Does the size of the neuroendocrine-carcinoma component determine the prognosis of gallbladder cancer?

Background: Gallbladder mixed neuroendocrine-non-neuroendocrine neoplasm generally consists of a gallbladder neuroendocrine tumor and a non-neuroendocrine component. The World Health Organization (WHO) in 2019 established a guideline requiring each component, both neuroendocrine and non-neuroendocrine, to account for a minimum of 30% of the tumor mass. Methods: Patients after surgery resection and diagnosed at microscopy evaluation with pure gallbladder neuroendocrine carcinoma (GBNEC), gallbladder mixed adeno-neuroendocrine carcinoma (GBMANEC, GBNEC≥30%), and gallbladder carcinoma mixed with a small fraction of GBNEC (GBNEC <30%) between 2010 and 2022 at West China Hospital of Sichuan University were collated for the analyses. Demographic features, surgical variables, and tumor characteristics were evaluated for association with patients' overall and recurrence-free survival (OS and RFS). Results: The study included 26 GBNEC, 11 GBMANEC, 4 gallbladder squamous-cell carcinoma (GBSCC), and 7 gallbladder adenocarcinoma (GBADC) mixed with a small fraction of GBNEC. All patients had stage III or higher tumors (AJCC8th edition). The majority of included patients (79.17%) underwent curative surgical resection (R0), with only ten patients having tumoral resection margins. In the analysis comparing patients with GBNEC percentage (GBNEC≥30% vs. GBNEC<30%), the basic demographics and tumor characteristics of most patients were comparable. The prognosis of these patients was also comparable, with a median OS of 23.65 months versus 20.40 months (P=0.13) and a median RFS of 17.1 months versus 12.3 months (P=0.24). However, patients with GBADC or GBSCC mixed with GBNEC <30% had a statistically significant decreased OS and RFS (both P<0.0001)) compared with GBNEC and GBMANEC. Patients with GBNEC who exhibited advanced tumor stages and lymphovascular invasion had a higher risk of experiencing worse overall survival (OS) and recurrence-free survival (RFS). However, a 30% GBNEC component was not identified as an independent risk factor. Conclusion: Patients with GBNEC were frequently diagnosed at advanced stages and their prognosis is poor. The 30% percentage of the GBNEC component is not related to the patient's survival.

Drug sensitivity tumor cell clusters in malignant peritoneal mesothelioma.

BACKGROUND: To explore the most effective adjuvant chemotherapy regimen for malignant peritoneal mesothelioma (MPM) through patient derived tumor-like cell clusters (PTC) drug sensitivity test. METHODS: PTC were cultured in vitro with intraoperative specimens, and drug sensitivity test was performed to calculate the most effective chemotherapy regimen for MPM. The patients were divided into conventional and individualized chemotherapy group according to whether they received PTC drug testing. Univariate and multivariate analyses were conducted to identify independent prognostic factors. RESULTS: Among 186 MPM patients included, 63 underwent PTC culture and drug sensitivity test. The results showed that the most effective chemotherapy regimen was oxaliplatin + gemcitabine. After propensity score matching, a total of 64 patients were enrolled in the following study, including 32 patients receiving individualized chemotherapy guided by PTC drug results as group 1 and 32 patients receiving conventional chemotherapy as group 2. Survival analysis showed that the median OS of group 1 was not reached, significantly longer than that of group 2 (23.5 months) (p < 0.05). CONCLUSIONS: Compared with conventional chemotherapy, individualized chemotherapy guided by PTC drug sensitivity tests can prolong patient survival, and oxaliplatin + gemcitabine + apatinib could be the optimal adjuvant treatment regimen for MPM.

MPGAN: Multi Pareto Generative Adversarial Network for the denoising and quantitative analysis of low-dose PET images of human brain.

Positron emission tomography (PET) imaging is widely used in medical imaging for analyzing neurological disorders and related brain diseases. Usually, full-dose imaging for PET ensures image quality but raises concerns about potential health risks of radiation exposure. The contradiction between reducing radiation exposure and maintaining diagnostic performance can be effectively addressed by reconstructing low-dose PET (L-PET) images to the same high-quality as full-dose (F-PET). This paper introduces the Multi Pareto Generative Adversarial Network (MPGAN) to achieve 3D end-to-end denoising for the L-PET images of human brain. MPGAN consists of two key modules: the diffused multi-round cascade generator (GDmc) and the dynamic Pareto-efficient discriminator (DPed), both of which play a zero-sum game for n(n∈1,2,3) rounds to ensure the quality of synthesized F-PET images. The Pareto-efficient dynamic discrimination process is introduced in DPed to adaptively adjust the weights of sub-discriminators for improved discrimination output. We validated the performance of MPGAN using three datasets, including two independent datasets and one mixed dataset, and compared it with 12 recent competing models. Experimental results indicate that the proposed MPGAN provides an effective solution for 3D end-to-end denoising of L-PET images of the human brain, which meets clinical standards and achieves state-of-the-art performance on commonly used metrics.

Celiac Axis Stenosis as an Independent Risk Factor for Bile Leakage in Laparoscopic Pancreaticoduodenectomy: A Retrospective Study.

Background: Celiac axis stenosis can potentially lead to insufficient blood supply to vital organs, such as the liver, spleen, pancreas, and stomach. This condition result in the development of collateral circulation between the superior mesenteric artery and the hepatic artery. However, these collateral circulations are often disrupted during pancreaticoduodenectomy (PD), which may increase the risk of postoperative complications. Methods: A retrospective analysis was conducted on patients who underwent laparoscopic pancreaticoduodenectomy (LPD) from April 2015 to April 2023. Celiac trunk stenosis is classified according to the degree of stenosis: no stenosis (<30%), grade A (30%-<50%), grade B (50%-≤80%), and grade C (>80%). The incidence of postoperative complications was evaluated, and both univariate and multivariate risk analyses were conducted. Results: A total of 997 patients were included in the study, with mild celiac axis stenosis present in 23 (2.3%) patients, moderate stenosis in 18 (1.8%) patients, and severe stenosis in 10 (1.0%) patients. Independent risk factors for the development of bile leakage, as identified by both univariate and multivariate analyses, included body mass index (BMI) (HR = 1.108, 95% CI = 1.008-1.218, P = .033), intra-abdominal infection (HR = 2.607, 95% CI = 1.308-5.196, P = .006), postoperative hemorrhage (HR = 4.510, 95% CI = 2.048-9.930, P = <0.001), and celiac axis stenosis (50%-≤80%, HR = 4.235, 95% CI = 1.153-15.558, P = .030), and (>80%, HR = 4.728, 95% CI = .882-25.341, P = .047). Celiac axis stenosis, however, was not determined to be an independent risk factor for pancreatic fistula (P > 0.05). Additionally, the presence of an aberrant hepatic artery did not significantly increase the risk of postoperative complications when compared with celiac axis stenosis alone. Conclusion: Severe celiac axis stenosis is an independent risk factor for postoperative bile leakage following LPD.

Guest-Induced Helical Superstructure from a Gold Nanocluster-Based Supramolecular Organic Framework Enables Efficient Catalysis.

Mimicking hierarchical assembly in nature to exploit atomically precise artificial systems with complex structures and versatile functions remains a long-standing challenge. Herein, we report two single-crystal supramolecular organic frameworks (MSOF-4 and MSOF-5) based on custom-designed atomically precise gold nanoclusters Au11(4-Mpy)3(PPh3)7, showing distinct and intriguing host-guest adaptation behaviors toward 1-/2-bromopropane (BPR) isomers. MSOF-4 exhibits sev topology and cylindrical channels with 4-mercaptopyridine (4-Mpy) ligands matching well with guest 1-BPR. Due to the confinement effect, solid MSOF-4 undergoes significant structural change upon selective adsorption of 1-BPR vapor over 2-BPR, resulting in strong near-infrared fluorescence. Single-crystal X-ray diffraction reveals that Au11(4-Mpy)3(PPh3)7 in MSOF-4 transforms into Au11Br3(PPh3)7 upon ligand exchange with 1-BPR, resulting in 1-BPR@MSOF-6 single crystals with a rarely reported helical assembly structure. Significantly, the double-helical structure of MSOF-6 facilitates efficient catalysis of the electron transfer (ET) reaction, resulting in a nearly 6 times increase of catalytic rates compared with MSOF-4. In sharp contrast, solid MSOF-5 possesses chb topology and cage-type channels with narrow windows, showing excellent selective physical adsorption toward 1-BPR vapor but a nonfluorescent feature upon guest adsorption. Our results demonstrate a powerful strategy for developing advanced assemblies with high-order complexity and engineering their functions in atomic precision.

[Application framework and model of Jingjin therapy in rehabilitation medicine].

The Jingjin therapy and rehabilitation medicine share commonalities and complement each other. The application of Jingjin therapy from a rehabilitation perspective can broaden the development path of traditional Chinese medicine (TCM) rehabilitation. This paper, based on relevant literature and research findings, elaborates on the connection between Jingjin syndrome differentiation acupuncture and rehabilitation assessment and treatment. It discusses the application framework of Jingjin's preventive treatment theory in disease prevention and rehabilitation, and forecasts the research model of Jingjin rehabilitation medicine from an integrative perspective of Chinese and western medicine. This study aims to improve the rehabilitation application thinking of Jingjin therapy and enrich the application methods and treatment approaches of TCM rehabilitation medicine.

A novel neuroprotective method against ischemic stroke by accelerating the drainage of brain interstitial fluid.

Ischemic stroke is a leading cause of death and disability worldwide. Inflammatory response after stroke determines the outcome of ischemic injury. A recent study has reported an efficient method, epidural arterial implantation (EAI), for accelerating interstitial fluid (ISF) drainage, which provides a promising strategy to clear pro-inflammatory cytokines in the brain extracellular space (ECS). In this study, the method of EAI was modified (m-EAI) to control its function of accelerating the ISF drainage at different time points following ischemic attack. The neuroprotective effect of m-EAI on ischemic stroke was evaluated with the transient middle cerebral artery occlusion (tMCAO) rat model. The results demonstrated the accumulation of IL-1ß, IL-6, and TNF-α was significantly decreased by activating m-EAI at 7 d before and immediately after ischemic attack in tMCAO rats, accompanied with decreased infarct volume and improved neurological function. This study consolidates the hypothesis of exacerbated ischemic damage by inflammatory response and provides a new perspective to treat encephalopathy via brain ECS. Further research is essential to investigate whether m-EAI combined with neuroprotective drugs could enhance the therapeutic effect on ischemic stroke.

Unveiling potential of cellulose gel electrolyte: Molecular engineering for enhanced electrostatic interactions with Mg adatoms in Mg-ion battery.

The Mg-ion battery faces significant limitations due to its liquid electrolyte, which suffers from inherent issues such as leakage and the growth of Mg dendrites. In contrast, gel polymer electrolytes (GPEs) offer heightened safety, a wide voltage window, and excellent flexibility, making them a promising alternative with outstanding electrochemical performance. In this study, a cyano-modified cellulose (CEC) GPE was engineered to aim at enhancing ion transportation and promoting uniform ion-flux through interactions between N and Mg2+ ions. The resulting CEC-based GPE demonstrated a high ionic conductivity of 1.73 mS cm-1 at room temperature. Furthermore, it exhibited remarkable Mg plating/stripping performance (coulombic efficiency ∼96.7 %) and compatibility with electrodes. Importantly, when employed in a Mo6S8//Mg battery configuration, the CEC GPE displayed exceptional cycle stability, with virtually no degradation observed even after 650 cycles at 1C, thereby significantly advancing Mg-ion battery technology due to its excellent electrochemical properties. This study provides valuable insights into the molecular engineering of cellulose-based GPEs.

Utilizing superheated steam to prepare traditional Chinese twice-cooked pork bellies, exploring its effects on the texture and flavor of fat layers.

Fat greatly impacts the overall texture and flavor of pork belly. Twice-cooked pork bellies (TPB), typically boiled and sliced before "back to pot" being stir-fried, is a classic Sichuan cuisine among stir-fried dishes. In this study, the effects of substituting conventional pan-frying (PCV) with superheated steam (SHS) technology on the sensory, texture, microstructure and flavor of the fat layers were investigated. SHS was used as an alternative to boiling (120 °C for 15, 20, 25, and 30 min), and "back to pot" stir-frying was also by SHS. TPB precooked for 25 min (P25) with SHS performed better quality characteristics than PCV, with less collagen fiber disruption and lipid droplet area, resulting in a lower hardness and higher shear force. Besides, the low-oxygen environment of SHS retarded the lipid peroxidation, showing a significantly lower MDA content than PCV. Differently, PCV exhibited more grassy and fatty flavors, while P25 exhibited a unique aroma of fruity and creamy due to its higher UFA/SFA ratios in the pre-cooking stage. Overall, the sensory scores of P25 were comparable to those of PCV (with no significant difference), revealing that SHS is expected to be applied to the industrial production of stir-fried dishes.

ALKBH5 governs human endoderm fate by regulating the DKK1/4-mediated Wnt/ß-catenin activation.

N6-methyladenonsine (m6A) is ubiquitously distributed in mammalian mRNA. However, the precise involvement of m6A in early development has yet to be fully elucidated. Here, we report that deletion of the m6A demethylase ALKBH5 in human embryonic stem cells (hESCs) severely impairs definitive endoderm (DE) differentiation. ALKBH5-/- hESCs fail to undergo the primitive streak (PS) intermediate transition that precedes endoderm specification. Mechanistically, we show that ALKBH5 deficiency induces m6A hypermethylation around the 3' untranslated region (3'UTR) of GATA6 transcripts and destabilizes GATA6 mRNA in a YTHDF2-dependent manner. Moreover, GATA6 binds to the promoters of critical regulatory genes involved in Wnt/ß-catenin signaling transduction, including the canonical Wnt antagonist DKK1 and DKK4, which are unexpectedly repressed upon the dysregulation of GATA6 mRNA metabolism. Remarkably, DKK1 and DKK4 both exhibit a pleiotropic effect in modulating the Wnt/ß-catenin cascade and guard the endogenous signaling activation underlying DE formation as potential downstream targets of the ALKBH5-GATA6 regulation. Here, we unravel a role of ALKBH5 in human endoderm formation in vitro by modulating the canonical Wnt signaling logic through the previously unrecognized functions of DKK1/4, thus capturing a more comprehensive role of m6A in early human embryogenesis.

Aerobic Copper-Catalyzed Oxysulfonylation of Vinylarenes with Sodium Sulfinates under Mild Conditions: A Modular Synthesis of ß-Ketosulfones.

An aerobic copper-catalyzed oxysulfonylation of vinylarenes with sodium sulfinates is described. This protocol features mild reaction conditions, convenient operation, and broad substrate scope with respect to vinylarenes and sodium sulfinates. Notably, the protocol demonstrates excellent tolerance of functional groups such as chloro, bromo, ester, cyano, and nitro groups. Mechanistic investigations indicated that the reaction should undergo radical cascades involving a sulfonyl radical generated from sodium sulfinate with air as the terminal oxidant, addition across alkene to deliver a benzylic radical, and subsequent cross-coupling with air.

Health and well-being of maturing adults with classic galactosemia.

Long-term outcomes in classic galactosemia (CG) have been studied previously, but all prior studies have relied on cohorts of patients that were small in number, or heavily skewed toward children and young adults, or both. Here, we extend what is known about the health and well-being of maturing adults with CG by analyzing the results of anonymous custom surveys completed by 92 affected individuals, ages 30-78, and 38 unaffected sibling controls, ages 30-79. The median age for patients was 38.5 years and for controls was 41 years. These study participants hailed from 12 different countries predominantly representing Europe and North America. Participants reported on their general life experiences and outcomes in seven different domains including: speech/voice/language, cognition, motor function, cataracts, bone health, psychosocial well-being, and gastrointestinal health. We also queried women about ovarian function. Our results indicated a prevalence of long-term complications across all outcome domains that aligned with levels previously reported in younger cohorts. Given the sample size and age range of participants in this study, these findings strongly suggest that the adverse developmental outcomes commonly linked to CG are not progressive with age for most patients. We also tested four candidate modifiers for possible association with each of the outcomes followed, including: days of neonatal milk exposure, rigor of dietary galactose restriction in early childhood, current age, and home continent. We observed no associations that reached even nominal significance, except for the following: cataracts with neonatal milk exposure (p = 2.347e-04), cataracts with age (p = 0.018), and bone health with home continent (p = 0.03).

Zr-MOF Carrier-Enhanced Dual-Mode Biosensing Platforms for Rapid and Sensitive Diagnosis of Mpox.

Dual-mode readout platforms with colorimetric and electrochemiluminescence (ECL) signal enhancement are proposed for the ultrasensitive and flexible detection of the monkeypox virus (MPXV) in different scenes. A new nanotag, Ru@U6-Ru/Pt NPs is constructed for dual-mode platforms by integrating double-layered ECL luminophores and the nanozyme using Zr-MOF (UiO-66-NH2) as the carrier, which not only generates enhanced ECL and colorimetric signals but also provide greater stability than that of commonly used nanotags. Dual-mode platforms are used within 15 min from the "sample in" to the "result out" steps, without nucleic acid amplification. The colorimetric mode allows the screening of MPXV with the visual limit of detection (vLOD) of 0.1 pM (6 × 108 copies µL-1) and the ECL mode supports quantitative detection of MPXV with an LOD as low as 10 aM (6 copies·µL-1), resulting in a broad sensing range of 60 to 3 × 1011 copies·µL-1 (10 orders of magnitude). Validation is conducted using 50 clinical samples, which is 100% concordant to those of quantitative polymerase chain reaction (qPCR), indicating that Ru@U6-Ru/Pt NPs-based dual-mode sensing platforms showed great promise as rapid, sensitive, and accurate tools for diagnosis of the nucleic acid of MPXV and other infectious pathogens.

Synergistic delivery of hADSC-Exos and antioxidants has inhibitory effects on UVB-induced skin photoaging.

Ultraviolet B (UVB) light exposure accelerates skin photoaging. Human adipose-derived stem cell exosomes (hADSC-Exos) and some antioxidants may have anti-photoaging effects. However, it is unknown whether the combination of hADSC-Exos and antioxidants plays a synergistic role in anti-photoaging. In cellular and 3D skin models, we showed that vitamin E (VE) and hADSC-Exos were optimal anti-photoaging combinations. In vivo, VE and hADSC-Exos increased skin tightening and elasticity in UVB-induced photoaging mice Combined treatment with VE and hADSC-Exos inhibited SIRT1/NF-κB pathway. These findings contribute to the understanding of hADSC-Exos in conjunction with other antioxidants, thereby providing valuable insights for the future pharmaceutical and cosmetic industries.

The ischemia-enhanced myocardial infarction protection-related lncRNA protects against acute myocardial infarction.

Long non-coding RNA RP11-64B16.4 (myocardial infarction protection-related lncRNA [MIPRL]) is among the most abundant and the most upregulated lncRNAs in ischemic human hearts. However, its role in ischemic heart disease is unknown. We found MIPRL was conserved between human and mouse and its expression was increased in mouse hearts after acute myocardial infarction (AMI) and in cultured human and mouse cardiomyocytes after hypoxia. The infarcted size, cardiac cell apoptosis, cardiac dysfunction, and cardiac fibrosis were aggravated in MIPRL knockout mice after AMI. The above adverse results could be reversed by re-expression of MIPRL via adenovirus expressing MIPRL. Both in vitro and in vivo, we identified that heat shock protein beta-8 (HSPB8) was a target gene of MIPRL, which was involved in MIPRL-mediated anti-apoptotic effects on cardiomyocytes. We further discovered that MIPRL could combine with the messenger RNA (mRNA) of HSPB8 and increase its expression in cardiomyocytes by enhancing the stability of HSPB8 mRNA. In summary, we have found for the first time that the ischemia-enhanced lncRNA MIPRL protects against AMI via its target gene HSPB8. MIPRL might be a novel promising therapeutic target for ischemic heart diseases such as AMI.