Endoplasmic reticulum protein of 57 kDa sulfhydration promotes intestinal calcium absorption to attenuate primary osteoporosis.

Endogenous hydrogen sulfide (H2S) plays an important role in bone metabolism. However, the exact role of H2S in intestinal calcium and phosphorus absorption and its potential in preventing and treating primary osteoporosis remains unknown. Therefore, this study aimed to investigate the potential of H2S in promoting intestinal calcium and phosphorus absorption and alleviating primary osteoporosis. We measured the apparent absorptivity of calcium, femoral bone density, expression and sulfhydration of the duodenal endoplasmic reticulum protein of 57 kDa (ERp57), duodenal cystathionine γ-lyase (CSE) expression, and serum H2S content in adult and old CSE-knockout and wild-type mice. We also assessed intracellular reactive oxygen species (ROS) and Ca2+ content in CSE-overexpressing or knockout intestinal epithelial cell (IEC)-6 cells. In senile mice, CSE knockout decreased endogenous H2S, ERp57 sulfhydration, and intestinal calcium absorption and worsened osteoporosis, which were partially reversed by GYY4137, an H2S donor. CSE overexpression in IEC-6 cells increased ERp57 sulfhydration, protein kinase A and C activity, and intracellular Ca2+, whereas CSE knockout exerted the opposite effects. Furthermore, hydrogen peroxide (H2O2) stimulation had similar effects as in CSE knockout, which were reversed by pretreatment with sodium hydrosulfide before H2O2 stimulation and restored by DL-dithiothreitol. These findings suggest that H2S attenuates primary osteoporosis by preventing ROS-induced ERp57 damage in intestinal epithelial cells by enhancing ERp57 activity and promoting intestinal calcium absorption, thereby aiding in developing therapeutic interventions to prevent osteoporosis.

A systematic review on reporting quality of economic evaluations for negotiated glucose-lowering drugs in China national reimbursement drug list.

BACKGROUND: This study aimed to examine the reporting quality of existing economic evaluations for negotiated glucose-lowering drugs (GLDs) included in China National Reimbursement Drug List (NRDL) using the Consolidated Health Economic Evaluation Reporting Standards 2013 (CHEERS 2013). METHODS: We performed a systematic literature research through 7 databases to identify published economic evaluations for GLDs included in the China NRDL up to March 2021. Reporting quality of identified studies was assessed by two independent reviewers based on the CHEERS checklist. The Kruskal-Wallis test and Mann-Whitney U test were performed to examine the association between reporting quality and characteristics of the identified studies. RESULTS: We have identified 24 studies, which evaluated six GLDs types. The average score rate of the included studies was 77.41% (SD:13.23%, Range 47.62%-91.67%). Among all the required reporting items, characterizing heterogeneity (score rate = 4.17%) was the least satisfied item. Among six parts of CHEERS, results part scored least at 0.55 (score rate = 54.79%) because of the incompleteness of characterizing uncertainty. Results from the Kruskal-Wallis test and Mann-Whitney U test showed that model choice, journal type, type of economic evaluations, and study perspective were associated with the reporting quality of the studies. CONCLUSIONS: There remains room to improve the reporting quality of economic evaluations for GLDs in NRDL. Checklists such as CHEERS should be widely used to improve the reporting quality of economic researches in China.

Fluorination Strategy Towards Symmetry Breaking of Boron-centered Tetrahedron for Poly-fluorinated Optical Crystals.

Borate crystals can be chemically and functionally modified by the fluorination strategy, which encourages the identification of emerging fluorooxoborates with a structure and set of characteristics not seen in any other oxide parents. However, the bulk of fluorooxoborates have been found accidentally, rational methods of synthesis are required, particularly for the infrequently occurring poly-fluorinated components. Herein, we reported the use of bifluoride salts as a potent source of fluorine to prepare fluorooxoborates that contain rarely tri-fluorinated [BF3 X] (X=O and CH3 ) tetrahedra and eleven compounds were found. We identified the optical properties of the organofluorinated group [CH3 BF3 ] and their potential for nonlinear optics for the first time. Among these, two non-centrosymmetric components hold potential for the production of 266 nm harmonic coherent light for nonlinear optics, and more crucially, have the benefit of growing large size single crystals. Our study establishes experimental conditions for the coexistence of the diverse functional groups, enabling the production of poly-fluorinated optical crystals.

Breaking the Inherent Interarrangement of [B3O6] Clusters for Nonlinear Optics with Orbital Hybridization Enhancement.

The [B3O6] group as a prime functional unit provides borates with intrinsic properties that are modified by coordination to cations. Inherent [B3O6] cluster structures in borates exclusively made of them have a near-plane configuration, with more than 90% of them having a maximum dihedral angle of zero and the remaining ones being less than 13°. Although such an inherent configuration can produce considerable birefringence for good phase-matching ability, this is not conducive to obtaining high conversion efficiency and beam quality due to the walk-off effects in the nonlinear optical process. In this article, two new borate halides Ca2B3O6X (X = Cl and Br) were reported, in which the confinement effects of distorted halogen-centered secondary building blocks compress the existence space of [B3O6] primitives, resulting in the nonparallel arrangement between [B3O6] clusters in this series. Both compounds show large second harmonic generation effects, and more importantly, the broken inherent interarrangement of [B3O6] clusters makes them a moderate birefringence and small walk-off angle. Their moderate birefringence is due to the large angular alignment between [B3O6] clusters, resulting from the orbital hybridization between the Ca s and the O p orbitals of the terminal O atoms on [B3O6] clusters. Our model supports this viewpoint and offers guidelines for rearranging [B3O6] clusters' arrangements in borates.

Finding a Deep-UV Borate BaZnB4 O8 with Edge-sharing [BO4 ] Tetrahedra and Strong Optical Anisotropy.

The polarization modulation of deep-UV light is an important process that incorporates functionality to selectively respond to light-mater interaction. Typically, optical anisotropy is foremost to the use efficiency of deep-UV birefringent crystals. Herein, a new congruently melting polyborate with extremely large birefringence (Δn(001) =0.14@589.3 nm) and band gap (6.89 eV) is discovered as a high performance birefringent crystal, which breaks the current deadlock of deep-UV polyborates that usually show small birefringence. The rigid tetrahedra, including [ZnO4 ] and edge-sharing [BO4 ] tetrahedra, make all the planar [BO3 ] triangles in the lattice adopt preferential arrangement and thereby lead to an extraordinary large birefringence that is larger than all the deep-UV borates with experimentally measured values. Structural analyses with the additional theoretical calculations were used to study the origin of strong optical anisotropy in BaZnB4 O8 .

Li2RbSO4Cl with a Short Ultraviolet Absorption Edge and an Acentric Structure through Assembling Heteroleptic [LiO3Cl] Tetrahedra.

Currently, short-wavelength nonlinear optical materials are urgently needed. Through substituting homoleptic [LiO4] in centrosymmetric LiRbSO4 with heteroleptic [LiO3Cl] tetrahedra, an acentric sulfate chloride, Li2RbSO4Cl, was designed and synthesized by the high-temperature melting method. Li2RbSO4Cl shows a relatively short ultraviolet absorption edge (<200 nm) among newly reported sulfate chlorides. Millimeter-sized crystals were grown due to the congruent melting behavior and high thermal stability of the compound.

Heterologous Isomorphic Substitution Induces Optical Property Enhancement for Deep-UV Crystals: a Case in Rb[B3O3F2(OH)2].

Optical anisotropy is pivotal for optical crystals, and it can be characterized by the maximum algebraic difference in refractive indices. Improving the optical anisotropy, especially for deep-ultraviolet (UV) crystals, is still a challenge and of interest. Herein, a new hydroxyfluorooxoborate, Rb[B3O3F2(OH)2], was obtained by the heterologous isomorphic substitution strategy. Dual enhancement for the band gap and birefringence compared with the parent A[B3O3F2(OH)2] (A = [Ph4P]/[Ph3MeP]) compounds was achieved in Rb[B3O3F2(OH)2]. This considerable enhancement originates from the removal of organic components and the retention of a birefringence-active anionic framework. This enhancement pushes the application region from UV to deep-UV. This discovery not only expands the structural chemistry of borates but also demonstrates the viability of heterologous isomorphic substitution to design deep-UV crystals with enhanced optical property.

Extracellular vesicle-mediated communication between hepatocytes and natural killer cells promotes hepatocellular tumorigenesis.

Hepatocellular carcinoma (HCC) is frequently characterized by metabolic and immune remodeling in the tumor microenvironment. We previously discovered that liver-specific deletion of fructose-1, 6-bisphosphatase 1 (FBP1), a gluconeogenic enzyme ubiquitously suppressed in HCC tissues, promotes liver tumorigenesis and induces metabolic and immune perturbations closely resembling human HCC. However, the underlying mechanisms remain incompletely understood. Here, we reported that FBP1-deficient livers exhibit diminished amounts of natural killer (NK) cells and accelerated tumorigenesis. Using the diethylnitrosamine-induced HCC mouse model, we analyzed potential changes in the immune cell populations purified from control and FBP1-depleted livers and found that NK cells were strongly suppressed. Mechanistically, FBP1 attenuation in hepatocytes derepresses an zeste homolog 2 (EZH2)-dependent transcriptional program to inhibit PKLR expression. This leads to reduced levels of PKLR cargo proteins sorted into hepatocyte-derived extracellular vesicles (EVs), dampened activity of EV-targeted NK cells, and accelerated liver tumorigenesis. Our study demonstrated that hepatic FBP1 depletion promotes HCC-associated immune remodeling, partly through the transfer of hepatocyte-secreted, PKLR-attenuated EVs to NK cells.

Improved Birefringence Activated by Tetrahedra Decorated with a Single Linear Unit.

Performance enhancement induced by structural modification has long been the target in materials science fields. Direct evidence to witness the effectivity of one strategy is challenging and necessary. In this work, a tetrahedra-decoration strategy was proposed to improve the birefringent performance sharply, namely decorating the tetrahedra with a single linear [S2 ] unit. The strategy was verified by comprehensive characterization of two thiogermanates K2 BaGeS4 and K2 BaGeS5 , which crystallize in the same space group, have similar unit cells and the same units arrangements. Theoretical characterization verified that the [GeS5 ] group has much larger polarization anisotropy than [GeS4 ], further demonstrated that the linear [S2 ] led to the sharp birefringence enlargement of K2 BaGeS5 (0.19 vs 0.03 of K2 BaGeS4 ). This work provides a new guiding thought to improve the birefringence performance.

Were economic evaluations well reported for the newly listed oncology drugs in China's national reimbursement drug list.

PURPOSE: To assess the reporting quality of published economic evaluations of the negotiated oncology drugs listed for China's 2020 National Reimbursement Drug List (NRDL). METHODS: A comprehensive search was conducted to identify economic evaluation studies of negotiated oncology drugs listed in China's 2020 NRDL using the PubMed/MEDLINE, Embase, Web of Science, CNKI, SinoMed, and WanFang Database up to March 31, 2021. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist scored the reporting quality between 0 and 100. A linear regression analysis was employed to examine the influence of various characteristics on the reporting quality scores. RESULTS: Eighty papers were included in the study, with the majority published during the past decade. Furthermore, more than half of the articles (57.5%, or 46 out of 80) were written in English. The average CHEERS score was 74.63 ± 12.75 and ranged from 43.48 to 93.75. The most inadequately reported items included choice of model, characterization of heterogeneity, and discussion, as well as currency, price date and conversion. Higher scores were associated with articles published from 2019 to 2021 and English publications. CONCLUSION: The economic evaluation studies of negotiated oncology drugs listed in 2020 NRDL had moderate reporting quality. The Chinese economic evaluation publications could improve the reporting quality if the CHEERS checklist is consistently implemented. Also, the Chinese journals maybe explore introducing a reporting standard for economic evaluations.

Na4 B8 O9 F10 : A Deep-Ultraviolet Transparent Nonlinear Optical Fluorooxoborate with Unexpected Short Phase-Matching Wavelength Induced by Optimized Chromatic Dispersion.

Exploring significant ultraviolet/deep-ultraviolet nonlinear optical (NLO) materials is hindered by rigorous and contradictory requirements, especially, possessing a moderate optical birefringence to meet phase-matching (PM). Except for suitable birefringence, small chromatic dispersion is also crucial to blue-shift the PM wavelength. Here, the introduction of a fluorinated tetrahedral boron-centred chromophore strategy was proposed to optimize the chromatic dispersion. Herein, the [BF4 ]- unit with a large HOMO-LUMO band gap was introduced to the Na-B-O-F system and Na4 B8 O9 F10 was designed and synthesized successfully for the first time. Na4 B8 O9 F10 with an optimized chromatic dispersion can achieve a short second harmonic generation PM wavelength of 240 nm with a relatively small birefringence (0.036@1064 nm). Notably, Na4 B8 O9 F10 is the first acentric crystal with [BF4 ]- units among the reported metal-fluorooxoborate systems, involving isolated [BF4 ]- and novel [B7 O10 F6 ]5- fundamental building blocks.

Strong Nonlinearity Induced by Coaxial Alignment of Polar Chain and Dense [BO3 ] Units in CaZn2 (BO3 )2.

Discovery of new efficient nonlinear optical (NLO) materials with large second-order nonlinearity for the short-wave ultraviolet spectral region (λPM ≤266 nm, PM=phase-matching) is still very challenging. Herein, a new beryllium-free borate CaZn2 (BO3 )2 with Sr2 Be2 B2 O7 (SBBO) double-layered like configuration was rationally designed, which not only preserves the structural merits but also eliminates the limitations of the SBBO crystal. CaZn2 (BO3 )2 shows a large PM second harmonic generation (SHG) reponse of 3.8×KDP, which is 38 times higher than that of its barium analogue. This enhancement mainly originates from the 1 [Zn2 O6 ]∞ polar chains with a large net dipole moment and [BO3 ] units with a high NLO active density. Our findings show the great significance of the [ZnO4 ] tetrahedra introduced strategy to design beryllium-free SBBO-type NLO crystals and also verify the feasibility of using simple non-isomorphic substitution to induce giant second-order nonlinearity enhancement.

Double-Modification Oriented Design of a Deep-UV Birefringent Crystal Functionalized by [B12 O16 F4 (OH)4 ] Clusters.

Polarization modulation of deep-UV light is of significance to current technologies, and to this end, the birefringent crystal has emerged as an invaluable material as it allows for effective light modulation. Herein, a double-modification strategy driven by F and OH anions that makes double effects towards the critical property enhancement of deep-UV birefringent crystals is proposed. This leads to a new hydroxyborate (NH4 )4 [B12 O16 F4 (OH)4 ] with giant cluster as a deep-UV birefringent crystal with large birefringence (Δnexp. =0.12@546.1 nm). This birefringence is a record among inorganic hydroxyborates with experimentally measured birefringence. Structural analysis shows that the near-plane arrangement of [B12 O16 F4 (OH)4 ] cluster is responsible for the large optical anisotropy. Theoretical calculations indicate that its π-conjugated [BO3 ] and [BO2 OH] units are the main source of this large optical anisotropy.

Cs4 B4 O3 F10 : First Fluorooxoborate with [BF4 ] Involving Heteroanionic Units and Extremely Low Melting Point.

Herein, a new congruently melting mixed-anion compound Cs4 B4 O3 F10 has been characterized as the first fluorooxoborate with [BF4 ] involving heteroanionic units. Compound Cs4 B4 O3 F10 possesses two highly fluorinated anionic clusters and therefore its formula can be expressed as Cs3 (B3 O3 F6 ) ⋅ Cs(BF4 ). The influence of [BF4 ] units on micro-symmetry and structural evolution was discussed based on the parent compound. More importantly, Cs4 B4 O3 F10 shows the lowest melting point among all the available borates and thus sets a new record for such system. This work is of great significance to enrich and tailor the structure of borates using perfluorinated [BF4 ] units.

In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis.

Lung cancer is the leading cause of cancer-related death worldwide. Inactivation of tumor suppressor genes (TSGs) promotes lung cancer malignant progression. Here, we take advantage of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated somatic gene knockout in a KrasG12D/+ mouse model to identify bona fide TSGs. From individual knockout of 55 potential TSGs, we identify five genes, including Utx, Ptip, Acp5, Acacb, and Clu, whose knockout significantly promotes lung tumorigenesis. These candidate genes are frequently down-regulated in human lung cancer specimens and significantly associated with survival in patients with lung cancer. Through crossing the conditional Utx knockout allele to the KrasG12D/+ mouse model, we further find that Utx deletion dramatically promotes lung cancer progression. The tumor-promotive effect of Utx knockout in vivo is mainly mediated through an increase of the EZH2 level, which up-regulates the H3K27me3 level. Moreover, the Utx-knockout lung tumors are preferentially sensitive to EZH2 inhibitor treatment. Collectively, our study provides a systematic screening of TSGs in vivo and identifies UTX as an important epigenetic regulator in lung tumorigenesis.

Discovery of First Magnesium Fluorooxoborate with Stable Fluorine Terminated Framework for Deep-UV Nonlinear Optical Application.

The generated light can be tuned to cover almost the entire spectral range from deep-ultraviolet to terahertz wavelengths by utilizing the nonlinear optical crystals with a simple frequency doubling process. Among them, the discovery of novel candidates for the production of deep-ultraviolet light is by extension a great challenge toward realizing the vast potential. Actually, the availability for this process mainly depends on whether the critical performance can be well coexisted in one practical crystal. Herein, the first magnesium fluorooxoborate MgB5 O7 F3 was synthesized as a new competitive candidate for deep-ultraviolet nonlinear optical application. It has a sufficiently large nonlinearity and a deep-ultraviolet phase matching wavelength, indicating that it holds great potential for the production of coherent light below 200 nm. The critical performance enhancement of MgB5 O7 F3 when compared with its isomorphic phases was demonstrated and discussed. More importantly, we proposed that fluorooxoborate system with the general formula of MB5 O7 F3 (M=divalent metal) possesses stable fluorine terminated framework, which makes them tend to retain their crystallized space groups unchanged.

Cost-Effectiveness Analysis of Sintilimab Plus Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer: A Societal Perspective.

INTRODUCTION: The updated ORIENT-11 study demonstrated that sintilimab, when combined with chemotherapy, had promising survival advantage compared to standard chemotherapy alone in the first-line treatment for previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer (nsNSCLC). This study aims to evaluate the cost-effectiveness of sintilimab plus chemotherapy for advanced nsNSCLC from a Chinese societal perspective. METHODS: A partitioned survival model with a embedded decision tree was developed to assess the economic value of sintilimab plus chemotherapy over a lifetime horizon. Clinical data was captured from the updated ORIENT-11 study, while costs, health productivity losses, and utility values were collected from a nationwide cross-sectional survey in tertiary hospitals across multiple provinces in China. The primary outcomes were measured using the metrics of quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER). Costs and health outcomes were discounted at an annual rate of 5% per annum. Sensitivity analyses, including one-way and probabilistic sensitivity analyses, subgroup analyses, and scenario analyses, were performed. RESULTS: Compared to standard chemotherapy, treatment with sintilimab plus chemotherapy incurred a mean total cost of $23,979 and gained 0.98 QALYs over the lifetime horizon, resulting in an ICER of $24,568 per QALY gained. The use of sintilimab accumulated direct non-medical costs of $9262 and indirect costs of $6780 over 16 years. Probabilistic sensitivity analyses showed an 84.2% probability of sintilimab plus chemotherapy being cost-effective at a threshold of three times China's per capita gross domestic product in 2022 ($38,201). The model was most sensitive to the discount rate of QALYs and costs, as well as the costs of pemetrexed, sintilimab, and subsequent therapy in progressive disease state. Subgroup analyses indicated favorable incremental net monetary benefits in all subgroups. CONCLUSION: Sintilimab plus chemotherapy is a cost-effective first-line treatment therapy for advanced nsNSCLC in China when compared to standard chemotherapy. These findings, along with the improved progression-free survival and overall survival (OS) observed in ORIENT-11, support the use of this regimen in eligible candidates for advanced nsNSCLC.

Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.

Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong cancer plasticity. We find that ALK rearrangement is detectable in 5.1-7.5% of human LUAS, and transgenic expression of EML4-ALK drives lung adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.