Cross-correlation effects in the solution NMR spectra of near-equivalent spin-1/2 pairs.

The nuclear magnetic resonance (NMR) spectra of spin-1/2 pairs contain four peaks, with two inner peaks much stronger than the outer peaks in the near-equivalence regime. We have observed that the strong inner peaks have significantly different linewidths when measurements were performed on a 13C2-labelled triyne derivative. This linewidth difference may be attributed to strong cross-correlation effects. We develop the theory of cross-correlated relaxation in the case of near-equivalent homonuclear spin-1/2 pairs, in the case of a molecule exhibiting strongly anisotropic rotational diffusion. Good agreement is found with the experimental NMR lineshapes.

Development of a prognostic score for recommended TACE candidates with hepatocellular carcinoma: A multicentre observational study.

BACKGROUND & AIMS: Previous prognostic scores for transarterial chemoembolization (TACE) were mainly derived from real-world settings, which are beyond guideline recommendations. A robust model for outcome prediction and risk stratification of recommended TACE candidates is lacking. We aimed to develop an easy-to-use tool specifically for these patients. METHODS: Between January 2010 and May 2016, 1,604 treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh A5-B7 and performance status 0 undergoing TACE were included from 24 tertiary centres. Patients were randomly divided into training (n = 807) and validation (n = 797) cohorts. A prognostic model was developed and subsequently validated. Predictive performance and discrimination were further evaluated and compared with other prognostic models. RESULTS: The final presentation of the model was "linear predictor = largest tumour diameter (cm) + tumour number", which consistently outperformed other currently available models in both training and validation datasets as well as in different subgroups. The thirtieth percentile and the third quartile of the linear predictor, namely 6 and 12, were further selected as cut-off values, leading to the "six-and-twelve" score which could divide patients into 3 strata with the sum of tumour size and number ≤6, >6 but ≤12, and >12 presenting significantly different median survival of 49.1 (95% CI 43.7-59.4) months, 32.0 (95% CI 29.9-37.5) months, and 15.8 (95% CI 14.1-17.7) months, respectively. CONCLUSIONS: The six-and-twelve score may prove an easy-to-use tool to stratify recommended TACE candidates (Barcelona Clinic Liver Cancer stage-A/B) and predict individual survival with favourable performance and discrimination. Moreover, the score could stratify these patients in clinical practice as well as help design clinical trials with comparable criteria involving these patients. Further external validation of the score is required. LAY SUMMARY: There is currently no prognostic model specifically developed for recommended or ideal transarterial chemoembolization (TACE) candidates with hepatocellular carcinoma, despite these patients being frequently identified as the best target population in pivotal randomized controlled trials. The six-and-twelve score provides patient survival prediction, especially in ideal candidates of TACE, outperforming other currently available models in both training and validation sets, as well as different subgroups. With cut-off values of 6 and 12, the score can stratify ideal TACE candidates into 3 strata with significantly different outcomes and may shed light on risk stratification of these patients in clinical practice as well as in clinical trials.

N-myc downstream-regulated gene 4, up-regulated by tumor necrosis factor-α and nuclear factor kappa B, aggravates cardiac ischemia/reperfusion injury by inhibiting reperfusion injury salvage kinase pathway.

N-myc downstream-regulated gene 4 (NDRG4) is expressed weakly in heart and has been reported to modulate cardiac development and QT interval duration, but the role of NDRG4 in myocardial ischemia/reperfusion (I/R) injury remains unknown. In the present study, we analyzed the expression as well as potential function of cardiac NDRG4 and investigated how NDRG4 expression is regulated by inflammation. We found that NDRG4 was weakly expressed in cardiomyocytes and that its expression increased significantly both in I/R injured heart and in hypoxia-reoxygenation (H/R) injured neonatal rat ventricular myocytes (NRVMs). The increased NDRG4 expression aggravated myocardial I/R injury by inhibiting the activation of the reperfusion injury salvage kinase (RISK) pathway. Forced over-expression of NDRG4 inhibited RISK activation and exacerbated injury not only in I/R injured heart, but also in H/R treated NRVMs, whereas short hairpin RNA (shRNA)-mediated knock-down of NDRG4 enhanced RISK activation and attenuated injury. Upon injury, myocardial NDRG4 expression was induced by tumor necrosis factor-α (TNF-α) through nuclear factor kappa B (NF-κB), and we found that pre-treatment with inhibitors of either TNF-α or NF-κB blocked NDRG4 expression as well as I/R injury in vivo and H/R injury in vitro. Our study indicates that up-regulation of NDRG4 aggravates myocardial I/R injury by inhibiting activation of the RISK pathway, thereby identifying NDRG4 as a potential therapeutic target in I/R injury.

Danlou tablet alleviates sepsis-induced acute lung and kidney injury by inhibiting the PARP1/HMGB1 pathway.

Background: Sepsis-associated acute lung injury (ALI) and acute kidney injury (AKI) are common complications that significantly impact patient prognosis. Danlou tablet (DLT) is a traditional herbal preparation with anti-inflammatory and antioxidant properties. However, its therapeutic potential in sepsis remains unknown. Methods: The impact of DLT on ALI and AKI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of DLT on macrophages were observed through LPS-stimulated RAW264.7 cell line. Inflammatory cytokines, oxidative stress indicators, HE, PAS, and DHE staining, lung wet-to-dry weight ratio, and serum creatinine and urea nitrogen levels were used to assess tissue injury. Network pharmacology, molecular docking, and molecular dynamics simulations were used to explore the potential regulatory mechanisms of DLT in sepsis. Western blot and immunohistochemical staining were used to validate the expression of mechanism-related proteins. Results: DLT inhibited the inflammatory response and oxidative stress, improved structural and functional abnormalities in lung and kidney tissues in CLP mice, and alleviated pro-inflammatory responses of LPS-stimulated macrophages. PARP1 and HMGB1 were identified as key regulatory targets. The results of in vitro and in vivo experiments suggest that DLT can effectively inhibit PARP1/HMGB1 and improve sepsis-associated ALI and AKI. Conclusion: The present study demonstrated that DLT suppressed pro-inflammatory responses of macrophage and alleviated ALI and AKI in the CLP mice by inhibiting the transition activation of PARP1/HMGB1. These findings partially elucidate the mechanism of DLT in sepsis-associated ALI and AKI and further clarify the active components of DLT, thereby providing a scientific theoretical basis for treating sepsis with DLT.

QiShenYiQi pills preserve endothelial barrier integrity to mitigate sepsis-induced acute lung injury by inhibiting ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: The QiShengYiQi pill (QSYQ) is a traditional Chinese medicinal formulation. The effectiveness and safety of QSYQ in treating respiratory system disorders have been confirmed. Its pharmacological actions include anti-inflammation, antioxidative stress, and improving energy metabolism. However, the mechanism of QSYQ in treating sepsis-induced acute lung injury (si-ALI) remains unclear. AIM OF THE STUDY: Si-ALI presents a clinical challenge with high incidence and mortality rates. This study aims to confirm the efficacy of QSYQ in si-ALI and to explore the potential mechanisms, providing a scientific foundation for its application and insights for optimizing treatment strategies and identifying potential active components. MATERIALS AND METHODS: The impact of QSYQ on si-ALI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of QSYQ on endothelial cells were observed through coculturing with LPS-stimulated macrophage-conditioned medium. Inflammatory cytokine levels, HE staining, Evans blue staining, lung wet/dry ratio, and cell count and protein content in bronchoalveolar lavage fluid were used to assess the degree of lung injury. Network pharmacology was utilized to investigate the potential mechanisms of QSYQ in treating si-ALI. Western blot and immunofluorescence analyses were used to evaluate barrier integrity and validate mechanistically relevant proteins. RESULTS: QSYQ reduced the inflammation and alleviated pulmonary vascular barrier damage in CLP mice (all P < 0.05). A total of 127 potential targets through which QSYQ regulates si-ALI were identified, predominantly enriched in the RAGE pathway. The results of protein-protein interaction analysis suggest that COX2, a well-established critical marker of ferroptosis, is among the key targets. In vitro and in vivo studies demonstrated that QSYQ mitigated ferroptosis and vascular barrier damage in sepsis (all P < 0.05), accompanied by a reduction in oxidative stress and the inhibition of the COX2 and RAGE (all P < 0.05). CONCLUSIONS: This study demonstrated that QSYQ maintains pulmonary vascular barrier integrity by inhibiting ferroptosis in CLP mice. These findings partially elucidate the mechanism of QSYQ in si-ALI and further clarify the active components of QSYQ, thereby providing a scientific theoretical basis for treating si-ALI with QSYQ.

Targeting macrophagic RasGRP1 with catechin hydrate ameliorates sepsis-induced multiorgan dysfunction.

BACKGROUND: The proinflammatory response induced by macrophages plays a crucial role in the development of sepsis and the resulting multiorgan dysfunction. Identifying new regulatory targets for macrophage homeostasis and devising effective treatment strategies remains a significant challenge in contemporary research. PURPOSE: This study aims to identify new regulatory targets for macrophage homeostasis and develop effective strategies for treating sepsis. STUDY DESIGN AND METHODS: Macrophage infiltration in septic patients and in lungs, kidneys, and brains of caecum ligation and puncture (CLP)-induced septic mice was observed using CIBERSORT and immunofluorescence (IF). Upon integrating the MSigDB database and GSE65682 dataset, differently expressed macrophage-associated genes (DEMAGs) were identified. Critical DEMAGs were confirmed through machine learning. The protein level of the critical DEMAG was detected in PBMCs of septic patients, RAW264.7 cells, and mice lungs, kidneys, and brains using ELISA, western blot, immunohistochemistry, and IF. siRNA was applied to investigate the effect of the critical DEMAG in RAW264.7 cells. A natural product library was screened to find a compound targeting the critical DEMAG protein. The binding of compounds and proteins was analyzed through molecular docking, molecular dynamics simulations, CETSA, and MST analysis. The therapeutic efficacy of the compounds against sepsis was then evaluated through in vitro and in vivo experiments. RESULTS: Macrophage infiltration was inversely correlated with survival in septic patients. The critical differentially expressed molecule RasGRP1 was frequently observed in the PBMCs of septic patients, LPS-induced RAW264.7 cells, and the lungs, kidneys, and brains of septic mice. Silencing RasGRP1 alleviated proinflammatory response and oxidative stress in LPS-treated RAW264.7 cells. Catechin Hydrate (CH) was identified as an inhibitor of RasGRP1, capable of maintaining macrophage homeostasis and mitigating lung, kidney, and brain damage during sepsis. CONCLUSION: This study demonstrates that RasGRP1, a novel activator of macrophage proinflammatory responses, plays a crucial role in the excessive inflammation and oxidative stress associated with sepsis. CH shows potential for treating sepsis by inhibiting RasGRP1.

Increased FAPI Activity in Pulmonary Tuberculosis.

ABSTRACT: A 50-year-old man presented with cough and hemoptysis for 1 month. Chest CT showed an irregular mass in the right lung, with enlarged lymph nodes in the mediastinum and right hilum. These findings were suggestive of lung cancer with lymph node metastases. The patient was subsequently enrolled in a 68Ga-DOTA-FAPI-04 PET/CT clinical trial. 68Ga-DOTA-FAPI-04 PET/CT revealed a mass in the upper lobe of right lung, with intense tracer uptake. Meanwhile, PET/CT showed enlarged lymph nodes in the mediastinum and right hilum, with mild FAPI uptake. However, pathological examination confirmed the mass was tuberculous granuloma.

Increased 68Ga-FAPI Uptake in Psammomatous Meningioma in a Patient With Gallbladder Cancer.

ABSTRACT: A 70-year-old woman with a gallbladder mass was enrolled in our clinical trial of 68Ga-FAPI PET/CT study in tumors. Increased tracer uptake was noted in the gallbladder. In addition, focal uptake was localized in a lesion beside the falx cerebri. According to the location and radiological and clinical characteristics, a diagnosis of meningioma was made.

68Ga-FAPI-04 PET/CT in the Detection of Non-FDG-Avid Solid Pseudopapillary Neoplasm of the Pancreas.

ABSTRACT: Solid pseudopapillary neoplasm of the pancreas is a rare tumor. A 46-year-old woman presented with chest pain for 6 months. Chest CT revealed a large mass of the right mediastinum. Then, she underwent 18F-FDG and 68Ga-FAPI-04 PET/CT scans for staging. However, we accidentally found that a non-FDG focus nodule in the body of the pancreas with elevated FAPI activity. Finally, biopsy of the nodule in the body of the pancreas confirmed the diagnosis of solid pseudopapillary neoplasm.

68Ga-FAPI PET/CT Imaging of Intracranial Syphilitic Gumma: Comparison to 18F-FDG PET/CT.

ABSTRACT: Intracranial syphilitic gumma is a rare neurological disease. We present 68Ga-DOTA-FAPI-04 and 18F-FDG PET/CT findings of intracranial syphilitic gumma in a 46-year-old man with HIV. In this case, 68Ga-DOTA-FAPI-04 PET/CT outperforms 18F-FDG in helping to visualizing syphilitic gumma. Syphilitic gumma can also cause increase FAPI activity. Our findings suggest the potential value of 68Ga-DOTA-FAPI-04 in the diagnosis of syphilis.

NDUFC2 deficiency exacerbates endothelial mesenchymal transformation during ischemia-reperfusion via NLRP3.

Ischemic stroke is the main type of cerebrovascular disease. Emergency thrombectomy combined with medication therapy is currently the primary treatment for stroke. Inflammation and oxidative stress induced by ischemia-reperfusion cause secondary damage to blood vessels, especially endothelial mesenchymal transformation (EndoMT). However, much is still unclear about the role of EndoMT in ischemia-reperfusion. In this study, an in vivo ischemia-reperfusion model was established by transient middle cerebral artery occlusion (tMCAO) in wild-type (WT) C57BL/6 mice and NLRP3 (NOD-like receptor thermal protein domain associated protein 3) knockout (KO) C57BL/6 mice. An in vitro ischemia-reperfusion model was established by oxygen glucose deprivation and reoxygenation (OGD/R) of human brain microvascular endothelial cells (HBMECs). α-SMA (alpha smooth muscle actin), CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1/CD31), NDUFC2 (NADH: ubiquinone oxidoreductase subunit C2), and NLRP3 were used to evaluate EndoMT and inflammation. Real-time PCR measured superoxide dismutase 1 (SOD1) and catalase (CAT) mRNA expression to evaluate oxidative stress levels. NLRP3 was activated by ischemia-reperfusion injury and NLRP3 inactivation inhibited the EndoMT in tMCAO mice. Further experiments demonstrated that OGD/R treatment induced NLRP3 activation and EndoMT in HBMECs, which resulted in NDUFC2 deficiency. NDUFC2 overexpression suppressed NLRP3 activation and EndoMT in HBMECs induced by OGD/R. Moreover, NDUFC2 overexpression rescued SOD1 and CAT mRNA expression. These results demonstrated that NDUFC2 deficiency decreased the antioxidant levels, leading to NLRP3 activation and EndoMT during ischemia-reperfusion injury and suggesting that NDUFC2 is a potential drug target for the treatment of ischemic stroke.

Increased 68Ga-FAPI Activity in Malignant Melanoma of the Nasal Cavity.

ABSTRACT: We report the case of a 56-year-old man who presented with a 1-month history of recurrent right-sided epistaxis. Nasal endoscopy revealed a mass in the right nasal cavity, and CT scans showed a nasal space-occupying lesion. 68Ga-FAPI PET/CT demonstrated a high FAPI uptake of the mass in the right nasal cavity. Biopsy revealed a malignant melanoma.

Progressive Multifocal Leukoencephalopathy Mimicking Malignancy on 68Ga-FAPI PET/CT: Potential Advantages of FAPI.

ABSTRACT: A 43-year-old man presented with weakness in his right upper limb for 2 months. Head MRI showed intracranial multiple abnormal signal foci. Malignancy was suspected. The patient was subsequently enrolled in the clinical trial of 68Ga-FAPI PET/CT. 68Ga-FAPI PET/CT showed intracranial multiple FAPI-avid foci. It was also highly suggestive of malignancy. However, the combination of clinical manifestations, imaging findings, cerebral spinal fluid examinations, and effective immunotherapy confirmed the diagnosis of progressive multifocal leukoencephalopathy. 68Ga-FAPI may have potential advantages in the diagnosis of progressive multifocal leukoencephalopathy.

Bone Tuberculous Granulomatous Inflammation Mimicking Malignancy on 68Ga-FAPI PET/CT.

ABSTRACT: A 50-year-old woman presented with back pain for 1 month. Chest CT showed osteolytic destruction of T6 vertebral body. A malignancy was suspected. The patient was subsequently enrolled in the clinical trial of 68Ga-FAPI PET/CT. 68Ga-FAPI PET/CT revealed multiple bone destruction with increased FAPI activity. It was also highly suggestive of malignancy or metastases. However, pathological examination after T6 vertebral surgery confirmed the diagnosis of tuberculous granulomatous inflammation.

Increased 68Ga-FAPI Uptake in Facet Joint Osteoarthritis in a Patient With Esophageal Cancer.

ABSTRACT: A 69-year-old man presented with newly diagnosed esophageal cancer was enrolled in our clinical trial of 68Ga-FAPI PET/CT study in tumors. Increased tracer uptake was noted in esophageal cancer. In addition, the facet joint osteoarthritis of T7/8 vertebrae also revealed elevated 68Ga-FAPI uptake.

68Ga-FAPI PET/CT Imaging of Multiple Muscle Metastases of Pancreatic Cancer.

ABSTRACT: A 67-year-old man presented with generalized muscle pain for 2 months. A potential malignancy was suspected. The patient was subsequently enrolled in the clinical trial of 68Ga-FAPI. Increased activity of FAPI and FDG was observed in muscle lesions. Moreover, 68Ga-FAPI PET/CT showed intense FAPI uptake in the pancreas. Finally, pancreas and left iliopsoas muscle biopsies confirmed the diagnosis of pancreatic cancer with multiple muscle metastases.

Primary Adrenal Sarcomatoid Carcinoma Detected by 18F-FDG PET/CT.

ABSTRACT: Adrenal sarcomatoid carcinoma is extremely rare. A 53-year-old man was admitted to our hospital due to pain in the upper right abdomen for 1 month. Abdominal CT revealed a huge mass in the right adrenal gland, and a malignancy was suspected. 18F-FDG PET/CT showed a mass in the right adrenal gland with intense FDG uptake. Finally, postoperative pathology confirmed the diagnosis of adrenal sarcomatoid carcinoma.

Intense 68Ga-FAPI Uptake in a Patient With Myositis Ossificans: Mimicking Bone Malignancy.

ABSTRACT: A 72-year-old man presented with right hip pain, difficulty in walking, and a mass in his right hip for 3 months. CT suggested osteonecrosis of the right femoral head and a mass in the right hip with calcification. A malignancy was suspected, and the patient was subsequently enrolled in the clinical trial of 68Ga-FAPI. 68Ga-FAPI PET/CT showed a mass in his right hip with intense FAPI activity. It was also highly suggestive of malignancy. The pathological examination after right-hip surgery confirmed the diagnosis of myositis ossificans.

Elevated 68 Ga-FAPI Uptake by Primary Benign Intraosseous Meningioma.

ABSTRACT: Intraosseous meningioma is an extremely rare benign tumor. We present the 68 Ga-fibroblast activation protein inhibitor (FAPI) PET/CT findings of primary intraosseous meningioma in a 71-year-old woman. 68 Ga-FAPI PET/CT revealed an intraosseous mass in the right parietal bone with increased FAPI activity. Primary skull malignancy was suspected. However, pathological examination after resection of the mass in the right parietal bone confirmed the diagnosis of benign meningioma (WHO I). A final diagnosis of benign intraosseous meningioma was made.