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Objective: Adropin is a unique hormone, which controls metabolism and energy homeostasis. Hyperthyroidism is a disease with a high metabolic rate that affects both glucose and lipid metabolism. We aimed to investigate the change of adropin levels and the association between adropin levels and clinical parameters in patients with hyperthyroidism. Methods: This cross‐sectional study comprised 90 newly diagnosed patients with hyperthyroidism and 90 age‐ and gender‐matched healthy controls. Circulating adropin levels and thyroid hormone levels were evaluated in each participant. Results: Compared with the healthy controls, the hyperthyroid patients had significantly higher levels of serum adropin (p < 0.001). In addition, adropin levels were positively correlated with free triiodothyronine (FT3) and free thyroxine (FT4), whereas they were negatively correlated with thyroid‐stimulating hormone (TSH). A multivariate linear regression analysis showed that serum adropin concentrations were independently correlated with FT3 and TSH after adjustment for age, gender, and other confounding factors (FT3: β = 0.231, p < 0.05; TSH: β = −0.301, p < 0.05). Conclusions: Patients with hyperthyroidism had elevated serum adropin levels. And the serum adropin concentrations were independently correlated with the FT3 and TSH levels. [ABSTRACT FROM AUTHOR]

Context Dipeptidyl peptidase-4 (DPP4) is originally described as a surface protein in lymphocytes. Lymphocyte infiltration and subsequent destruction of thyroid tissue have been considered as the central pathological mechanism in Hashimoto thyroiditis (HT). Objective The present study aimed to investigate DPP4 expression in peripheral blood and thyroid tissue in HT patients, and explore the role of DPP4 in the pathophysiological process of HT. Methods This case-control study recruited 40 drug-naive HT patients and 81 control individuals. Peripheral blood and thyroid specimens were collected for assessing the expression and activity of DPP4. Moreover, single-cell RNA sequencing (scRNA-seq) analysis of 6 "para-tumor tissues" samples from scRNA-seq data set GSE184362 and in vitro cell experiments were also conducted. Results The HT patients had similar DPP4 serum concentration and activity as the controls. However, the expression and activity of DPP4 was significantly increased in the thyroid of the HT group than in the control group. The scRNA-seq analysis showed that DPP4 expression was significantly increased in the HT group, and mainly expressed in T cells. Further in vitro studies showed that inhibition of lymphocyte DPP4 activity with sitagliptin downregulated the production of inflammatory factors in co-cultured thyroid cells. Conclusion DPP4 expression was significantly increased in the thyroid of the HT group compared with the control group, and was mainly localized in the lymphocytes. Inhibition of lymphocyte DPP4 activity reduced the production of inflammatory factors in co-cultured thyroid cells. Therefore, inhibition of DPP4 may have a beneficial effect by alleviating inflammatory reactions in HT patients. [ABSTRACT FROM AUTHOR]

Some patients with marginal zone lymphoma (MZL) experience histological transformation to diffuse large B‐cell lymphoma (DLBCL). Because of the paucity of long‐term data on transformation, we conducted a population‐based study to estimate the risk of transformation and its impact on survival in MZL. Using the Surveillance, Epidemiology and End Results database, we identified 23 221 patients with histology‐proven MZL between 2000 and 2018. Competing risk method, Kaplan‐Meier and Cox proportional hazards regression were performed to analyze time‐to‐event outcomes. Based on 420 events of transformation, the 10‐year cumulative incidence rate of transformation is 2.23% (95% CI: 2.00%‐2.46%) in MZL, 1.5% (95% CI: 1.3%‐1.8%), 2.7% (95% CI: 2.3%‐3.2%) and 5.8% (95% CI: 4.6%‐7.1%) in extranodal, nodal and splenic MZL (EMZL, NMZL and SMZL), respectively. Patients with SMZL (subdistribution hazard ratio [SHR], 2.96; 95% CI: 2.21‐3.96) or NMZL (SHR, 1.49; 95% CI: 1.17‐1.90) have a higher risk of transformation than those with EMZL. For each MZL subtype, patients with transformation had a significantly shorter overall survival. Patients with transformation >18 months since MZL diagnosis had longer OS than those who presented within 18 months (5‐year rate, 87.4% [95% CI: 83.7%‐91.2%] vs 47.9% [95% CI: 38.8%‐59.0%]; P <.001). Compared to patients with matched de novo DLBCL, those whose DLBCL was transformed from MZL had a shorter OS (5‐year rate, 56.6% [95% CI: 51.9%‐61.8%] vs 46.1% [95% CI: 40.9%‐51.9%]; P <.001). We concluded that patients with SMZL had the highest risk of transformation. Regardless of MZL subtype, transformation resulted in significantly increased mortality. [ABSTRACT FROM AUTHOR]

Background: The relationship between molecular characteristics and the prognosis of colorectal cancer (CRC) patients has not been fully understood. This study explored the impact of targeted therapy on the prognosis of CRC patients with different TP53 mutations, in the context of comprehensive treatment. Methods: This study included patients with stage III/IV primary CRC from the electronic medical record system. TP53 mutations were detected via next‐generation sequencing (NGS) using formalin‐fixed paraffin‐embedded (FFPE) tissues. Applying two methods, we classified TP53 mutations as gain of function (GOF)/non‐GOF mutations or known/likely loss of function (LOF) mutations. Kaplan–Meier plot and parametric survival analysis were performed to evaluate the prognosis of CRC patients and identify potential predictors. Results: There were 286 patients included, of which 166 (58.04%) patients received targeted therapy and 120 (41.96%) did not. There were 286 patients in the TP53 GOF classification set and 247 in the TP53 LOF classification set. Parametric survival analysis, adjusted for sex, onset, KRAS mutation, sidedness, stage, and surgery, showed that receiving targeted therapy predicted better overall survival (OS) among patients who harbored TP53 GOF mutations (HR 0.40, 95% confidence interval (CI) [0.21, 0.76], p = 0.005) or known LOF mutations (HR 0.21, 95% CI [0.07, 0.60], p = 0.002). However, there was no significant impact of receiving targeted therapy on OS among patients harboring TP53 non‐GOF mutations (HR 1.68, 95% CI [0.50, 5.63], p = 0.403) or likely LOF mutations (HR 0.90, 95% CI [0.34, 2.39], p = 0.837). Conclusions: Receiving targeted therapy had a heterogeneous impact on the prognosis of CRC patients harboring different TP53 mutations. These results provide promising value for future personalized treatment and precision medicine. [ABSTRACT FROM AUTHOR]

Graves' disease (GD) is an organ-specific autoimmune disease. The production of anti-thyrotropin receptor antibodies (TRAb) is associated with a loss of immune tolerance. Dipeptidyl peptidase-4 (DPP-4) is expressed on multiple immune cells. This study aimed to investigate the relationship between serum concentration/activity of DPP4 and the severity of hyperthyroidism in GD patients. A total of 82 newly diagnosed drug-naive patients with GD hyperthyroidism, 20 patients with non-autoimmune thyrotoxicosis and 122 age- and sex- matched healthy controls were enrolled. The clinical parameters and serum concentration and activity of DPP4 were measured. The GD group had increased serum concentration and activity of DPP4 than the healthy controls and patients with non-autoimmune thyrotoxicosis, while no significant difference was observed in the latter two groups. Multivariate linear regression indicated that the serum concentration/activity of DPP4 were positively associated with FT3, FT4 and TRAb levels in the GD patients. And the positive association between serum concentration/activity of DPP4 and TRAb was remained even after adjustment for confounding factors (all p < 0.05). The GD patients had significantly increased serum concentration/activity of DPP4. And the serum concentration/activity of DPP4 was positively associated with the severity of hyperthyroidism in GD patients. The activity and concentration of DPP4 in patients with Graves' disease were higher than those in healthy controls. There was a significant positive correlation between serum DPP4 concentration and TRAb levels in patients with Graves' disease. In patients with Graves 'disease, serum DPP4 activity was positively correlated with TRAb levels. [ABSTRACT FROM AUTHOR]

To the best of the author's knowledge, studies of mature plasmacytoid dendritic cell proliferation associated with T lymphoblastic lymphoma were extremely rare in the literature. Here, we report a patient who underwent both mature plasmacytoid dendritic cell proliferation and T lymphoblastic lymphoma. With the findings of lymph node biopsy taken from the right cervical and inguinal regions, we identified eye-catching mature plasmacytoid dendritic cells that were considered to be responsible for this lesion at the beginning, until the immunostaining of Ki67 and TDT showed a small group of positive cells hiding in these plasmacytoid dendritic cells. A bone marrow biopsy was also performed on this patient. Microscopically, the hematopoietic tissue was almost completely replaced by lymphoblastoid cells with condensed chromatin, inconspicuous nucleoli and scanty cytoplasm, which were basically the same as those seen in the lymph nodes in morphology. However, there was no sign of plasmacytoid dendritic cells or Langerhans cells in the bone marrow biopsy. With the help of bone marrow biopsy, our final diagnosis of the lymph node was T lymphoblastic lymphoma coexisting with mature plasmacytoid dendritic cell proliferation. Although accumulations of plasmacytoid dendritic cells may occur in some infections or reactive lymphadenopathy, the presence of extensive nodules or infiltration of plasmacytoid dendritic cells strongly reminds the pathologist to carefully evaluate the bone marrow or peripheral blood status of the patient to exclude a hidden myeloid or other neoplasm. [ABSTRACT FROM AUTHOR]

Objectives: To investigate if different methods of pancreatoduodenectomy (with or without pyloric preservation) would have different impacts on postoperative nutrition and body composition changes among pancreatic cancer patients. Methods: Demographic and clinicopathological data, perioperative data were collected, body composition (e.g. skeletal muscle cross‐sectional area [CSA], visceral fat area [VFA]) were evaluated with abdominal CT before and after surgery. Sarcopenia patients' proportion changes were also recorded. Results: The hospital stay in the PRPD group was significantly less than that in the PPPD group (p < 0.05). A significant difference was found in CSA, skeletal muscle index (SMI), VFA, VFA/CSA and albumin (ALB) in both groups between preoperative, 3, and 12 months after surgery. The loss of visceral fat in the PRPD group was more prominent than that in the PPPD group at 3 months and 12 months after surgery (p < 0.05). VFA/CSA was higher in the PPPD group than in the PRPD group (3 months: p < 0.05, 12 months: p < 0.001). The proportion of sarcopenic patients increased significantly over time in the PPPD and PRPD groups (p < 0.001). Conclusions: Postoperative CSA and VFA continued to significantly decrease in both PPPD and PRPD groups, while the incidence of sarcopenia continued to increase. Compared with PRPD, PPPD has a protective effect on visceral fat. PPPD may contribute to better maintaining visceral fat mass and blood ALB levels. CT quantification can be an objective and effective method to evaluate the nutritional status of pancreatic cancer patients during the pre‐ and postoperative period and can provide a useful objective basis for guiding clinical treatment. [ABSTRACT FROM AUTHOR]

Background. Intrapancreatic fat deposition (IPFD) usually occurs in individuals with type 2 diabetes mellitus (T2DM), but its physiopathological influence remains controversial. The present study aimed to investigate IPFD and its associations with various aspects of glucose and lipid metabolism in individuals with newly diagnosed T2DM. Methods. A total of 100 individuals were included, consisting of 80 patients with newly diagnosed T2DM and 20 age- and sex-matched healthy controls. Then, we assessed IPFD using magnetic resonance imaging (MRI) and various parameters of glucose and lipid metabolism. Results. Individuals with newly diagnosed T2DM had a significantly higher IPFD (median: 12.34%; IQR, 9.19–16.60%) compared with healthy controls (median: 6.35%; IQR, 5.12–8.96%) p < 0.001 . In individuals with newly diagnosed T2DM, IPFD was significantly associated with FINS and HOMA-IR in unadjusted model (β = 0.239, p = 0.022 ; β = 0.578, p = 0.007 , respectively) and adjusted model for age and sex (β = 0.241, p = 0.022 ; β = 0.535, p = 0.014 , respectively), but these associations vanished after adjustment for age, sex, and BMI. The OR of lower HDL-C for the prevalence of high IPFD was 4.22 (95% CI, 1.41 to 12.69; p = 0.010) after adjustment for age, sex, BMI, and HbA1c. Conclusions. Lower HDL-C was an independent predictor for a high degree of IPFD. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease with limited therapeutic options. Pseudognaphalium affine (D. Don) Anderb. is a medicinal and edible plant used to treat cough, asthma, and COPD for a long time in folk medicine. The objective of this study is to evaluate the effect of Pseudognaphalium affine (D. Don) Anderb. extract (GAE) and investigate the possible underlying mechanism in vivo and in vitro. In vivo, the administration of GAE in a rat COPD model could significantly ameliorate lung damage and pulmonary function by inhibiting the production of pro-inflammatory cytokines. Western blot and real-time PCR results showed that GAE could suppress nuclear translocation of nuclear factor-kappa B (NF-κB), which indicated that GAE down-regulated the NF-κB pathway. Moreover, GAE protected against tumor necrosis factor (TNF)-α induced inflammatory response in BEAS-2B and inhibited the NF-κB pathway. All data suggested that GAE exhibited its anti-COPD effect by inhibiting pro-inflammatory cytokines, which may be associated with the inhibition of the NF-κB pathway. [ABSTRACT FROM AUTHOR]

Objective: Adipose tissue plays a crucial role in serum uric acid (UA) metabolism, but the relative contribution of adipose tissue insulin resistance (IR) to serum UA levels and hyperuricemia have not explicitly been illustrated. Herein, we aimed to investigate the association between the adipose tissue insulin resistance index (Adipo-IR) and hyperuricemia in this cross-sectional study. The homeostasis model assessment of insulin resistance (HOMA-IR) index, another widely applied marker to determine systemic IR, was also explored. Methods: A total of 5821 adults were included in this study. The relationship between Adipo-IR or HOMA-IR and serum UA levels was assessed by multivariate linear regression. Binary logistic regression analyses were applied to determine the sex-specific association of the Adipo-IR tertiles and HOMA-IR tertiles with hyperuricemia. Participants were then divided into normal BMI (18.5 ≤ BMI < 24) and elevated BMI (BMI ≥ 24) groups for further analysis. Results: Both Adipo-IR and HOMA-IR were positively correlated with serum UA (P < 0.001). Compared with the lowest tertile, the risks of hyperuricemia increased across Adipo-IR tertiles (middle tertile: OR 1.52, 95%CI 1.24-1.88; highest tertile: OR 2.10, 95%CI 1.67–2.63) in men after full adjustment (P for trend < 0.001). In women, only the highest tertile (OR 2.09, 95%CI 1.52-2.87) was significantly associated with hyperuricemia. Those associations remained significant in participants with normal BMI status. As for HOMA-IR, only the highest tertile showed positive relationships with hyperuricemia in both genders after full adjustment (P for trend < 0.001). The association between HOMA-IR and hyperuricemia disappeared in men with normal BMI status. Conclusions: Adipo-IR was strongly associated with serum UA and hyperuricemia regardless of BMI classification. In men with normal BMI, Adipo-IR, rather than HOMA-IR, was closely associated with hyperuricemia. Altogether, our finding highlights a critical role of adipose tissue IR on serum UA metabolism and hyperuricemia. [ABSTRACT FROM AUTHOR]

Objective. Patients with Hashimoto thyroiditis (HT) frequently have some complaints despite achieving euthyroidism after levothyroxine (LT4) treatment. This study aimed to investigate the relevant factors affecting the quality of life (QoL) in euthyroid HT patients after LT4 treatment. Methods. In this case-control study, 133 participants with HT were included. They were divided into two groups: 64 euthyroid HT subjects (control group) and 69 HT patients were rendered euthyroid by LT4 treatment (well-controlled group). QoL was measured with the Thyroid-Related Patient-Reported Outcome (ThyPRO-39) questionnaire. Results. Both study groups were well matched with respect to gender, age, BMI, euthyroidism, and thyroid antibodies (TPOAb and TGAb). Compared with the control group, the well-controlled group had lower FT3 (P < 0.01) levels. Of note, QoL was impaired on all scales in the well-controlled group. Moreover, ThyPRO-39 scores among the well-controlled group were significantly higher (worse) than the control group in all scales. Regarding the composite scale, its score was related to FT3 (r = −0.176, P = 0.043) but not to FT4 and TSH levels. Further logistic regression analysis revealed FT3 was significantly associated with elevated composite QoL [0.128 (0.029–0.577), P < 0.01 ] after adjustment of potential confounders. Conclusion. Relatively lower FT3 concentrations, even within the normal reference range, were related to impaired QoL in HT patients treated with LT4. This finding supports the great value of FT3 in clinical decision-making on dose adequacy. [ABSTRACT FROM AUTHOR]

Neuroinflammation plays a crucial part in the commencement and advancement of ischemic stroke. Gualou Guizhi granule (GLGZG) is known to well exhibit neuroprotective effect, but it is not known whether GLGZG can regulate the inflammatory process at the cellular level in BV2 microglia cells and protect against microglia-mediated neurotoxicity in neurons. Herein, we aimed to investigate the anti-inflammatory effects of GLGZG on BV2 microglia cells and protection against microglia-mediated neurotoxicity in neurons. Methods. The cell model of neuroinflammation was constructed by lipopolysaccharide (LPS) to observe the effect of GLGZG in the presence or absence of GLGZG. The production of nitric oxide (NO), inflammatory mediators, was detected. Moreover, potential mechanisms associated with the anti-inflammatory effect, such as inhibition of microglial activation and nuclear factor kappa B (NF-κB), were also investigated. In addition, to prove whether GLGZG protects against microglia-mediated neurotoxicity, neuronal HT-22 cells were cultured in the conditioned medium. And cell survivability and neuronal apoptosis of HT-22 were evaluated. Results. It was found that a main regulator of inflammation, NO, is suppressed by GLGZG in BV2 microglial cells. Moreover, GLGZG dose dependently decreased the mRNA and protein levels of inducible NO synthase (iNOS) in LPS-stimulated BV2 cells. Additionally, GLGZG inhibited the expression and secretion of proinflammatory cytokines in BV2 microglial cells. Also, GLGZG inhibited LPS-activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in BV2 microglial cells at the intracellular level. GLGZG significantly affected Akt phosphorylation: phosphorylated forms of Akt increased. To check whether GLGZG protects against microglia-mediated neurotoxicity, neuronal HT-22 cells were incubated in the conditioned medium. GLGZG showed a neuroprotective effect by promoting cell survivability and suppressing neuronal apoptosis. Conclusions. GLGZG exerted its potential effects on suppressing inflammatory responses in LPS-induced BV2 cells by regulating NF-κB and Akt pathways. In addition, GLGZG could protect against microglia-mediated neurotoxicity in HT-22. [ABSTRACT FROM AUTHOR]

Introduction: Intracranial enterogenous cysts are rare and mainly occur in the posterior fossa. These cysts are usually extra-axial, midline, anterior to the brainstem, or at the cerebellopontine angle. We report a case of an enterogenous cyst in which diagnosis was difficult because the lesion showed atypical pathologic findings. Case presentation: A healthy 41-year-old man complained of paroxysmal occipital headaches lasting over a week, with increased severity for 3 days accompanied by slight dizziness and mild nausea. Magnetic resonance imaging showed a cystic lesion between clivus and brainstem. The patient underwent surgery for removal of the lesion via the right-sided far-later approach, and the lesion was resected totally. Although pathologic examinations showed a cyst had a mono-to-multilayered squamous epithelium, which are not accord with typical enterogenous cyst, the diagnosis was finally made based on the presence of basement membrane and immunohistochemical results. Discussion and Evaluation: To confirm the diagnosis of enterogenous cyst, further pathologic examinations were performed and immunohistochemical characters were summarized. Chemical meningitis, a rare complication of enterogenous cyst, happened in current case. Use a syringe and aspirate the contents before incision might be a procedure to prevent chemical meningitis. Conclusions: To our knowledge, this is the first report of an enterogenous cyst associated with mono-to-multilayered squamous epithelium. Although during the follow-up time, no recurrence happened, long-term follow-up is needed. [ABSTRACT FROM AUTHOR]

ABSTRACT NTRK (neurotropic tropomyosin receptor kinase)‐rearranged spindle cell tumours represent a rare group of molecularly defined soft tissue neoplasms. These tumours, excluding infantile fibrosarcomas, are characterised by NTRK gene rearrangements and exhibit a range of histomorphologies, including spindle, epithelioid or rhabdoid cells with invasive growth. Their prognosis correlates with histological grade, and surgical resection is the primary treatment. The abnormally expressed oncogenic receptor tyrosine kinases TRK‐A, TRK‐B and TRK‐C in this tumour have been shown to be therapeutical targetable, which may improve patient prognosis. We report a 17‐year‐old male patient presenting with a left axillary mass. Both fine‐needle aspiration cytology (FNAC) and surgical resection specimens were submitted for examination. Comprehensive analysis of cytomorphology, immunohistochemical staining results and next‐generation sequencing (NGS) data led to a final diagnosis of NTRK‐rearranged spindle cell tumour. By comparing cytological and histological morphologies, we identified diagnostic clues in cytological specimens. NTRK‐rearranged spindle cell tumours' definitive diagnosis enables targeted therapy. Fine‐needle aspiration cytology, being minimally invasive, offers the potential for earlier and more definitive diagnoses, thereby improving patient treatment options. [ABSTRACT FROM AUTHOR]

Background: Dyslipidemia has been implicated in the pathogenesis of several diseases, including thyroid dysfunction and immune disorders. However, whether circulating lipids and long-term use of lipid-lowering drugs influence the development of autoimmune thyroid disease (AITD) remains unclear. This study aims to evaluate the effects of lipid-lowering drugs on AITD and explore their potential mechanisms., Methods: Two-sample and two-step Mendelian randomization (MR) studies were performed to assess the causal relationships between circulating lipids (LDL-C, TC, TG, and ApoB) and seven lipid-lowering drug targets ( ApoB, CETP, HMGCR, LDLR, NPC1L1, PCSK9 , and PPARα ) with AITD. Mediation analyses were conducted to explore potential mediating factors., Results: There was no clear causality between circulating lipids (ApoB, LDL-C, TC, and TG) and AITD ( p > 0.05). ApoB inhibition is related to a reduced risk of autoimmune thyroiditis (AT) (OR = 0.462, p = 0.046), while PCSK9 inhibition is related to reduced Graves' disease (GD) risk (OR = 0. 551, p = 0.033). Moreover, PCSK9 inhibition (OR = 0.735, p = 0.003), LDLR inhibition (OR = 0.779, p = 0.027), and NPC1L1 inhibition (OR = 0.599, p = 0.016) reduced the risk of autoimmune hypothyroidism (AIH). Mediation analysis showed that NPC1L1 inhibition and PCSK9 inhibition exerted effects on AIH through IL-4 and FGF-19 levels. And the effect of PCSK9 inhibition on GD through TNF-β levels., Conclusion: There was no clear causality between circulating lipids (ApoB, LDL-C, TC, and TG) and AITD. Lipid-lowering drug target gene inhibitors reduced the AITD risk by modulating inflammatory factors., Competing Interests: The authors have no conflict of interest to disclose. This paper has been uploaded to ResearchSquare as a preprint:https://doi.org/10.21203/rs.3.rs-4428352/v1., (© 2024 Su et al.)

Introduction: Urban green space is one of the most closely related ecosystem services to residents' lives, and it can be regarded as a preventive public health measure. Residents living in parks and other green environments can help improve their physical and mental health, reduce stress and even prevent crime and violence. Therefore, based on the actual situation in China, this paper analyzes the relationship between urban green space and the health of middle-aged and older adults and its mechanisms., Methods: This study used multiple linear regression, based the data from the China Health and Retirement Longitudinal Study (CHARLS) in 2013, 2015, and 2018, to explore the relationship between urban green space and the health of middle-aged and older adults. At the same time, group regression was conducted to identify the heterogeneity of health effects of urban green space., Results: The research shows that the increase of urban green space areas can significantly improve the health status of middle-aged and older adults. After a series of robustness tests, the results are still valid. In addition, the health effects of urban green space are different because of gender, age, education level, marital status residence, geographical location of the respondents and park quantity distribution. Further research found that reducing hot weather and optimizing air quality are the potential mechanisms of urban green space affecting the health of middle-aged and older adults, providing new evidence for the causal mechanism between urban green space and the health of middle-aged and older adults., Discussion: This study expanded the research scope of the impact of urban green space on the health of middle-aged and older adults, covering a representative sample in China. The results show that urban green space has an important impact on the health of middle-aged and older adults. Policy suggestions are made to help cities optimize the landscape and residents to enjoy ecology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Liu, Yang, Ge, Chang and Zhang.)

This study develops a method combining a convolutional neural network model, INSIGHT, with a self-attention model, WiseMSI, to predict microsatellite instability (MSI) based on the tiles in colorectal cancer patients from a multicenter Chinese cohort. After INSIGHT differentiates tumor tiles from normal tissue tiles in a whole slide image, features of tumor tiles are extracted with a ResNet model pre-trained on ImageNet. Attention-based pooling is adopted to aggregate tile-level features into slide-level representation. INSIGHT has an area under the curve (AUC) of 0.985 for tumor patch classification. The Spearman correlation coefficient of tumor cell fraction given by expert pathologist and INSIGHT is 0.7909. WiseMSI achieves a specificity of 94.7% (95% confidence interval [CI] 93.7%-95.7%), a sensitivity of 84.7% (95% CI 82.6%-86.9%), and an AUC of 0.954 (95% CI 0.948-0.960). Comparative analysis shows that this method has better performance than the other five classic deep learning methods., Competing Interests: Declaration of interests Patent is pending, and the patent application does not affect reproduction of this study’s results for research purposes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Autoimmune thyroiditis (AIT) is a common organ-specific autoimmune disease. Longitudinal relaxation time mapping (T1-mapping) analyzed by magnetic resonance imaging is a new method for evaluating inflammation or fibrosis. This study aimed to investigate the relationship between thyroid T1-mapping value and degree of intrathyroidal inflammation and destruction in euthyroid AIT patients., Methods: This case-control study recruited 28 drug-naïve AIT patients and 18 healthy controls. Thyroid specimens were collected for assessing the mRNA expression of inflammatory factors and histopathologic examination. T1-mapping values were measured using a modified look-locker inversion-recovery sequence in all participants., Results: The positive rate of pathological diagnosed AIT was only 83.3% in the AIT group diagnosed by positive TPOAb and/or TgAb and typical ultrasonic manifestations, while 7.1% of the control group was diagnosed as AIT by pathological manifestations. Receiver operating characteristic curve analysis revealed a very high diagnostic value of thyroid T1-mapping values for pathological diagnosed AIT (area under the curve was 0.950, 95% CI : 0.843 - 0.993, P < 0.001). In the patients with pathological diagnosed AIT, thyroid T1-mapping values were significantly associated with the mRNA expression of INF-γ ( r = 0.343, P < 0.05), TNF-α ( r = 0.352, P < 0.01), and IL-1β ( r = 0.673, P < 0.01) in thyroid tissues. Moreover, histopathologic examination showed that thyroid T1-mapping values can properly reflect the degree of thyroid destruction in AIT patients., Conclusions: Thyroid T1-mapping values had a very high diagnostic value for AIT. In euthyroid AIT patients, thyroid T1-mapping values better reflect degree of intrathyroidal inflammation and destruction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Chang, Wang, Ding, Jiang and Wang.)

Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) and proficient DNA mismatch repair (pMMR) exhibit heterogeneous tumor characteristics, distinct responses to immunotherapy, and different survival outcomes. However, it is unclear whether gut microbiota is distinct between CRCs with different MMR status. In this study, we used immunohistochemistry for four major MMR proteins to determine the MMR status in 230 CRC patients. The gut microbiota was profiled in cancerous and adjacent normal tissues by using bacterial 16S rRNA sequencing. The differences in microbiota diversity, composition and related metabolic pathways between patients with dMMR and pMMR CRCs were explored. Linear discriminant analysis effect size (LEfSe) analysis was further applied to validate the significant taxonomic differences at the genus level. In our study cohort, dMMR status was identified in 29 of 230 (12.61%) tumors. The richness (alpha-diversity) of gut microbiome in dMMR tumor tissue was higher compared with pMMR tumor tissues. The microbial community composition (beta-diversity) between the two groups was significantly different. The dMMR group was enriched considerably for some microbiota, including Fusobacteria, Firmicutes, Verrucomicrobia, and Actinobacteria at the phylum level and Fusobacterium, Akkermansia , Bifidobacterium , Faecalibacterium , Streptococcus , and Prevotella bacteria at the genus level. However, the pMMR group was dominated by Proteobacteria at the phylum level and Serratia , Cupriavidu s and Sphingobium at the genus level. Moreover, a wide variety of microbiota associated functional pathways were observed with different MMR status. KEGG pathway analysis indicated a higher abundance of the biosynthesis and metabolic pathways of glycan and nucleotide, cell growth and death pathways, genetic replication and repair pathways in dMMR samples compared with the pMMR group. These findings demonstrate that CRC patients with different MMR status have distinct gut bacterial community richness, compositions and related metabolic pathways, suggesting basis that may explain the effectiveness of immunotherapy in dMMR tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jin, Wu, Shi, Zhou, Shang, Chang, Dong, Deng, Liu, Cai, Nie, Zhang, Fan and Liu.)

Background: Meteorin-like (Metrnl), a novel adipokine, is highly expressed in adipose tissue and has a beneficial effect on energy metabolism. However, data on circulating Metrnl levels in obesity are scarce and inconsistent. This study aimed to evaluate the serum levels of Metrnl in adults with obesity and its association with glucose and lipid metabolism., Methods: 182 subjects were included in the cross-sectional study. The participants were divided into three groups according to BMI: normal (n = 95), overweight (n = 46), and obesity (n = 41). Serum Metrnl concentrations were measured by enzyme-linked immunosorbent assay., Results: Serum Metrnl levels in overweight or obese subjects were significantly lower than in the normal group. Circulating Metrnl levels were negatively correlated with TG, TC, LDL-C, and sdLDL and positively correlated with HDL-C before and after adjusting for age, sex, BMI, diabetes, HOMA-IR, and eGFR (all P < 0.05). Furthermore, logistic regression analysis indicated that compared with the highest tertile, the lowest tertile of Metrnl levels were significantly associated with the presence of hyper-TG, hyper-TC, and Hyper-LDL after full adjustment (all P for trend < 0.05)., Conclusions: Serum Metrnl levels were reduced in individuals with overweight or obesity and were independently associated with adverse lipid profile, suggesting that modifying circulating Metrnl levels may serve as a potential therapeutic target for atherogenic dyslipidemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ding, Chang, Wang, Bian, An, Wang and Liu.)

Objectives: Survivors of diffuse large B-cell lymphoma (DLBCL) are at an increased risk of developing second primary malignancies. However, the risk of secondary acute myeloid leukaemia (sAML) has not been previously described in detail, and the outcomes of patients with sAML are also undiscovered compared with their de novo counterparts (de novo acute myeloid leukaemia, dnAML)., Design: This study is a retrospective database study., Setting and Participants: A total of 70 280 patients with primary DLBCL, diagnosed between 2000 and 2016, were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Another cohort with dnAML matching with sAML was also obtained from SEER database., Results: The standardised incidence ratio was 6.23 (95% CI: 5.50 to 7.03) for sAML among survivors of DLBCL. The estimated cumulative incidence of sAML was 0.61% 15 years after the diagnosis of DLBCL. Patients aged 60-74 years were more likely to have sAML than those <60 years (subdistribution HR (sHR)=1.417; 95% CI: 1.087 to 1.850), whereas patients aged ≥75 years were less likely to have sAML (sHR=0.648; 95% CI: 0.452 to 0.930). Patients with advanced-stage DLBCL were more prone to sAML than those with early-stage disease (sHR=1.307; 95% CI: 1.012 to 1.690). There was a significant difference of survival between patients with dnAML and those with sAML (HR=1.25; 95% CI: 1.01 to 1.53)., Conclusions: The risk of developing sAML after DLBCL is substantial. Patients aged 60-74 years and with advanced-stage are more prone to sAML. And, compared with their dnAML counterparts, patients with sAML have a worse prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Administration of anti-PD-1 is now a standard therapy in advanced non-small cell lung carcinoma (NSCLC) patients. The clinical application of biomarkers reflecting tumor immune microenvironment is hurdled by the invasiveness of obtaining tissues despite its importance in immunotherapy. This study aimed to develop a robust and non-invasive radiomics/deep learning machine biomarker for predicting the response to immunotherapy in NSCLC patients. Radiomics/deep learning features were exacted from computed tomography (CT) images of NSCLC patients treated with Nivolumab or Pembrolizumab. The robustness of radiomics/deep learning features was assessed against various perturbations, then robust features were selected based on the Intraclass Correlation Coefficient (ICC). Radiomics/deep learning machine-learning classifiers were constructed by combining seven feature exactors, 13 feature selection methods, and 12 classifiers. The optimal model was selected using the mean area under the curve (AUC) and relative standard deviation (RSD). The consistency of image features against various perturbations was high (the range of median ICC: 0.78-0.97), but the consistency was poor in test-retest testing (the range of median ICC: 0.42-0.67). The optimal model, InceptionV3&#95;RELF&#95;Nearest Neighbors classifiers, had the highest prediction efficacy (AUC: 0.96 and RSD: 0.50) for anti-PD-1/PD-L1 treatment. Accuracy (ACC), sensitivity, specificity, precision, and F1 score were 95.24%, 95.00%, 95.50%, 91.67%, and 95.30%, respectively. For successful model robustification, tailoring perturbations for robustness testing to the target dataset is key. Robust radiomics/deep learning features, when paired with machine-learning methodologies, will work on the exactness and the repeatability of anticipating immunotherapy adequacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ren, Xiong, Zhu, Chang, Wang, He and Jin.)

Antidiabetic oral agents and nutrition management are frequently used together as first-line therapies for type 2 diabetes mellitus (T2DM). However, less is known about their interaction. The interactive effect of two classic antidiabetic medications, namely, acarbose and metformin, with dietary intakes of macronutrients on glycemic control and cardiometabolic risk factors was investigated in the metformin and acarbose in Chinese as the initial hypoglycemic treatment (MARCH) randomized clinical trial. The patients with newly diagnosed T2DM from China were included in the trial. Participants were randomized to receive either metformin or acarbose monotherapy as the initial treatment, followed by a 24-week treatment phase, during which add-on therapy was used if necessary. Dietary intakes of carbohydrate, protein, fat, and total energy were calculated by a 24-h food diary recall method. Linear mixed-effect models combined with a subgroup analysis were used to investigate independent and interactive effects of drugs and diet on clinical outcomes. A data analysis was performed on 551 of the 788 patients randomly assigned to treatment groups. Metformin therapy was independently associated with higher triglycerides (TGs, β = 0.471, P = 0.003), 2 h postprandial plasma glucose (2hPPG, β = 0.381, P = 0.046) but lower low-density lipoprotein cholesterol (LDL-C, β = -0.149, P = 0.013) compared with acarbose therapy. Higher carbohydrates and lower fat intakes were independently associated with poorer glycemic control, less weight loss, and greater insulin secretion. Higher total energy intake was also independently associated with higher fasting (β = 0.0002, P = 0.001) and postprandial blood glucose (β = 0.0004, P = 0.001). Interaction and subgroup analyses demonstrated that glucagon-like peptide-1 (GLP-1) was positively related to total energy (β = 0.268, P = 0.033), carbohydrates intake, and insulin secretion (β = 2,045.2, P = 0.003) only in the acarbose group, while systolic blood pressure (SBP) was negatively related to protein intake in the metformin group (β = 23.21, P = 0.014). The results of this study showed that metformin and acarbose mainly exerted different interactive effects with dietary energy, carbohydrate, and protein intakes on GLP-1 secretion, insulin release, and SBP. The interaction between drug therapy and nutrition intervention in glycemia highlights the complexity of combination therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 An, Li, Bian, Ding, Chang, Liu and Wang.)

We aimed to determine whether Neuropilin-1 (NRP1) promotes gastric cancer (GC) metastasis by inducing epithelial-mesenchymal transition (EMT), and to clarify its regulatory mechanism. Using the data of GC patients in The Cancer Genome Atlas (TCGA) and Gene Tissue Expression (GTEx) databases, combined with the data of GC patients in our medical center, the effect of NRP1 on the prognosis of GC patients were analyzed. Then, we investigated the role of NRP1 in GC metastasis and its potential mechanism. The level of NRP1 was up-regulated in GC tissues and associated with poor prognosis of GC patients. The expression of NRP1 was closely related to maximum tumor diameter, invasion depth, lymphnode metastasis, distant metastasis, and advanced TNM stage, and was an independent prognostic factor for overall survival (OS) in GC patients. Besides, the results of in vitro indicated that NRP1 could induce EMT to promote the migration and invasion of GC cells by activating PI3K/Akt signaling pathway, and the HGF/c-Met axis was involved in this process. This study determined that NRP1 was a gene that promotes gastric cancer. NRP1 induced EMT to enhance the migration and invasion ability of GC cells by activating PI3K/Akt signaling pathway. NRP1 was an independent prognostic marker for OS in GC patients and expected to be a therapeutic target for GC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Metastatic prostate cancer is associated with high mortality rates. Identification of metastasis-related proteins may facilitate the development of novel therapies for the treatment of metastatic disease. In the present study, we aimed to identify prostate cancer metastasis-associated membrane proteins. We developed a phage-displayed 7-mer peptide library to screen the target peptides that were specifically bound to PC-3M cells with subtractive panning from normal prostate cells and PC-3 prostate cancer cells. A novel short peptide (B04) was found to have high affinity to highly metastatic PC-3M cells. ATP synthase β subunit (ATP5B) was then identified as a binding partner of B04 on the PC-3M cell surface. ATP5B was expressed on the PC-3M cell membrane and on highly malignant human prostate cancer specimens, as shown using multiple methodologies. Furthermore, ATP5B-positive gold particles were detected on the cellular and mitochondrial membranes by immunoelectromicroscopy. These results implied the possibility that ATP5B may translocate from the inner mitochondrial membrane to the outer surface of PC-3M cells. Additional analysis showed that incubation of B04 with PC-3M cells reduced the detection of ATP5B by western blotting and flow cytometry and significantly inhibited the proliferation, invasion and metastasis of PC-3M cells. In conclusion, ATP5B, as a binding partner of a metastasis-related short peptide (B04) on prostate cancer cells, is involved in promoting prostate cancer metastasis. In conclusion, ATP5B may be a promising biomarker and therapeutic target for highly metastatic malignancies.

The limited availability of qualified endothelial progenitor cells (EPCs) is a major challenge for regenerative medicine. In the present study, we isolated human EPCs from human umbilical vein endothelial cells (HUVECs) by using magnetic micro-beads coated with an antibody against human CD34. Flow cytometric assay showed that majority of these cells expressed VEGFR2 (KDR), CD34 and CD133, three molecular markers for early EPCs. It was also found that a bioreactor micro-carrier cell culture system (bio-MCCS) was superior to dish culture for in vitro expansion of EPCs. It expanded more EPCs which were in the early stage, as shown by the expression of characteristic molecular markers and had better angiogenic potential, as shown by matrix-gel based in vitro angiogenesis assay. These results suggest that HUVECs might be a novel promising resource of EPCs for regenerative medicine and that a bio-MCCS cell culture system might be broadly used for in vitro expansion of EPCs., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) treatment is effective for the treatment of primary tumors, but not sufficient for the treatment of metastatic tumors, likely owing to the effects of the tumor microenvironment. In this study, we aimed to determine the therapeutic effects of combined treatment with a matrix metalloproteinase (MMP) inhibitor (MMPI) and anti-CTLA-4 antibody in a breast cancer model in mice. Interestingly, combined treatment with MMPI and anti-CTLA-4 antibody delayed tumor growth and reduced lung and liver metastases compared with anti-CTLA-4 alone or vehicle treatment. The functions of the liver and kidney in mice in the different groups did not differ significantly compared with that in normal mice. The CD8+/CD4+ ratio in T cells in the spleen and tumor were increased after monotherapy or combined anti-CTLA-4 antibody plus MMPI therapy compared with that in vehicle-treated mice. Anti-CTLA-4 antibody plus MMPI therapy reduced the percentage of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and decreased the Treg/Th17 cell ratio in the spleen compared with those in the vehicle-treated group. Additionally, anti-CTLA-4 antibody plus MMPI therapy reduced the percentages of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and Th17 cells in tumors compared with that in the vehicle-treated group. Moreover, combined treatment with MMPI and anti-CTLA-4 antibody reduced the microvessel density (MVD) in tumors compared with that in vehicle or MMPI-treated mice. There was a negative correlation between MVD and the CD8+ T cell percentage, CD4+ T cell percentage, and CD8+/CD4+ T cell ratio, but a positive correlation with Tregs, Th17 cells, Treg/Th17 cell ratio, and MDSCs. Thus, these data demonstrated that addition of MMPI enhanced the effects of anti-CTLA-4 antibody treatment in a mouse model of breast cancer by delaying tumor growth and reducing metastases.