104 TCID50 ALV-B virus infection, but had no inhibitory effect on other subgroup ALV. This means that the DF-1/B cell line is specifically resistant to ALV-B and can be used as a tool for ALV-B diagnosis.

BAY 87-2243 sensitizes hepatocellular carcinoma Hep3B cells to histone deacetylase inhibitors treatment via GSK-3ß activation.

Hepatocellular carcinoma (HCC) is associated with some of the highest cancer-associated mortality rates. Histone deacetylase (HDAC) inhibitors anti-HCC activities have been shown to promote Snail-induced metastasis. In the present study, it was shown that BAY 87-2243, a hypoxia-inducible transcription factor-1α inhibitor, could enhance the anti-HCC effects of HDAC inhibitors, including trichostatin A and vorinostat. In addition, BAY 87-2243 plus HDAC inhibitors exhibited synergistic cytotoxicity and induced significant cell death in Hep3B cells. Additionally, BAY 87-2243 combined with HDAC inhibitors-treated Hep3B cells formed fewer and smaller colonies as compared with either the control or single agent-treated cells. Furthermore, glycogen synthase kinase-3ß might be involved in the enhanced cell death induced by BAY 87-2243 plus HDAC inhibitors. The present data also indicated that BAY 87-2243 combined with HDAC inhibitors could suppress the migration of Hep3B cells, and BAY 87-2243 could reverse the HDAC inhibitor-induced Snail activation in Hep3B cells. In conclusion, BAY 87-2243 combined with HDAC inhibitors might be an attractive chemotherapy strategy for HCC therapy.

An Ultimate Stereocontrol in Supramolecular Photochirogenesis: Photocyclodimerization of 2-Anthracenecarboxylate Mediated by Sulfur-Linked ß-Cyclodextrin Dimers.

Stereoisomeric ß-cyclodextrin (CD) dimers linked with a sulfur atom or an arene spacer were designed to create a tethered dual CD capsule for precisely manipulating the regio- and enantioselectivities of the photocyclodimerization of 2-anthracenecarboxylate (AC) to four stereoisomeric classical 9,10:9',10'-cyclodimers and two nonclassical 5,8:9',10'-cyclodimers. Among the dimeric CD hosts prepared, exo-3-thia-ß-CD dimer formed 1:1 and 1:2 host-guest complexes with AC in aqueous solutions, the former of which hindered but the latter facilitated the AC photocyclodimerization with regio- and enantioselectivities much higher than those obtained with native ß-CD or the rest of the ß-CD dimers. The stereochemical outcomes turned out to be highly sensitive to and hence critically manipulable by the linking position and configuration of the connected saccharide units and the linker length, as well as the external variants, such as temperature, pH, and added salt. Eventually, the photocyclodimerization of AC mediated by the dimeric ß-CD host gave enantiopure syn-head-to-tail-9,10:9',10'-cyclodimer in 97-98% yield in a pH 5.1 buffer solution at 0.5 °C and also in an aqueous CsCl solution at -20 °C.

Effects of Temperature and Host Concentration on the Supramolecular Enantiodifferentiating [4 + 4] Photodimerization of 2-Anthracenecarboxylate through Triplet-Triplet Annihilation Catalyzed by Pt-Modified Cyclodextrins.

Visible-light-driven photocatalytic supramolecular enantiodifferentiating dimerization of 2-anthracenecarboxylic acid (AC) through triplet-triplet annihilation (TTA), mediated by the Schiff base Pt(II) complex (Pt-1, Pt-2, and Pt-3) was studied. The host concentration and the temperature effects on the stereoselectivity were comprehensively investigated. Increasing the concentration of sensitizers/hosts significantly enhanced the conversion of the photoreaction but led to reduced enantioselectivities of the chiral photodimers 2 and 3 when the photoreaction was triggered by a 532 nm laser, which was in contrast with the results obtained by direct irradiation of AC with a 365 nm light-emitting diode (LED) lamp, due to the aggregation of the sensitizer/host in water. The cyclization of AC through triplet-triplet annihilation displayed significant temperature dependency when Pt-3 was employed as the sensitizer/host. Increasing the temperature from 0 °C to 30 °C with 5% equiv. of Pt-3 led to a great increase of the ee of 2 from 2.1% to 31.6%. However, hardly any temperature dependency was observed when the photodimerization was mediated by other sensitizers and/or hosts, or the photoreaction was triggered directly with a 365 nm LED lamp.