Intermolecular Regioselective Alkylarylation of Vinylarenes via Photoredox/Nickel Dual Catalysis.

A novel photoredox/nickel dual catalytic intermolecular alkylarylation of vinylarenes with tertiary and secondary alkyltrifluoroborates and aryl bromides is described, which affords 1,1-diarylalkane frameworks that are found in various natural products as well as functionalized molecules in good to excellent yield and regioselectivity through a radical relay process. Notably, this redox-neutral reaction could proceed efficiently with good tolerance of various substrates, including a great diversity of commercially available (hetero)aryl bromides, alkyltrifluoroborates, and vinylarenes.

[Clinical Analysis of PD-1 Inhibitor Combined with Lenalidomide in Treatment of Relapsed CD5+ Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To investigate the clinical characteristics and treatment of relapsed CD5+ diffuse large B-cell lymphoma (DLBCL). METHODS: The data of a patient with CD5+ DLBCL was collected, and its clinical characteristics and treatment outcome were analyzed. RESULTS: The patient developed hemophagocytic syndrome and achieved complete remission (CR) after 6 cycles of R-ECHOP chemotherapy, then relapsed. After 2 cycles of PD-1 inhibitor combined with lenalidomide treatment, the patient achieved CR again accompanied by a decrease of interleukin (IL)-10 expression level. After a total of 15 cycles of chemotherapy, the patient remained in CR for 24 months, and the level of IL-10 remained in the normal range. CONCLUSION: PD-1 inhibitor combined with lenalidomide regimen may be a new treatment for relapsed CD5+ DLBCL.

Evaluating the effects of laver cultivation on tidal flat erosion: Toward sustainable environmental practices.

The rapid expansion of laver (Porphyra yezoensis) cultivation on lower tidal flats has become integral to the local economy, yet it also raises concerns regarding its potential impact on the morphological evolution due to increasing human activities. This study utilizes integrated near-bed field measurements to assess morphological dynamics and quantify sediment erosion processes, highlighting the significant impact of laver harvest on tidal flat stability. Our results show that erosion and bed coarsening in the cultivated areas experienced a notable intensification immediately after harvest, with net erosion in cultivated areas reaching approximately -38.2 mm during the first tide post-harvest, markedly higher-more than an order of magnitude-compared to adjacent uncultivated areas. The erosion rate notably spiked with the average bed level change rate increasing to -13.8 × 10-4 mm/s, compared to a rate of +0.3 × 10-4 mm/s during the unharvest period. Subsequently, the cultivated areas entered a recovery phase with a deposition amount of +12.5 mm, while the net cumulative erosion thickness throughout the entire observation period was -25.2 mm. The cultivation method, characterized by consistent harvests every 10 days, means that even minor erosion from continuous harvests can escalate into significant degradation. This study suggests that long-term cultivation cycle practices may result in irreversible changes to the depositional environment, potentially jeopardizing the habitat viability and ecological function. Sustainable agricultural strategies, including site selection, infrastructure planning, monitoring environmental changes, ecological assessments and sustainable practices, are recommended to mitigate the negative impacts of cultivation on regional stability and preserve the coastal ecological balance.

PKM2/Hif-1α signal suppression involved in therapeutics of pulmonary fibrosis with microcystin-RR but not with pirfenidone.

To date there are only pirfenidone (PFD) and nintedanib to be given conditional recommendation in idiopathic pulmonary fibrosis (IPF) therapies with slowing disease progression, but neither has prospectively shown a reduced mortality. It is one of the urgent topics to find effective drugs for pulmonary fibrosis in medicine. Previous studies have demonstrated that microcystin-RR (MC-RR) effectively alleviates bleomycin-induced pulmonary fibrosis, but the mechanism has not been fully elucidated yet. We further conducted a comparison of therapeutic effect on the model animals of pulmonary fibrosis between MC-RR and PFD with histopathology and the expression of the molecular markers involved in differentiation, proliferation and metabolism of myofibroblasts, a major effector cell of tissue fibrosis. The levels of the enzyme molecules for maintaining the stability of interstitial structure were also evaluated. Our results showed that MC-RR and PFD effectively alleviated pulmonary fibrosis in model mice with a decreased signaling and marker molecules associated with myofibroblast differentiation and lung fibrotic lesion. In the meantime, both MC-RR and PFD treatment are beneficial to restore molecular dynamics of interstitial tissue and maintain the stability of interstitial architecture. Unexpectedly, MC-RR, rather than PFD, showed a significant effect on inhibiting PKM2-HIF-1α signaling and reducing the level of p-STAT3. Additionally, MC-RR showed a better inhibition effect on FGFR1 expression. Given that PKM2-HIF-1α and activated STAT3 molecular present a critical role in promoting the proliferation of myofibroblasts, MC-RR as a new strategy for IPF treatment has potential advantage over PFD.

The safety and feasibility assessment of overlap esophagojejunostomy with self-pulling and latter transection technique in totally laparoscopic total gastrectomy.

BACKGROUND: This study presented an innovative technique in totally laparoscopic total gastrectomy (TLTG) for overlap esophagojejunostomy (E-J), termed self-pulling and latter transection (SPLT) (overlap SPLT). It evaluated the effectiveness and short-term outcomes of this novel method through a comparative analysis with the established functional end-to-end (FETE) E-J incorporating SPLT. METHODS: From September 2018 to September 2023, this study enrolled 68 patients with gastric cancer who underwent TLTG with overlap SPLT anastomosis and 120 patients who underwent TLTG with FETE SPLT anastomosis. Clinicopathologic characteristics and surgical and postoperative outcomes data for overlap SPLT cases were gathered and retrospectively compared with those from FETE SPLT TLTG to evaluate the effectiveness and clinical safety. RESULTS: The duration of anastomosis for overlap SPLT was 25.3 ± 7.4 minutes, significantly longer than that for the FETE SPLT (18.1 ± 4.0 minutes, P = .031). Perioperatively, 1 anastomosis-related complication occurred in each group, but this did not constitute a statistically significant difference (P = .682). No statistically significant differences were found between the 2 groups in terms of operative time, postoperative hospital stay, operative cost, surgical margins, or number of lymph nodes removed. Postoperative morbidity rates were similar between the groups (4.4% vs 5.8%, P = .676). CONCLUSION: The overlap SPLT technique is regarded as a safe and feasible method for anastomosis. There were no apparent differences in complications between overlap SPLT and FETE SPLT, but overlap SPLT costed 1 additional stapler cartridge and required a longer duration.

Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction.

BACKGROUND: Leukemia stem cells (LSCs) are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia (AML), as they are protected by the bone marrow microenvironment (BMM) against conventional therapies. Gossypol acetic acid (GAA), which is extracted from the seeds of cotton plants, exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2. AIM: To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism. METHODS: In this study, LSCs were magnetically sorted from AML cell lines and the CD34+CD38- population was obtained. The expression of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) and forkhead box M1 (FOXM1) was evaluated in LSCs, and the effects of GAA on malignancies and mitochondrial function were measured. RESULTS: LRPPRC was found to be upregulated, and GAA inhibited cell proliferation by degrading LRPPRC. GAA induced LRPPRC degradation and inhibited the activation of interleukin 6 (IL-6)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 3 signaling, enhancing chemosensitivity in LSCs against conventional chemotherapies, including L-Asparaginase, Dexamethasone, and cytarabine. GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC. Furthermore, GAA induced reactive oxygen species accumulation, disturbed mitochondrial homeostasis, and caused mitochondrial dysfunction. By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC, GAA resulted in the elimination of LSCs. Meanwhile, GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage. CONCLUSION: Taken together, the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.

Hidden delta degradation due to fluvial sediment decline and intensified marine storms.

Deltas are threatened by erosion due to climate change and reduced sediment supply, but their response to these changes remains poorly quantified. We investigate the abandoned Yellow River delta that has transitioned from rapid growth to ongoing deterioration due to a river avulsion removing the sediment supply. Integrating bathymetric data, process observations, and sediment transport modeling, we find that while the subaerial delta was stabilized by engineering measures, the subaqueous delta continued to erode due to intensified storms, losing 39% of its mass deposited before the avulsion. Long-term observations show that winter storms initiate scouring of the subaqueous delta, contributing up to 70% of seabed erosion. We then analyze 108 global deltas to assess subaqueous delta erosion risks and identify 17 deltas facing similar situations of sediment decline and storm intensification during the past 40 years. Our findings suggest that subaqueous delta erosion must be integrated into delta sustainability evaluations.

Evaluation of a concise fall risk stratification among older adults with cataracts in day surgery settings: A historically controlled study.

AIM: This study aimed to evaluate the use of a concise fall risk stratification in assessing and predicting falls compared with the Morse Falls Scale among older adults with cataracts in day surgery settings. METHODS: A historically controlled study conducted from July 2020 to June 2022 was used in a municipal ophthalmic hospital in China. The concise fall risk stratification which directly graded fall risk by multifactorial judgment was used during the intervention period, while the Morse Falls Scale which graded fall risk by scale scores was used during the control period. The fall risk levels, fall assessment time, fall rates, fall-related injuries, predictive validity, and patient satisfaction with day surgery care were extracted. Propensity score matching was performed to balance baselines. RESULTS: After matching, 4132 patients were included in the final analysis. Compared with the control group, the intervention group had significantly higher assessment results for fall risk level, a significantly shorter (by 48.15%) fall assessment time, and higher patient satisfaction. There were no differences in fall rates and fall-related injuries. Compared with the Morse Falls Scale, the concise fall risk stratification had higher sensitivity and negative predictive validity, and lower specificity and positive predictive validity, while the area under curve did not differ significantly. CONCLUSION: The use of the concise fall risk stratification reduced fall assessment time, improved patient satisfaction, and is unlikely to impact falls with an overall predictive performance comparable to that of the Morse Falls Scale for older cataract adults in day surgery settings.

Cobalt(II)-Catalyzed Enantioselective Propargyl Claisen Rearrangement: Access to Allenyl-Substituted Quaternary ß-Ketoesters.

Highly enantioselective propargyl Claisen rearrangement of O-propargyl ß-ketoesters was achieved under 2.5 mol % of the chiral cobalt complex as the catalyst under mild reaction conditions. With Co(OTf)2 as the Lewis acid and C1-symmetric imidazoline-pyrroloimidazolone pyridine as the ligand, diverse chiral allenyl-substituted all-carbon quaternary ß-ketoesters were obtained in good yields (up to 97% yield) and high enantioselectivities (up to 98% ee).

Radio- and Photosensitizing Os(II)-Based Nanocage for Combined Radio-/Chemo-/X-ray-Induced Photodynamic Therapies, NIR Imaging, and Drug Delivery.

Integration of clinical imaging and collaborative multimodal therapies into a single nanomaterial for multipurpose diagnosis and treatment is of great interest to theranostic nanomedicine. Here, we report a rational design of a discrete Os-based metal-organic nanocage Pd6(OsL3)828+ (MOC-43) as a versatile theranostic nanoplatform to meet the following demands simultaneously: (1) synergistic treatments of radio-, chemo-, and X-ray-induced photodynamic therapies (X-PDT) for breast cancer, (2) NIR imaging for cancer cell tracking and tumor-targeting, and (3) anticancer drug transport through a host-guest strategy. The nanoscale MOC-43 incorporates high-Z Os-element to interact with X-ray irradiation for dual radiosensitization and photosensitization, showing efficient energy transfer to endogenous oxygen in cancer cells to enhance X-PDT efficacy. It also features intrinsic NIR emission originating from metal-to-ligand charge transfer (MLCT) as an excellent imaging probe. Meanwhile, its 12 pockets can capture and concentrate low-water-soluble molecules for anticancer drug delivery. These multifunctions are implemented and demonstrated by micellization of coumarin-loaded cages with DSPE-PEG2000 into coumarin ⊂ MOC-43 nanoparticles (CMNPs) for efficient subcellular endocytosis and uptake. The cancer treatments in vitro/in vivo show promising antitumor performance, providing a conceptual protocol to combine cage-cargo drug transport with diagnosis and treatment for collaborative cancer theranostics by virtue of multifunction synergism on a single-nanomaterial platform.

Clinicopathological correlations of peritoneal endometriosis and deep infiltrating endometriosis.

OBJECTIVE: The present study aims to investigate the clinical and histopathological features of peritoneal endometriosis (PEM) and deep infiltrating endometriosis (DIE). METHODS: A total of 100 patients with PEM and DIE admitted to Dalian Women and Children's Hospital/Dalian Women and Children's Medical Center between October 2018 and December 2021 were selected as the study subjects. One hundred and thirty-one PEM specimens and 37 DIE were collected, 22 cases of these patients' eutopic endometrium were used as control (15 in PEM, seven in DIE). The present study mainly analysed the pelvic distribution, the histopathological and immunohistochemical features and peritoneal invasion of PEM and DIE. RESULTS: The main distribution of PEM and DIE was located in the posterior pelvic cavity (p < .001). The histopathological characteristics of different PEM forms were different: the contents of endometrioid glands, endometrioid stroma, smooth muscle, fibrous tissue and blood vessels in different lesions were statistically significant (all p < .050). Estrogen receptor (ER) of PEM and DIE was highly expressed in endometrioid glandular epithelium and endometrioid stroma, without statistical significance (p = .330/.113). Progesterone receptor (PR) was also highly expressed in endometrioid glandular epithelium and endometrioid stroma without statistical significance (p = .757/.798). Ki-67 expression of DIE in endometrioid glandular epithelium was significantly higher than that in brown and white lesions (p < .001), while its expression in the endometrioid stroma was not statistically significant in red lesions (p = .070), but higher than that in other PEM lesions (p < .001). Different morphological lesions had different invasiveness rates and depths of invasion to the peritoneum. White lesions had a deeper subperitoneal invasion level than transparent and vesicular lesions. CONCLUSIONS: Although different morphological appearance of PEM is a degenerative process, some active brown lesions of PEM have invasive effects during the process and may further develop into DIE. PEM and DIE may be different developmental stages of the same disease.

In summary, PEM is a progressive disease, and its different morphological appearance reflects different stages of lesion development.Ectopic endometrial cells have a destructive effect on the peritoneal structures; as the lesion progresses, it continuously infiltrates the subperitoneum.PEM and DIE are different development stages of the same disease. The homology of the two lesions has yet to be explored in terms of pathogenesis.

General Method for Selective Three-Component Carboacylation of Alkenes via Visible-Light Dual Photoredox/Nickel Catalysis.

A photoredox/nickel dual catalytic protocol for the regioselective three-component carboacylation of alkenes with tertiary and secondary alkyltrifluoroborates as well as acyl chlorides is described. This redox-neutral protocol can be applied to the rapid synthesis of ketones with high diversity and complexity via a radical relay process. Many functional groups, allowing for various commercially available acyl chlorides, alkyltrifluoroborates, and alkenes, are tolerated under these mild conditions.

The anti-hepatocellular carcinoma effects of polysaccharides from Ganoderma lucidum by regulating macrophage polarization via the MAPK/NF-κB signaling pathway.

The response of macrophages to environmental signals demonstrates its heterogeneity and plasticity. After different forms of polarized activation, macrophages reach the M1 or M2 activation state according to their respective environment. Ganoderma lucidum polysaccharide (GLPS) is a major bioactive component of Ganoderma lucidum, a well-known medicinal mushroom. Although the immunomodulatory and anti-tumor effects of GLPS have been proven, GLPS's effect on inhibiting hepatocellular carcinoma (HCC) by regulating macrophage polarization is little known. Our data showed that GLPS notably inhibited the growth of a Hepa1-6 allograft. The expression of M1 marker CD86 was higher in the tumor tissue of the GLPS treatment group than in the control group in vivo. In vitro, the phagocytic activity and NO production of macrophages were increased by GLPS treatment. Moreover, it was discovered that GLPS was able to increase the expression of the M1 phenotype marker CD86, iNOS, and pro-inflammatory cytokines comprising IL-12a, IL-23a, IL-27 and TNF-α, but inhibited macrophage polarization towards the M2 phenotype by decreasing the expression of CD206, Arg-1, and inflammation-related cytokines comprising IL-6 and IL-10. The data suggest that GLPS may regulate macrophage polarization. Mechanistically, GLPS increased the phosphorylation of MEK and ERK. In addition, the phosphorylation of IκBα and P65 was increased by GLPS treatment. These data showed that GLPS can regulate the MAPK/NF-κB signaling pathway responsible for M1 polarization. In a nutshell, our research puts forward a new application of GLPS in anti-HCC treatment by regulating macrophage polarization through activating MAPK/NF-κB signaling.

Morinda officinalis oligosaccharides increase serotonin in the brain and ameliorate depression via promoting 5-hydroxytryptophan production in the gut microbiota.

Morinda officinalis oligosaccharides (MOO) are an oral drug approved in China for the treatment of depression in China. However, MOO is hardly absorbed so that their anti-depressant mechanism has not been elucidated. Here, we show that oral MOO acted on tryptophan â†’ 5-hydroxytryptophan (5-HTP) â†’ serotonin (5-HT) metabolic pathway in the gut microbiota. MOO could increase tryptophan hydroxylase levels in the gut microbiota which accelerated 5-HTP production from tryptophan; meanwhile, MOO inhibited 5-hydroxytryptophan decarboxylase activity, thus reduced 5-HT generation, and accumulated 5-HTP. The raised 5-HTP from the gut microbiota was absorbed to the blood, and then passed across the blood-brain barrier to improve 5-HT levels in the brain. Additionally, pentasaccharide, as one of the main components in MOO, exerted the significant anti-depressant effect through a mechanism identical to that of MOO. This study reveals for the first time that MOO can alleviate depression via increasing 5-HTP in the gut microbiota.

[Vascular endothelial growth factor induces inflammatory injury of pancreatic tissue by activating autophagy in hyperlipidemic acute pancreatitis rats].

This study was to investigate the changes of autophagy in pancreatic tissue cells from hyperlipidemic acute pancreatitis (HLAP) rats and the molecular mechanism of autophagy to induce inflammatory injury in pancreatic tissue cells. Male Sprague Dawley (SD) rats were intraperitoneally injected with caerulein to establish acute pancreatitis (AP) model and then given a high fat diet to further prepare HLAP model. The HLAP rats were treated with autophagy inducer rapamycin or inhibitor 3-methyladenine. Pancreatic acinar (AR42J) cells were treated with caerulein to establish HLAP cell model. The HLAP cell model were treated with rapamycin or transfected with vascular endothelial growth factor (VEGF) siRNA. The inflammatory factors in serum and cell culture supernatant were detected by ELISA method. The histopathological changes of pancreatic tissue were observed by HE staining. The changes of ultrastructure and autophagy in pancreatic tissue were observed by electron microscopy. The expression levels of Beclin-1, microtubule- associated protein light chain 3-II (LC3-II), mammalian target of rapamycin complex 1 (mTORC1), and VEGF were measured by immunohistochemistry and Western blot. The results showed that, compared with control group, the autophagy levels and inflammatory injury of pancreatic tissue cells from HLAP model rats were obviously increased, and these changes were aggravated by rapamycin treatment, but alleviated by 3-methyladenine treatment. In HLAP cell model, rapamycin aggravated the autophagy levels and inflammatory injury, whereas VEGF siRNA transfection increased mTORC1 protein expression, thus alleviating the autophagy and inflammatory injury of HLAP cell model. These results suggest that VEGF-induced autophagy plays a key role in HLAP pancreatic tissue cell injury, and interference with VEGF-mTORC1 pathway can reduce the autophagy levels and alleviate the inflammatory injury. The present study provides a new target for prevention and treatment of HLAP.

Charge Compensation Mechanisms and Oxygen Vacancy Formations in LiNi1/3Co1/3Mn1/3O2: First-Principles Calculations.

Charge compensation mechanisms in the delithiation processes of LiNi1/3Co1/3Mn1/3O2 (NCM111) are compared in detail by the first-principles calculations with GGA and GGA+U methods under different U values reported in the literature. The calculations suggested that different sets of U values lead to different charge compensation mechanisms in the delithiation process. Co3+/Co4+ couples were shown to dominate the redox reaction for 1 ≥ x ≥ 2/3 by using the GGA+U 1 method (U 1 = 6.0 3.4 3.9 for Ni, Co, and Mn, respectively). However, by using the GGA+U 2 (U 2 = 6.0 5.5 4.2) method, the results indicated that the redox reaction of Ni2+/Ni3+ took place in the range of 1 ≥ x ≥ 2/3. Therefore, according to our study, experimental charge compensation processes during delithiation are of great importance to evaluate the theoretical calculations. The results also indicated that all the GGA+U i (i = 1, 2, 3) schemes predicted better voltage platforms than the GGA method. The oxygen anionic redox reactions during delithiation are also compared with GGA+U calculations under different U values. The electronic density of states and magnetic moments of transition metals have been employed to illustrate the redox reactions during the lithium extractions in NCM111. We have also investigated the formation energies of an oxygen vacancy in NCM111 under different values of U, which is important in understanding the possible occurrence of oxygen release. The formation energy of an O vacancy is essentially dependent on the experimental conditions. As expected, the decreased temperature and increased oxygen partial pressure can suppress the formation of the oxygen vacancy. The calculations can help improve the stability of the lattice oxygen.

Northwestern Pacific tropical cyclone activity enhanced by increased Asian dust emissions during the Little Ice Age.

Instrumental records reveal that intense tropical cyclone (TC) activity varies with tropical sea surface temperature (SST) on annual-decadal scales. Drivers of intense TC activity at the centennial-millennial scale are less clear, due to the sparseness of pre-observational reconstructions. Here, we present a new 2 kyr continuous activity record of intense TCs from offshore eastern China. Our reconstruction indicates that this site witnessed enhanced TC activity during relatively warm periods, with a widespread increase in TC activity during the later part of the Little Ice Age. This latter observation reveals that enhanced TC activity was synchronized with increased Asian dust emissions during the Little Ice Age. TC activity was also lower in the late Roman Warm Period, when SST was higher but Asian dust emissions were lower than in the early phase. Such patterns suggest a centennial-millennial link between TC climatology and a combination of SST changes and Asian dust levels.

Effect of different oesophagojejunostomy methods on the quality of life of gastric cancer patients after totally laparoscopic total gastrectomy with self-pulling and latter transected technique: study protocol for a randomised trial.

INTRODUCTION: Gastric cancer is the fifth most common cancer worldwide and the detection rate of proximal gastric cancer has been increasing. Currently, surgical resection using gastrectomy and proper perigastric lymphadenectomy is the only treatment option to enhance the survival rate of patients with gastric cancer. Laparoscopic total gastrectomy (LTG) is increasingly performed for adenocarcinoma of the oesophagogastric junction. However, totally LTG (TLTG) is only performed by a few surgeons due to difficulty associated with oesophagojejunostomy (OJ), in which there is no consensus on a standardised anastomosis technique. We propose a randomised trial to compare functional end-to-end anastomosis (FETE) and side-to-side anastomosis (Overlap) for OJ. METHODS AND ANALYSIS: A prospective, randomised, open-label, single-centre, interventional trial has been designed to evaluate the quality of life (QoL) outcomes and safety of FETE and Overlap, with a 1-year follow-up as the primary endpoint. The trial began in 2020 and is scheduled to enrol 96 patients according to a previous sample size calculation. Patients were randomly allocated to the FETE or Overlap groups with a follow-up of 1 year to assess QoL after the procedure. All relevant clinical data including biological markers were collected. The primary indicator is the D-value between the postoperative and preoperative QoL. Student's t-tests will be used to compare continuous variables, while χ2 tests or Fisher's exact tests will be used to compare categorical variables. Statistical analysis will be performed with SPSS V.23.0 statistical software. A p<0.05 will be considered statistically significant. ETHICS AND DISSEMINATION: This study has been approved by the Hospital Institutional Review Board of Huashan Hospital, Fudan University (2020-1055). The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2000035583.