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Abstract Strong background interference signals from normal tissues have significantly compromised the sensitive fluorescence imaging of early disease tissues with exogenous probes in vivo, particularly for sensitive fluorescence imaging of early liver disease due to the liver’s significant uptake and accumulation of exogenous nanoprobes, coupled with high tissue autofluorescence and deep tissue depth. As a proof-of-concept study, we herein report a near-infrared-II (NIR-II, 1.0-1.7 μm) light-excited “off-on-off” NIR-II fluorescent probe (NDP). It has near-ideal zero initial probe fluorescence but can turn on its NIR-II fluorescence in liver cancer tissues and then turn off the fluorescence again upon migration from cancer to normal tissues to minimize background interference. Due to its low background, a blind study employing our probes could identify female mice with orthotopic liver tumors with 100% accuracy from mixed subjects of healthy and tumor mice, and implemented sensitive locating of early orthotopic liver tumors with sizes as small as 4 mm. Our NIR-II-excited “off-on-off” probe design concept not only provides a promising molecular design guideline for sensitive imaging of early liver cancer but also could be generalized for sensitive imaging of other early disease lesions.

Abstract Cancer stem cells, characterized by high tumorigenicity and drug-resistance, are often responsible for tumor progression and metastasis. Aldehyde dehydrogenases, often overexpressed in cancer stem cells enriched tumors, present a potential target for specific anti-cancer stem cells treatment. In this study, we report a self-assembled nano-prodrug composed of aldehyde dehydrogenases activatable photosensitizer and disulfide-linked all-trans retinoic acid for diagnosis and targeted treatment of cancer stem cells enriched tumors. The disulfide-linked all-trans retinoic acid can load with photosensitizer and self-assemble into a stable nano-prodrug, which can be disassembled into all-trans retinoic acid and photosensitizer in cancer stem cells by high level of glutathione. As for the released photosensitizer, overexpressed aldehyde dehydrogenase catalyzes the oxidation of aldehydes to carboxyl under cancer stem cells enriched microenvironment, activating the generation of reactive oxygen species and fluorescence emission. This generation of reactive oxygen species leads to direct killing of cancer stem cells and is accompanied by a noticeable fluorescence enhancement for real-time monitoring of the cancer stem cells enriched microenvironment. Moreover, the released all-trans retinoic acid, as a differentiation agent, reduce the cancer stem cells stemness and improve the cancer stem cells enriched microenvironment, offering a synergistic effect for enhanced anti-cancer stem cells treatment of photosensitizer in inhibition of in vivo tumor growth and metastasis.

BackgroundCognitive impairment is a major public health concern in aging societies. This study aimed to investigate the prevalence of cognitive impairment and its associated factors among Chinese adults aged 60 years and older using data from the 2018 China Health and Retirement Longitudinal Study (CHARLS).MethodsUtilizing data from the 2018 wave of CHARLS, we assessed participants’ cognitive status using the Mini-Mental State Examination (MMSE), and the influencing factors related to cognitive impairment were analyzed by using the chi-square test and multifactor logistic regression. The prevalence of cognitive impairment was stratified by gender, education level, residence, marital status, daytime napping, and nighttime sleep duration, and the trend of cognitive impairment prevalence with age was observed.Results9,804 participants were finally included in the study and the overall prevalence of cognitive impairment was 44.04% (95%CI, 43.02–45.06%). The prevalence was significantly higher in females (50.8%) than males (37.1%), and increased with age, from 41.5% in those aged 60–64 years to 57.7% in those aged ≥75 years. Lower educational level, rural residence, and being divorced/ widowed/unmarried were associated with a higher prevalence of cognitive impairment (all p

ObjectiveTo identify the risk factors of postoperative severe hyperkalemia after total parathyroidectomy (TPTX) without auto-transplantation in patients with secondary hyperparathyroidism (SHPT).MethodsData on 406 consecutive patients who underwent TPTX without auto-transplantation for secondary hyperparathyroidism at the General Hospital of Northern Theater Command between January 2013 and January 2023, were prospectively collected. Then, patients were divided into the training set (n=203) and the validation set (n=203) in a ratio of 1:1 by timeline. The patients were divided into severe hyperkalemia group and non-hyperkalemia group according to the postoperative serum kalium level >6.0 mmol/L with ECG changes or serum kalium level ≥6.5 mmol/L. Univariate and multivariate logistic regression analyses were used to evaluate the possible risk factors associated with postoperative severe hyperkalemia after TPTX. The predictive performance was evaluated with receiver operating characteristic (ROC) curves with the areas under the ROC curve (AUC) and calibration curve. Decision curve and clinical impact curve analyses were used to validate the clinical application of the value.ResultsThe incidence of postoperative severe hyperkalemia was 15.5% in all patients, 17.2% and 13.8% in the training and validation cohorts, respectively. The risk factors associated with postoperative severe hyperkalemia was higher preoperative kalium level. The optimal cut-off value for preoperative serum kalium level was 5.0mmol/L according to the ROC curve. The area under the curve (AUC) achieved good concordance indexes of 0.845 (95%CI, 0.776-0.914) in the training cohort. The sensitivities were 0.829 (95%CI: 0.663-0.934) and 0.857 (95%CI: 0.673-0.960) in the training and validation cohorts, respectively. The specificities were 0.798 (95%CI: 0.729-0.856) and 0.720 (95%CI:0.647-0.785) in the training and validation cohorts, respectively. Calibration curve exhibited a good consistency between actual observations and predicted severe hyperkalemia in the training and validation cohorts.ConclusionsOur study found that the preoperative kalium levels is only a risk factor for postoperative severe hyperkalemia in patients undergoing TPTX for secondary hyperparathyroidism. The threshold for preoperative serum kalium levels is 5.0mmol/L that can serve as a useful indicator for identifying patients with severe hyperkalemia after surgery. These results provide valuable suggestion for clinical practice.

The metaverse, a rapidly evolving virtual reality space, holds immense potential to revolutionize nuclear medicine by enhancing education, training, diagnostics, and therapeutics. This review explores the transformative applications of the metaverse in nuclear medicine, where immersive virtual learning environments, simulation-based training, artificial intelligence (AI)-powered decision support systems integrated into interactive three-dimensional (3D) visualizations, and personalized dosimetry using realistic patient-specific virtual models are seamlessly incorporated into the metaverse ecosystem, creating a synergistic platform for healthcare professionals and patients alike. However, the responsible and sustainable adoption of the metaverse in nuclear medicine requires a multidisciplinary approach to address challenges related to standardization, accessibility, data security, and ethical concerns. The formation of cross-disciplinary consortia, increased research and development (R&D) investment, and the strengthening of data governance and cybersecurity measures are crucial steps in ensuring the safe and effective integration of the metaverse in healthcare. As the metaverse continues to evolve, researchers, practitioners, and policymakers must collaborate and explore its potential, navigate the challenges, and shape a future where technology and medicine seamlessly integrate to enhance patient care and outcomes in nuclear medicine. Further research is needed to fully understand the implications of the metaverse in clinical practice, education, and research, as well as to develop evidence-based guidelines for its responsible implementation. By embracing responsible innovation and collaboration, the nuclear medicine community can harness the power of the metaverse to transform and improve patient care.

Ionizing radiation is a significant risk factor for cataracts, but the pathogenesis of radiation-induced cataracts remains incompletely understood. Ferroptosis, an iron-dependent form of programmed cell death discovered in recent years, has gained increasing attention for its role in various diseases. This article systematically reviews research progress on ionizing radiation, ferroptosis, age-related cataracts, and radiation-induced cataracts. It proposes the “ferroptosis hypothesis” for the pathogenesis of radiation-induced cataracts. Through ionization and oxidative stress effects, ionizing radiation leads to elevated free iron levels and exacerbated lipid peroxidation in lens cells, activating the ferroptosis pathway and resulting in lens opacity. The involvement of ferroptosis in the development of age-related cataracts suggests that it may also be an important pathogenic mechanism of radiation-induced cataracts. Targeting the ferroptosis pathway may be a novel strategy for preventing and treating radiation-induced cataracts. Furthermore, developing new ferroptosis-specific inhibitors with improved targeting and pharmacokinetic properties is also an essential direction for research on preventing and treating radiation-induced cataracts. The study of ferroptosis provides new insights into the mechanism and management of radiation-induced cataracts, potentially transforming radiation-induced cataracts from “inevitable” to “preventable and treatable.”

Abstract Photodynamic therapy (PDT) is a promising cancer treatment but has limitations due to its dependence on oxygen and high-power-density photoexcitation. Here, we report polymer-based organic photosensitizers (PSs) through rational PS skeleton design and precise side-chain engineering to generate •O2 − and •OH under oxygen-free conditions using ultralow-power 808 nm photoexcitation for tumor-specific photodynamic ablation. The designed organic PS skeletons can generate electron-hole pairs to sensitize H2O into •O2 − and •OH under oxygen-free conditions with 808 nm photoexcitation, achieving NIR-photoexcited and oxygen-independent •O2 − and •OH production. Further, compared with commonly used alkyl side chains, glycol oligomer as the PS side chain mitigates electron-hole recombination and offers more H2O molecules around the electron-hole pairs generated from the hydrophobic PS skeletons, which can yield 4-fold stronger •O2 − and •OH production, thus allowing an ultralow-power photoexcitation to yield high PDT effect. Finally, the feasibility of developing activatable PSs for tumor-specific photodynamic therapy in female mice is further demonstrated under 808 nm irradiation with an ultralow-power of 15 mW cm−2. The study not only provides further insights into the PDT mechanism but also offers a general design guideline to develop an oxygen-independent organic PS using ultralow-power NIR photoexcitation for tumor-specific PDT.

Abstract Background Primary hepatocellular carcinoma (HCC) is a malignancy with high morbidity and mortality. KH domain-containing, RNA-binding signal transduction-associated protein 3 (KHDRBS3) is an RNA-binding protein that is aberrantly expressed in multiple tumors; however, its expression and biological function in HCC have not been reported. Methods KHDRBS3 knockdown and overexpression were performed using the lentiviral vector system to investigate the effects of KHDRBS3 on cell proliferation, apoptosis, chemoresistance, and glycolysis. Murine xenograft tumor models were constructed to study the role of KHDRBS3 on tumor growth in vivo. Furthermore, RNA-Pull Down and RNA immunoprecipitation were utilized to explore the interaction between KHDRBS3 and 14-3-3ζ, a phosphopeptide-binding molecule encoded by YWHAZ. Results KHDRBS3 was highly expressed in human HCC tissues and predicted the poor prognosis of patients with HCC. Knockdown of KHDRBS3 exhibited a carcinostatic effect in HCC and impeded proliferation and tumor growth, reduced glycolysis, enhanced cell sensitivity to doxorubicin, and induced apoptosis. On the contrary, forced expression of KHDRBS3 expedited the malignant biological behaviors of HCC cells. The expression of KHDRBS3 was positively correlated with the expression of 14-3-3ζ. RNA immunoprecipitation and RNA pull-down assays demonstrated that KHDRBS3 bound to YWHAZ. We further confirmed that 14-3-3ζ silencing significantly reversed the promotion of proliferation and glycolysis and the inhibition of apoptosis caused by KHDRBS3 overexpression. Conclusions Our findings suggest that KHDRBS3 promotes glycolysis and malignant progression of HCC through upregulating 14-3-3ζ expression, providing a possible target for HCC therapy.

BackgroundImmunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is frequently accompanied with type 1 autoimmune pancreatitis (AIP). Isolated IgG4-SC which is not accompanied with AIP is uncommon in clinical practice, and its manifestations are similar to those of hilar cholangiocarcinoma.Case presentationA 55-year-old male presented with persistent aggravation of icteric sclera and skin. He was initially diagnosed with hilar cholangiocarcinoma and underwent surgery. However, positive IgG4 plasma cells were found in the surgical specimens. Thus, a pathological diagnosis of IgG4-SC was established. After that, steroid therapy was given and initially effective. But he was steroid dependent, and then received rituximab therapy twice. Unfortunately, the response to rituximab therapy was poor.ConclusionIt is crucial to differentiate isolated IgG4-SC from hilar cholangiocarcinoma to avoid unnecessary surgery. Future studies should further explore effective treatment strategy in patients who do not respond to steroids therapy. It is also required to develop novel and accurate diagnostic approaches to avoid unnecessary surgical procedures.

BackgroundThe metaverse, as a new digital interactive platform, is garnering significant attention and exploration across industries due to technological advancements and societal digital transformation. In occupational health, there is immense potential for leveraging the metaverse to enhance work environments and occupational health management. It offers companies more efficient and intelligent solutions for occupational health management while providing employees with safer and more comfortable work environments.MethodsA comprehensive literature search was conducted using PubMed, Web of Science, IEEE Xplore, and Google Scholar databases to identify relevant studies published between January 2015 and March 2024. The search terms included “metaverse,” “virtual reality,” “occupational health,” “workplace safety,” “job training,” and “telemedicine.” The selected articles were analyzed, and key findings were summarized narratively.ResultsThe review summarizes the broad application prospects of metaverse technology in immersive training, occupational risk identification and assessment, and occupational disease monitoring and diagnosis. However, applying the metaverse in occupational health also faces challenges such as inadequate technical standards, data privacy issues, human health hazards, high costs, personnel training, and lagging regulations.ConclusionMetaverse offers new possibilities for addressing the numerous challenges faced in occupational health and has broad application prospects. In the future, collaborative efforts from multiple stakeholders will be necessary to promote the sustainable development of metaverse technology in occupational health and better protect workers’ occupational health.

Abstract Objective Postoperative pancreatic fistula (POPF) following distal pancreatectomy (DP) is a serious complication. In the present study, we aimed to identify the risk factors associated with clinically relevant postoperative pancreatic fistula (CR-POPF) and establish a nomogram model for predicting CR-POPF after DP. Methods In total, 115 patients who underwent DP at the General Hospital of Northern Theater Command between January 2005 and December 2020 were retrospectively studied. Univariate and multivariable logistic regression analyses were used to identify the independent risk factors associated with CR-POPF. Then, a nomogram was formulated based on the results of multivariable logistic regression analysis. The predictive performance was evaluated with receiver operating characteristic (ROC) curves. Decision curve and clinical impact curve analyses were used to validate the clinical application value of the model. Results The incidence of CR-POPF was 33.0% (38/115) in the present study. Multivariate logistic regression analysis identified the following variables as independent risk factors for POPF: body mass index (BMI) (OR 4.658, P = 0.004), preoperative albumin level (OR 7.934, P = 0.001), pancreatic thickness (OR 1.256, P = 0.003) and pancreatic texture (OR 3.143, P = 0.021). We created a nomogram by incorporating the above mentioned risk factors. The nomogram model showed better predictive value, with a concordance index of 0.842, sensitivity of 0.710, and specificity of 0.870 when compared to each risk factor. Decision curve and clinical impact curve analyses also indicated that the nomogram conferred a high clinical net benefit. Conclusion Our nomogram could accurately and objectively predict the risk of postoperative CR-POPF in individuals who underwent DP, which could help clinicians with early identification of patients who might develop CR-POPF and early development of a suitable fistula mitigation strategy and postoperative management.

BackgroundSurgical parathyroidectomy (PTX) is necessary for patients with severe and progressive secondary hyperparathyroidism (SHPT) refractory to medical treatment. Recurrence of SHPT after PTX is a serious clinical problem. Both supernumerary mediastinal parathyroid gland and parathyromatosis are the rare causes of recurrent renal SHPT. We report a rare case of recurrent renal SHPT due to supernumerary mediastinal parathyroid gland and parathyromatosis.Case presentationA 53-year-old man underwent total parathyroidectomy with autotransplantation due to the drug-refractory SHPT 17 years ago. In the last 11 months, the patient experienced symptoms including bone pain and skin itch, and the serum intact parathyroid hormone (iPTH) level elevated to 1,587 pg/ml. Ultrasound detected two hypoechoic lesions located at the dorsal area of right lobe of the thyroid gland, and both lesions presented as characteristics of hyperparathyroidism in contrast-enhanced ultrasound. 99mTc-MIBI/SPECT detected a nodule in the mediastinum. A reoperation involved a cervicotomy for excising parathyromatosis lesions and the surrounding tissue and a thoracoscopic surgery for resecting a mediastinal parathyroid gland. According to a histological examination, two lesions behind the right thyroid lobe and one lesion in the central region had been defined as parathyromatosis. A nodule in the mediastinum was consistent with hyperplastic parathyroid. The patient remained well for 10 months with alleviated symptoms and stabilized iPTH levels in the range of 123–201 pg/ml.ConclusionAlthough rare, recurrent SHPT may be caused by a coexistence of both supernumerary parathyroid glands and parathyromatosis, which should receive more attention. The combination of imaging modalities is important for reoperative locations of parathyroid lesions. To successfully treat parathyromatosis, all the lesions and the surrounding tissue must be excised. Thoracoscopic surgery is a reliable and safe approach for the resection of ectopic mediastinal parathyroid glands.

Abstract Second near‐infrared (NIR‐II, 1000–1700 nm) window fluorescence imaging‐guided photothermal therapy probes are promising for precise cancer phototheranostics. However, most of the currently reported probes do not demonstrate high NIR‐II fluorescent brightness (molar absorption coefficient (ε) × quantum yield (QY)) and photothermal performance (ε × photothermal conversion efficiency (PCE)) in a single molecule. Herein, a versatile strategy to solve this challenge is reported by fabricating a large π‐conjugated molecule (BNDI‐Me) with a rigid molecular skeleton and flexible side groups. The proposed BNDI‐Me nanoprobe boosts the ε and simultaneously optimizes its QY and PCE. Therefore, high NIR‐II fluorescent brightness (ε × QY = 2296 m−1 cm−1) and strong photothermal performance (ε × PCE = 82 000) are successfully incorporated in a single small molecule, and, to the best of knowledge, either of these two parameters is better than the best currently available fluorescent or photothermal probes. Thus, superior NIR‐II imaging effect in vivo and high photothermal tumor inhibition rate (81.2%) at low systemic injection doses are obtained. The work provides further insights into the relationship of photophysical mechanisms and structures, and presents promising molecular design guidelines for the integration of more efficient multiple theranostic functions in a single molecule.

Objective. Our study aimed to develop and validate a nomogram to predict severe hypocalcemia (SH) before total parathyroidectomy (TPTX) without auto-transplantation in patients with secondary hyperparathyroidism. Methods. A total of 299 consecutive patients who underwent TPTX without transplantation for secondary hyperparathyroidism were selected from the General Hospital of Northern Theater Command between January 2013 and December 2021. Of these, patients who underwent surgery between January 2013 and December 2020 formed the training cohort (n = 208) to develop a nomogram, and those who underwent surgery thereafter formed the validation cohort (n = 91) to validate the performance of this nomogram. Univariate and multivariate logistic regression analyses were used to identify the risk factors associated with SH, and then, a nomogram was constructed. Results. The incidence of postoperative SH was 27.9% and 35.2% in the training and validation cohorts, respectively. The preoperative factors associated with SH were younger age, lower serum calcium (Ca) level, higher intact parathyroid hormone (iPTH) level, and higher serum alkaline phosphatase (ALP) level. Incorporating these 4 factors, the nomogram achieved good concordance indexes of 0.866 (95%CI, 0.816–0.916) and 0.867 (95% CI, 0.793–0.941) in predicting SH in the training and validation cohorts, respectively, and had well-fitted calibration curves. The positive predictive values of the nomogram were 64.7% (54.1%–78.4%) and 75.0% (58.6%–88.5%), and negative predictive values of the nomogram were 90.0% (82.9%–93.6%) and 86.4% (73.5%–94.0%) for the training and validation cohorts, respectively. Conclusions. We developed and validated a nomogram for the prediction of SH in patients who underwent TPTX without auto-transplantation for secondary hyperparathyroidism. Our nomogram may facilitate the identification of high-risk SH in patients after TPTX and optimization of preoperative decision-making.

Background: Coronavirus disease 2019 (COVID-19) has triggered a global public health crisis. Proton pump inhibitors (PPIs) are one of the most commonly prescribed drugs. However, the effect of PPIs on the clinical outcomes of COVID-19 patients remains unclear. Methods: All COVID-19 patients admitted to the Wuhan Huoshenshan Hospital from February 2020 to April 2020 were retrospectively collected. Patients were divided into PPIs and non-PPIs groups. Logistic regression analyses were performed to explore the effects of PPIs on the outcomes of COVID-19 patients, including transfer to intensive care unit, mechanical ventilation, and death. Subgroup analyses were performed according to the presence of upper gastrointestinal symptoms potentially associated with acid and the routes, types, median total dosage, and duration of PPIs. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: Of the 3024 COVID-19 patients included, 694 and 2330 were in PPIs and non-PPIs groups, respectively. Univariate logistic regression analysis showed that PPIs significantly increased the risk of reaching the composite endpoint in COVID-19 patients (OR = 10.23, 95% CI = 6.90–15.16, p

Abstract Nanotheranostics aims to utilize nanomaterials to prevent, diagnose, and treat diseases to improve the quality of patients’ lives. Blood vessels are responsible to deliver nutrients and oxygen to the whole body, eliminate waste, and provide access for patrolling immune cells for healthy tissues. Meanwhile, they can also nourish disease tissues, spread disease factors or cells into other healthy tissues, and deliver nanotheranostic agents to cover all the regions of a disease tissue. Thus, blood vessels are the first and the most important barrier for highly efficient nanotheranostics. Here, the structure and function of blood vessels are explored and how these characteristics affect nanotheranostics is discussed. Moreover, new mechanisms and related strategies about overcoming vascular obstacles for improved nanotheranostic outcomes are critically summarized, and their merits and demerits of each strategy are analyzed. Moreover, the present challenges to completely exhibit the potential of overcoming vascular barriers to improve the theranostic outcomes of nanomedicines in life science are also discussed. Finally, the future perspective is further discussed.

Background: Liver cirrhosis is a major global health burden worldwide due to its high risk of morbidity and mortality. Role of terlipressin for the management of liver cirrhosis–related complications has been recognized during recent years. This article aims to develop evidence-based clinical practice guidance on the use of terlipressin for liver cirrhosis–related complications. Methods: Hepatobiliary Study Group of the Chinese Society of Gastroenterology of the Chinese Medical Association and Hepatology Committee of the Chinese Research Hospital Association have invited gastroenterologists, hepatologists, infectious disease specialists, surgeons, and clinical pharmacists to formulate the clinical practice guidance based on comprehensive literature review and experts’ clinical experiences. Results: Overall, 10 major guidance statements regarding efficacy and safety of terlipressin in liver cirrhosis were proposed. Terlipressin can be beneficial for the management of cirrhotic patients with acute variceal bleeding and hepatorenal syndrome (HRS). However, the evidence regarding the use of terlipressin in cirrhotic patients with ascites, post-paracentesis circulatory dysfunction, and bacterial infections and in those undergoing hepatic resection and liver transplantation remains insufficient. Terlipressin-related adverse events, mainly including gastrointestinal symptoms, electrolyte disturbance, and cardiovascular and respiratory adverse events, should be closely monitored. Conclusion: The current clinical practice guidance supports the use of terlipressin for gastroesophageal variceal bleeding and HRS in liver cirrhosis. High-quality studies are needed to further clarify its potential effects in other liver cirrhosis–related complications.

Background: Patients with coronavirus disease 2019 (COVID-19) can present with gastrointestinal (GI) symptoms. However, the prevalence of GI symptoms and their association with outcomes remain controversial in COVID-19 patients.Methods: All COVID-19 patients consecutively admitted to the Wuhan Huoshenshan hospital from February 2020 to April 2020 were collected. Disease severity and outcomes were compared between COVID-19 patients with and without GI symptoms. Logistic regression analyses were performed to evaluate the association of GI symptoms with the composite endpoint and death in COVID-19 patients. A composite endpoint was defined as transfer to intensive care unit, requirement of mechanical ventilation, and death. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.Results: Overall, 2,552 COVID-19 patients were included. The prevalence of GI symptoms was 21.0% (537/2,552). Diarrhea (8.9%, 226/2,552) was the most common GI symptom. Patients with GI symptoms had significantly higher proportions of severe COVID-19 and worse outcomes than those without. Univariate logistic regression analyses demonstrated that GI symptoms were significantly associated with the composite endpoint (OR = 2.426, 95% CI = 1.608–3.661; P < 0.001) and death (OR = 2.137, 95% CI = 1.209–3.778; P = 0.009). After adjusting for age, sex, and severe/critical COVID-19, GI symptoms were still independently associated with the composite endpoint (OR = 2.029, 95% CI = 1.294–3.182; P = 0.002), but not death (OR = 1.726, 95% CI = 0.946–3.150; P = 0.075). According to the type of GI symptoms, GI bleeding was an independent predictor of the composite endpoint (OR = 8.416, 95% CI = 3.465–20.438, P < 0.001) and death (OR = 6.640, 95% CI = 2.567–17.179, P < 0.001), but not other GI symptoms (i.e., diarrhea, abdominal discomfort, nausea and/or vomiting, constipation, acid reflux and/or heartburn, or abdominal pain).Conclusion: GI symptoms are common in COVID-19 patients and may be associated with their worse outcomes. Notably, such a negative impact of GI symptoms on the outcomes should be attributed to GI bleeding.

Rheumatoid arthritis (RA) is one of the most prevalent inflammatory joint disorders. Early diagnosis, accurate staging, and imaging guided treatment response of RA remain crucial clinical significances for improving treatment outcomes. In this study, we introduced endogenous melanin nanoparticles (MNPs) conjugated with Cyclic Arg-Gly-Asp (RGD) peptide (MNP-PEG-RGD) as a contrast agent for accurate photoacoustic imaging (PAI) of RA diagnosis. It was observed that the prepared nanoprobes had favorable PA sensitivity, photostability and biocompatibility. In vivo studies using RA mouse model revealed that this nanoprobe could target αvβ3 actively at 1 h post-injection, while the signal was remarkably increased in the arthritic joint which could earlier diagnose RA than conventional imaging system. It was of crucial importance to staging RA by PAI with significant difference in nanoprobes accumulation. Furthermore, we tracked the therapeutic efficacy of etanercept in RA treatment by PAI. The observed advancement of arthritis on the PAI was confirmed by histological and immunohistochemical analysis. In conclusion, this study shed light on the development of innovative multifunctional theranostic nanoplatform for both RA monitoring and treatment with a promising future in clinical translation.

Abstract 14‐3‐3ζ, a phosphopeptide‐binding molecule, is reportedly overexpressed in the cancerous tissues of patients with hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) protein X (HBx) draws intensive attention in HBV‐related HCC because it not only regulates HBV replication, but also promotes carcinogenesis by interacting with various tumor or antitumor molecules. This study is performed to investigate whether and how 14‐3‐3ζ interacts with HBx. The coimmunoprecipitation (Co‐IP) results showed that 14‐3‐3ζ bond to HBx in HBV‐infected Hep3B HCC cells and CSQT‐2 portal vein tumor thrombosis (PVTT) cells. By performing Co‐IP assay in HBV‐free Huh7 cells expressing wild‐type HBx, mutant HBx‐S31A, or HBx‐S31D (serine31 was mutated into alanine31 or aspartic acid31), we found that the phosphorylated serine31 with its near amino acid residues constituted a RPLphosphoS31GP (R, arginine; P, proline; L, leucine; S, serine; G, glycine) motif in HBx for 14‐3‐3ζ docking. This 14‐3‐3ζ‐HBx interaction was partly impaired when Akt signaling transduction was blocked by LY294002. Furthermore, 14‐3‐3ζ silencing augmented HBx ubiquitination and decreased its expression in cancer cells and xenograft tumor. The migratory and invasive abilities of CSQT‐2 cells were inhibited upon 14‐3‐3ζ silencing, whereas partly restored by HBx overexpression. Additionally, 14‐3‐3ζ positively correlated with HBx to be overexpressed in the primary HCC tissues (r = 0.344) and metastatic PVTT (r = 0.348). In summary, findings of this study reveal a novel 14‐3‐3ζ‐HBx interaction in HCC cells and suggest 14‐3‐3ζ as a candidate target for treating HBV‐related HCC.

Background/Aims: Gluconeogenesis, a reverse process of glycolysis, is suppressed in neoplastic livers. Cytoplasmic phosphoenolpyruvate carboxykinase (PEPCK-C/PCK1, encoded by PCK1) is a step limiting enzyme of gluconeogenesis. The induced expression of the factor is reported to initiate gluconeogenesis process and antagonize hepatocellular carcinoma (HCC). In the current study, the effect of the modulation of PCK1 expression on HCC was assessed. Methods: The levels of PCK1 in clinical HCC tissues and different HCC cell lines were investigated with real time quantitative PCR, immunochemistry, and western blotting. Thereafter, the expression of PCK1 gene was induced in two HCC cell lines and the effect of the overexpression on proliferation and migration potentials of HCC cells was detected with CCK-8 assay, flow cytometry, TUNEL staining, and transwell assay. The activities of glycolysis and gluconeogenesis pathways in PCK1-overexpressed HCC cell lines were detected with specific kits to underlie the mechanism by which PCK1 exerted its function. The results of the in vitro experiments were validated with HCC xenograft rat models. Results: The expression levels of PCK1 were suppressed in HCC samples and in cells derived from HCC tissues. According to the results of the in vitro assays, the overexpression of PCK1 decreased viability, induced apoptosis, and inhibited migration in both HCC cell lines. The effect was associated with the suppressed glycolysis and the induced gluconeogenesis pathways, represented by the enhanced production of glucose and the limited production of pyruvic acid, lactate, citrate, and malate. The results of the in vitro assays were confirmed in rat models in that the growth rate of solid HCC tumors was reduced in mice transplanted with PCK1-overexpressed HCC cells. Conclusion: Findings outlined in the current study demonstrated that activating gluconeogenesis process via PCK1 overexpression was a potential treating strategy against HCC.

Background/Aims: 14-3-3ζ is involved in the regulation of PI3K/Akt pathway which is closely associated with carcinogenesis. However, the clinical significance of combined detection of 14-3-3ζ and p-Akt in hepatocellular carcinoma (HCC) remains unclear. Methods: Two-hundred pairs of HCC and adjacent liver specimens were subjected to tissue microarray. The association of 14-3-3ζ and p-Akt levels with the postoperative survival and recurrence in HCC patients was analyzed with univariate and multivariate methods. Moreover, the effects of 14-3-3ζ overexpression on the growth of HCC and the expressions of p-Akt and HIF-1α were assessed in a xenograft mouse model. Results: Elevated levels of 14-3-3ζ and p-Akt were detected in HCC and a positive correlation between the levels of 14-3-3ζ and p-Akt was verified. HCC patients with satellite nodules, microvascular invasion, portal vein tumor thrombosis, poor tumor differentiation and an advanced tumor stage tended to have higher levels of 14-3-3ζ and p-Akt. In addition, the postoperative 3-, 5-, and 7-year overall survival rates in HCC patients with 14-3-3ζhigh and p-Akthigh were significantly lower compared with those with 14-3-3ζlow and p-Aktlow, and the cumulative recurrence rate in HCC patients with 14-3-3ζhigh and p-Akthigh was significantly higher than that in those with 14-3-3ζlow and p-Aktlow. The multivariate Cox proportional hazard analysis indicated that concomitant upregulation of 14-3-3ζ and p-Akt was an independent factor that predicted poor survival and high recurrence in HCC patients. Furthermore, animal experiment showed that overexpression of 14-3-3ζ accelerated the growth of HCC xenograft tumors and induced the expressions of p-Akt and HIF-1α in vivo. Conclusion: Co-upregulation of 14-3-3ζ and p-Akt predicts poor prognosis in patients with HCC, and 14-3-3ζ-induced activation of the Akt signaling pathway contributes to HCC progression.

Background: To improve the early diagnosis of hepatocellular carcinoma (HCC), more effective diagnostic biomarkers are needed. A combination of biomarkers is reported to distinguish individuals with early-stage HCC from at-risk individuals. Methods: Participants in this study were recruited from six hospitals in China. Literature review was used to choose 19 candidate proteins, a case-control study in the discovery stage was used to identify five proteins (P5) that constituted a diagnostic model. In the training and validation stages, the effectiveness of P5 for detecting early-stage HCC was tested (cross-sectional study). Finally, a nested case-control study independent of the other stages was set up to evaluate the P5 in the preclinical diagnosis of HCC. Findings: Between February 2013 and June 2017, a total of 1396 participants were recruited. A panel of 5 proteins (P5: OPN, GDF15, NSE, TRAP5 and OPG) showed high diagnostic accuracy when differentiating the early-stage HCC from the at-risk group, with AUCs of 0·892, 0·907 and 0·852 for the training stage, validation cohort 1 and cohort 2 data sets, respectively. In the prediction set, the sensitivity of P5 for diagnosing preclinical HCC increased with time, starting from 12 months before to the time of definitive clinical diagnosis (range, 46·15% to 86·67%). Interpretation: The P5 panel has the potential to screen populations at high risk of developing HCC and can enable the early diagnosis of HCC. Funding: Research supported by grants from eight funds. All sources of funding were declared at the end of the text. Keywords: Peripheral blood, Multi-tumor markers, Earlier detection, Liver cancer, Multi-center study

14-3-3β has been demonstrated to possess the oncogenic potential, and its increased expression has been detected in multiple types of carcinomas. However, majority of previous studies focused on the role of 14-3-3β in tumor cell proliferation and apoptosis, leaving much to be elucidated about its function in tumor cell invasion and metastasis. Hence, the present study aimed to investigate the role of 14-3-3β in the invasion of hepatocellular carcinoma (HCC) cells and the implications in the prognosis of HCC patients. We first examined the expression of 14-3-3β in the primary tumors of HCC patients with or without portal vein tumor thrombus (PVTT), and found that 14-3-3β expression was higher in the primary tumors with PVTT, and the level was even higher in the PVTTs. Kaplan-Meier curves and multivariate analysis revealed that high expression of 14-3-3β was associated with overall survival (OS) and time to recurrence (TTR) of HCC patients. In addition, ectopic expression of 14-3-3β in HCC cell lines led to enhanced migration ability and invasiveness, as well as up-regulation of matrix metalloproteinase 2 and 9, which could be suppressed by inhibiting the activation of Akt and nuclear factor-κB (NF-κB) signaling. Furthermore, we identified a correlated elevation of 14-3-3β and p-Akt in the primary tumors of HCC patients, and showed that a combinatory detection of 14-3-3β and p-Akt could better predict post-surgical outcome of HCC patients.

Chronic obstructive pulmonary disease (COPD) has seriously impacted the health of individuals and populations. In this study, proton nuclear magnetic resonance ((1)H NMR)-based metabonomics combined with multivariate pattern recognition analysis was applied to investigate the metabolic signatures of patients with COPD. Serum and urine samples were collected from COPD patients (n = 32) and healthy controls (n = 21), respectively. Samples were analyzed by high resolution (1)H NMR (600 MHz), and the obtained spectral profiles were then subjected to multivariate data analysis. Consistent metabolic differences have been found in serum as well as in urine samples from COPD patients and healthy controls. Compared to healthy controls, COPD patients displayed decreased lipoprotein and amino acids, including branched-chain amino acids (BCAAs), and increased glycerolphosphocholine in serum. Moreover, metabolic differences in urine were more significant than in serum. Decreased urinary 1-methylnicotinamide, creatinine and lactate have been discovered in COPD patients in comparison with healthy controls. Conversely, acetate, ketone bodies, carnosine, m-hydroxyphenylacetate, phenylacetyglycine, pyruvate and α-ketoglutarate exhibited enhanced expression levels in COPD patients relative to healthy subjects. Our results illustrate the potential application of NMR-based metabonomics in early diagnosis and understanding the mechanisms of COPD.