The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes.

Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8+ T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8+ T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8+ T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8+ cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (TTSM) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-TTSM cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-TTSM cells could be harnessed to potentiate anti-tumor immunotherapy.

Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer.

Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12 mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12 mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.

Association of domain-specific physical activity with albuminuria among prediabetes and diabetes: a large cross-sectional study.

BACKGROUND: Albuminuria, the presence of excess of protein in urine, is a well-known risk factor for early kidney damage among diabetic/prediabetic patients. There is a complex interaction between physical activity (PA) and albuminuria. However, the relationship of specific-domain PA and albuminuria remained obscure. METHODS: Albuminuria was defined as urinary albumin/creatinine ratio (ACR) > 30 mg/g. PA was self-reported by participants and classified into transportation-related PA (TPA), occupation-related PA (OPA), and leisure-time PA (LTPA). Weighted logistic regression was conducted to compute the odds ratios (ORs) and 95% confidence intervals (CIs). Restricted cubic spline (RCS) was used to evaluate the dose-response of PA domains with the risk of albuminuria. RESULTS: A total of 6739 diabetic/prediabetic patients (mean age: 56.52 ± 0.29 years) were enrolled in our study, including 3181 (47.20%) females and 3558 (52.80%) males. Of them, 1578 (23.42%) were identified with albuminuria, and 5161(76.58%) were without albuminuria. Diabetic/prediabetic patients who adhered the PA guidelines for total PA had a 22% decreased risk of albuminuria (OR = 0.78, 95%CI 0.64-0.95), and those met the PA guidelines for LTPA had a 28% decreased of albuminuria (OR = 0.72, 95%CI 0.57-0.92). However, OPA and TPA were both not associated with decreased risk of albuminuria. RCS showed linear relationship between the risk of albuminuria with LTPA. CONCLUSIONS: Meeting the PA guideline for LTPA, but not OPA and TPA, was inversely related to the risk of albuminuria among diabetic/prediabetic patients. Additionally, achieving more than 300 min/week of LTPA conferred the positive effects in reducing albuminuria among diabetic/prediabetic patients.

Apoptosis dysfunction: unravelling the interplay between ZBP1 activation and viral invasion in innate immune responses.

Apoptosis plays a pivotal role in pathogen elimination and maintaining homeostasis. However, viruses have evolved strategies to evade apoptosis, enabling their persistence within the host. Z-DNA binding protein 1 (ZBP1) is a potent innate immune sensor that detects cytoplasmic nucleic acids and activates the innate immune response to clear pathogens. When apoptosis is inhibited by viral invasion, ZBP1 can be activated to compensate for the effect of apoptosis by triggering an innate immune response. This review examined the mechanisms of apoptosis inhibition and ZBP1 activation during viral invasion. The authors outlined the mechanisms of ZBP1-induced type I interferon, pyroptosis and necroptosis, as well as the crosstalk between ZBP1 and the cGAS-STING signalling pathway. Furthermore, ZBP1 can reverse the suppression of apoptotic signals induced by viruses. Intriguingly, a positive feedback loop exists in the ZBP1 signalling pathway, which intensifies the innate immune response while triggering a cytokine storm, leading to tissue and organ damage. The prudent use of ZBP1, which is a double-edged sword, has significant clinical implications for treating infections and inflammation.

A meta-analysis of predictive value of blood biomarkers in gestational trophoblastic neoplasia.

Background: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to play a diagnostic and predictive role in gestational trophoblastic disease. However, the conclusions are still ambiguous. This meta-analysis aimed to evaluate the combined predictive value of NLR and PLR in the malignant progression of gestational trophoblastic disease. Method: Electronic databases including PubMed, Embase, the Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, Wanfang and China Biomedical Literature Database were searched for the relevant literature published up to 1 October 2022. Study selection and data extraction were performed independently by two reviewers. All analyses were performed using Revman, MetaDisc and STATA software. Results: A total of 858 patients from five studies were included in this meta-analysis. The pooled sensitivity and specificity of NLR were 0.8 (95% CI: 0.71-0.88) and 0.73 (95% CI: 0.69-0.76), respectively, and the area under curve of the summary receiver operating curve was 0.81. The pooled sensitivity and specificity of PLR were 0.87 (95% CI: 0.75-0.95) and 0.49 (95% CI: 0.44-0.54), respectively, and the area under curve of the summary receiver operating curve was 0.88. I2 statistic and Deek's funnel plot showed no heterogeneity and publication bias. Conclusion: NLR can accurately predict the progression from hydatidiform mole to gestational trophoblastic neoplasia and is a promising biomarker in further follow-up.

Effect of lung metastasis on the treatment and prognosis of patients with gestational trophoblastic neoplasia: A systematic review and meta-analysis.

INTRODUCTION: Gestational trophoblastic neoplasia (GTN) is a highly invasive tumor, mainly spreading to the lungs. However, lung metastasis in GTN is usually not considered as an adverse prognostic factor. Therefore, the aim of this study was to summarize the results of previous studies and evaluate the effects of lung metastasis on the treatment and prognosis of GTN. MATERIAL AND METHODS: The study was prospectively registered in PROSPERO (CRD42023372371). Electronic databases including PubMed, Embase, the Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and China Biomedical Literature Database were used for a systematical search of relevant studies published up to November 21, 2022. The observational studies reporting the clinical outcomes of GTN patients with and without lung metastasis were selected. The incidences of resistance, relapse, and mortality of GTN patients were extracted and successively grouped based on the presence of lung metastasis. The pooled relative risks (RRs) and 95% confidence interval (95% CI) of the eligible studies were calculated. The qualities of included studies were assessed with the Newcastle-Ottawa Scale and the certainty of evidence was graded based on the GRADE. The meta-analysis was performed using Stata 12.0 and GradePro software. RESULTS: Five publications with 3629 GTN patients were included. The meta-analysis revealed that the GTN with lung metastasis was strongly correlated with first-line chemoresistance (pooled RR = 1.40, 95% CI: 1.22 to 1.61, p < 0.001), recurrence (pooled RR = 3.03, 95% CI: 1.21 to 7.62, p = 0.018), and disease-specific death (pooled RR = 22.11, 95% CI: 3.37 to 145.08, p = 0.001). Ethnicity was also an important factor and Caucasian GTN patients with lung metastasis showed a higher risk of recurrence as revealed by the subgroup analysis (pooled RR = 5.10, 95% CI: 2.38 to 10.94, p < 0.001). CONCLUSIONS: GTN patients with lung metastasis exhibited a higher risk of chemoresistance, relapse, and disease-specific death. Patients with lung metastasis among the Caucasian population had a higher risk of recurrence than Asian populations. Therefore, the presence of lung metastases might be considered as a high-risk factor for prognosis of GTN and deserves more attention in the choice of first-line chemotherapy regimens and follow-up.

AGO2 promotes tumor progression in KRAS-driven mouse models of non-small cell lung cancer.

Lung cancer is the deadliest malignancy in the United States. Non-small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)-a component of the RNA-induced silencing complex (RISC)-physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC (LSL-KrasG12D/+;p53f/f;Cre) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53 Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the Clara cell-specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of KPC nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with Ago2 ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance.

Enhancing Diagnostic Precision with Utilizing Combined CRP and IL-6 Testing for Deep Vein Thrombosis Detection Post-Endometrial Cancer Surgery.

Background: Deep vein thrombosis is a common complication after surgery, particularly in cancer patients, necessitating efficient diagnostic methods for timely intervention. Objective: This study aimed to investigate the potential of combining C-reactive protein (CRP) and interleukin-6 (IL-6) tests in diagnosing deep vein thrombosis (DVT) following endometrial cancer surgery. Methods: A cohort of 60 patients who developed DVT post-endometrial cancer surgery and were admitted to the First Hospital of Hebei Medical University between March 2018 and March 2022 constituted the DVT group. Additionally, 60 patients who underwent endometrial cancer surgery during the same period but did not develop DVT formed the non-DVT group. Serum levels of CRP and IL-6 were quantified and compared between the two groups using reliable laboratory techniques. Subsequently, the diagnostic accuracy of single-parameter testing (CRP or IL-6 alone) versus combined testing (CRP and IL-6) for postoperative DVT was assessed. Results: Analysis revealed significantly elevated levels of CRP and IL-6 in the serum of patients in the DVT group compared to those in the non-DVT group (P < .05). Furthermore, combined testing of CRP and IL-6 exhibited heightened sensitivity (0.85%), specificity (0.917%), and area under the curve (AUC) (0.952) compared to single-parameter testing alone, indicating its superiority in diagnosing postoperative DVT. Conclusions: The combination of CRP and IL-6 testing presents a promising diagnostic strategy for identifying postoperative DVT in endometrial cancer patients. Implementing this approach in clinical practice could facilitate early detection and prompt management of DVT, thereby potentially reducing associated morbidity and mortality.

Application of Thermal Cycling Amplification Chip Method in the Detection of Respiratory Machine-Associated Pneumonia Pathogens.

Objective: Investigating the application effectiveness of using loop-mediated isothermal amplification (LAMP) on a microfluidic chip to detect the pathogens associated with ventilator-associated pneumonia (VAP). Methods: Eighty samples of bronchoalveolar lavage fluid from patients with ventilator-associated pneumonia (VAP) were collected at The First Hospital of Hebei Medical University from July 2022 to July 2023. The bacterial culture technique and the LAMP method were used to detect the nucleic acid of the pathogens in the patient samples. The positivity rates of bacterial culture and LAMP method in detecting VAP pathogens were analyzed. Results: A total of 80 specimens were examined, with 73 positive specimens detected using the LAMP method (positivity rate of 91.25%) and 60 positive specimens detected using bacterial culture (positivity rate of 75.00%). The LAMP method exhibited a higher number of positive detections compared to bacterial culture. Both methods showed a high level of concordance and were virtually identical in detecting methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Enterobacter aerogenes, Haemophilus influenzae, and Streptococcus pneumoniae. Conclusion: The LAMP method demonstrates significantly improved performance in the detection of pathogens for VAP, with a higher pathogen positivity rate compared to bacterial culture. This method holds promising prospects for clinical application.

Concentration Effect, Structural Properties, and Driving Force on Aß28 Dimerization with and without Zn2+ Cooperation: Learning from Replica Exchange Sampling.

Zn2+ is a very important factor in promoting the formation of amyloid beta (Aß) aggregates and amyloid plaques. The Zn2+ -bound Aß species generate amorphous or low molecular-weight oligomers. However, it is a lack of studies to approach the starting structural features (dimerization) in Aß nucleation processes with and without Zn2+ , which is the key point in understanding Zn2+ -induced nucleation mechanisms. To better understand the effect of concentration, structural properties, and the driving force, 14 independent replica exchange molecular dynamics simulations were performed in Aß28 dimerization with and without Zn2+ (zAß28 ) cooperation. Our scanning results show that the aggregation propensity is easier in Aß28 -Aß28 and Aß28 -zAß28 systems than zAß28 -zAß28 system. In binding property, the Aß28 -Aß28 model (-61.5 kcal mol-1 ) is stronger than zAß28 -zAß28 (-26.6 kcal mol-1 ) and Aß28 -zAß28 (-7.24 kcal mol-1 ) models. Further analysis confirmed that H13 and H14 residues play specific roles in the three systems. The key point is the orientation of N atom of the imidazole ring in histidine residues. Furthermore, we discovered different driving forces for each system. Our current study contributes to the understanding of how the Aß28 dimer interacts with Zn2+ , which could lead to new insights into Zn2+ -induced nucleation mechanisms.

CircRIMS promotes cerebral ischemia-reperfusion injury through increasing apoptosis and targeting the miR-96-5p/JAK/STAT1 axis.

OBJECTIVE: This study aims to explore the function of circRIMS in cerebral ischemia/reperfusion (CIR) and its regulatory mechanism. METHOD: The expression of the circRIMS was examined in GEO chip data and validated by qRT-PCR analysis. A middle cerebral artery occlusion/repression (MCAO/R) model was developed using C57BL/6J mice. Starbase and circinteractome were employed to identify the target miRNA and mRNA. The result was confirmed by dual-luciferase reporter assay, and biotinylated RNA-pulldown assay. The cell viability and apoptosis were confirmed through CCK-8 and flow cytometry assay. RESULTS: This study revealed that circRIMS expression was upregulated in MCAO mice model and OGD/RX-simulated cell model. Knockdown circRIMS demonstrated the functional of circRIMS in increasing cell viability, reducing apoptosis, LDH activity and inflammatory factors secretion in OGD/RX-simulated CIR injury in vitro. Additionally, miR-96-5p was identified as a target of circRIMS, while the STAT1 gene is a downstream gene of miR-96-5p, and JAK was also considered to be a downstream gene of the JAK-STAT pathway. Furthermore, inhibition of miR-96-5p or overexpression of STAT1 promoted the progression of CIR injury by elevating apoptosis, reducing cell viability, and increasing the secretion of inflammatory cytokines. CONCLUSION: CircRIMS contributes to the progression of CIR injury via regulating miR-96-5p/JAK/STAT1 axis.

The Recycling of Spent Lithium-Ion Batteries: Crucial Flotation for the Separation of Cathode and Anode Materials.

The recycling of spent lithium-ion batteries (LIBs) has attracted great attention, mainly because of its significant impact on resource recycling and environmental protection. Currently, the processes involved in recovering valuable metals from spent LIBs have shown remarkable progress, but little attention has been paid to the effective separation of spent cathode and anode materials. Significantly, it not only can reduce the difficulty in the subsequent processing of spent cathode materials, but also contribute to the recovery of graphite. Considering the difference in their chemical properties on the surface, flotation is an effective method to separate materials, owing to its low-cost and eco-friendly characteristics. In this paper, the chemical principles of flotation separation for spent cathodes and materials from spent LIBs is summarized first. Then, the research progress in flotation separation of various spent cathode materials (LiCoO2, LiNixCoyMnzO2, and LiFePO4) and graphite is summarized. Given this, the work is expected to offer the significant reviews and insights about the flotation separation for high-value recycling of spent LIBs.

Transgenic insect-resistant Bt cotton expressing Cry1Ac/1Ab does not harm the insect predator Geocoris pallidipennis.

The large-scale commercial cultivation of genetically modified (GM) cotton has brought significant economic and environmental benefits. However, GM crops must undergo strict environmental monitoring and long-term observation. An important natural enemy insect in cotton fields, Geocoris pallidipennis, can ingest the Bt protein expressed in GM cotton by feeding on herbivorous insects that feed on the cotton. However, the potential risk of GM cotton to G. pallidipennis is still unclear. We here evaluated the effects of Bt cotton expressing the Cry1Ac/1Ab protein on nymphs and adults G. pallidipennis. Cry1Ac protein was detected in the midgut of the cotton bollworm, Helicoverpa armigera, after it ingested Bt cotton, and in the midgut of G. pallidipennis nymphs and adults preying on Bt-fed H. armigera. However, the survival rate, growth, development, and fecundity of G. pallidipennis were not adversely affected. Furthermore, G. pallidipennis cadherins, and those genes related to detoxification, antioxidant activity, nutrient utilization, and immune function were not differentially expressed in response to Cry1Ac exposure. Finally, we showed that Cry1Ac could not bind to brush border membrane vesicles (BBMV) proteins in G. pallidipennis nymphs or adults. In summary, these results indicate that the potential negative effect of transgenic Cry1Ac/1Ab cotton on the insect redator G. pallidipennis is negligible.

Expression and change of miR-199b-5p, s HLA-G in thyroid carcinoma.

OBJECTIVE: This research aims to investigate the relationship between the expression of microRNA-199b-5p (miR-199b-5p) and soluble human leukocyte antigen G (sHLA-G) in thyroid cancer tissues and its clinicopathological characteristics, as well as its impact on prognosis. METHODS: Frozen tissues and serum from 85 patients with thyroid cancer, 27 with thyroid adenoma, 19 with Hashimoto's thyroiditis and 14 with nodular goiter from February 2014 to March 2016 were sampled. The miR-199b-5pmRNA expression in tissues was analyzed by real-time quantitative PCR. Serum HLA-G expression was detected by ELISA, and the relationship between s HLA-G expression and clinicopathological characteristics of thyroid cancer was analyzed. The relationship between 1- and 3-year survival rates of all patients and the expression of both detection indexes was observed. RESULTS: Compared with normal thyroid specimens, nodular goiter, Hashimoto's thyroiditis, thyroid adenoma and thyroid cancer patients, the relative expression of miR-199b-5pmRNA in thyroid cancer tissues was the lowest, while that of s HLA-G was the highest in serum of patients (P < 0.05). The levels of miR-199b-5pmRNA and serum s HLA-G in tumor tissues were correlated with clinical pathological features such as tumor size, differentiation degree, capsule invasion, lymph node metastasis, etc. (all P < 0.05). The expression of miR-199b-5pmRNA and s HLA-G were negatively correlated. ROC curve identified that miR-199b-5pmRNA and HLA-g had obvious diagnostic value for thyroid cancer patients. Kaplan-Meier survival analysis manifested that the 1- and 3-year survival rates of the miR-199b-5p low expression group in thyroid cancer tissues were lower than the miR-199b-5p high expression group, and the rates of the s HLA-G low expression group were higher than the s HLA-G high expression group. CONCLUSION: The miR-199b-5p expression in thyroid cancer tissues and HLA-g in serum were related to tumor size, differentiation degree, capsular invasion, lymph node metastasis and other characteristics. MiR-199b-5p may jointly affect the progression of thyroid cancer with s HLA-G.

Effects of temperature on the nitrate reductase activity and growth of Ulva prolifera.

To better understand the effect of temperature on the growth and nitrate reductase activity (NRA) of Ulva prolifera and their relationships, the effects of five different temperatures (10, 15, 20, 25, and 30°C) were investigated in a laboratory setup. In this study, an optimization in vitro analysis method for Ulva prolifera NRA was developed. Under different treatments, the NRA, nitrate concentration, pH, the intracellular nitrate and nitrite concentrations, and the POC/PON were evaluated. The results of the in vitro analysis method showed it was optimal for the NRA assay when the extraction time was 6 min, enzymatic reaction time 30 min, volume of phenazine methosulfate (PMS) solution 50 µL, NADH concentration 0.36 mM, and KNO3 concentration 10 mM. The maximal NRA (NRAmax ) appeared on the 2nd day in the 10, 15, and 20°C (low-temperature) groups and on the 1st day in the 25 and 30°C (high-temperature) groups. The algal growth ended earlier at a high temperature, ending after 5 d at 30 and 25°C and 7 d at 20°C and 9 d at 15°C, and the alga at 10°C had been growing during the incubation period. Ulva prolifera cultivated in a range of 10-20°C had a long growth cycle and the NRA decreased with increasing temperature when exceeded 15°C, a positive correlation between algal growth and NRA was observed. This study supports NRA is a suitable proxy of the effects of temperature changes on the ability of Ulva prolifera to uptake and metabolize nitrogen nutrients.

Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor.

Bromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on the N-terminal tails of histones through two bromodomains (BD1 and BD2) to regulate gene transcription. Inhibiting one or both of bromodomains resulted in different phenotypes, suggesting BD1 and BD2 may have different functions. Here we report the characterisation of a natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 inhibitor. The compound is 100-fold more selective for BRD4-BD2 (IC50 = 204 nM) than BRD4-BD1 (IC50=17.9 µM). Co-crystal structures show 3',4',7,8-tetrahydroxyflavone binds to the acetylated lysine binding pocket of BRD4-BD1 or BRD4-BD2, but establishes more interactions with BRD4-BD2 than BRD4-BD1. Our data suggest 3',4',7,8-tetrahydroxyflavone as a potent selective inhibitor of BRD4-BD2 with a novel chemical scaffold. Given its distinct chemical structure from current BRD4 inhibitors, this compound may open the door for a novel class of anti-BRD4 inhibitors by serving as a lead compound.

Gadolinium-enhanced magnetic resonance versus computed tomography angiography for renal artery stenosis: A systematic review and meta-analysis.

Gadolinium-enhanced magnetic resonance angiography (MRA) and computed tomography angiography (CTA) are commonly used for diagnosing renal arterial stenosis (RAS); however, the diagnostic value is yet controversial. The aim of the study was to evaluate the diagnostic values of both methods. Electronic databases, including PubMed, Embase, and the Cochrane Library, were searched for studies, since inception until October 2017. A total of four articles involving 486 subjects were included in the analysis. The summary of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic (ROC) (AUC) were 0.70, 0.82, 14.54, 0.29, 63.80, and 0.81 for MRA-based diagnosis of RAS, respectively. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC for CTA detecting RAS were 0.73, 0.96, 13.04, 0.29, 71.99, and 0.93, respectively. Gadolinium-enhanced MRA and CTA provide a satisfactory diagnostic accuracy, thereby playing a critical role in the diagnosis of RAS.

Homeostasis Imbalance of Microglia and Astrocytes Leads to Alteration in the Metabolites of the Kynurenine Pathway in LPS-Induced Depressive-Like Mice.

In the pathology-oriented study of depression, inflammation hypothesis has received increasing attention for recent years. To mimic the depressive state caused by inflammation, rodents injected intraperitoneally with lipopolysaccharide (LPS) are usually used to stimulate an immune response. However, the dose of LPS that causes depressive-like behavior varies widely across many literatures. Previous study has uncovered the non-linearity in the dose-effect relationship for the depressive-like behavior induced by LPS administration, while the reason for this is still unclear. The present study aims to investigate the underlying mechanisms of this non-linear dose-dependent relationship. Four groups of mice were injected intraperitoneally with different doses of LPS (0, 0.32, 0.8, and 2 mg/kg). The tail suspension test was conducted to evaluate the depressive-like behavior within 23-25 h after the LPS administration. The neuroplasticity was assessed by the levels of related proteins, TrkB and PSD-95, and by the quantification of neurons using Nissl staining. The levels of the two metabolites of the kynurenine (KYN) pathway, 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA), in the brain were analyzed by LC-MS/MS. Activation of microglia and astrocytes in the brain were also determined by immunohistochemistry and western blotting, respectively. The results showed that, compared with the control group, the mice in the 0.8 mg/kg LPS-treated group exhibited a remarkable increase of immobility time in the tail suspension test. The neuroplasticity of mice in the 0.8 mg/kg LPS-treated group was also significantly reduced. The neurotoxic metabolite, 3-HK, was accumulated significantly in the hippocampus of the 0.8 mg/kg LPS-treated mice. Surprisingly, the 2 mg/kg LPS-treated mice did not exhibit a remarkable change of 3-HK but expressed increased KYNA significantly, which is neuroprotective. Furthermore, the activation of microglia and astrocytes, which were recognized as the primary source of 3-HK and KYNA, respectively, corresponded to the content of these two metabolites of the KYN pathway in each group. Consequently, it was speculated that the homeostasis of different glial cells could lead to a non-linear dose-dependent behavior by regulating the KYN pathway in the LPS-induced depressive-like mice.

Activation of MET signaling by HDAC6 offers a rationale for a novel ricolinostat and crizotinib combinatorial therapeutic strategy in diffuse large B-cell lymphoma.

Some histone deacetylases (HDACs) promote tumor cell growth and pan- or selective HDAC inhibitors are active in some cancers; however, the pivotal HDAC enzyme and its functions in human diffuse large B-cell lymphoma (DLBCL) remain largely unknown. Using NanoString nCounter assays, we profiled HDAC mRNA expression and identified HDAC6 as an upregulated HDAC family member in DLBCL tissue samples. We then found that HDAC6 plays an oncogenic role in DLBCL, as evidenced by its promotion of cell proliferation in vitro and tumor xenograft growth in vivo. Mechanistically, the interaction between HDAC6 and HR23B downregulated HR23B expression, thereby reducing the levels of casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase for hepatocyte growth factor receptor (MET), which resulted in the inhibition of MET ubiquitination-dependent degradation. In addition, enhanced HDAC6 expression and decreased HR23B expression were correlated with poor overall survival rates among patients with DLBCL. Taken together, these results establish an HDAC6-HR23B-MET axis and indicate that HDAC6 is a potent promoter of lymphomagenesis in DLBCL. Thus, a therapeutic strategy based on HDAC6 inhibitors in combination with MET inhibitors is promising. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Merkel cell carcinoma arising in association with cutaneous T-cell lymphoma: A potential diagnostic pitfall.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma with increased prevalence in patients with immunosuppression or B-cell neoplasms. To the best of our knowledge, an association with cutaneous T-cell lymphoma (CTCL) has not been previously described. In this report, we present two cases of MCC arising in the setting of CTCL. The first case was a female during her 70s with previously diagnosed stage IVA1 Sezary syndrome. Biopsy of a scaly patch showed two distinct abnormal cell populations. The first population consisted of hyperchromatic dermal and epidermotropic lymphocytes, expressing CD3 and CD4 with diminished CD7. The second population consisted of intraepidermal clusters of larger atypical cells that expressed synaptophysin, neurofilament, CK20, and Merkel cell polyomavirus transcript. The combination of findings was consistent with intraepidermal MCC in a background of CTCL. Excision showed residual intraepidermal MCC without dermal involvement. The second case was a male during his 50s with a longstanding history of mycosis fungoides, who presented with a new lesion on his right thigh. Biopsy and excision showed dermal MCC without secondary involvement by CTCL. Our cases show that MCC may rarely occur in the setting of T-cell lymphoma, and that intraepidermal MCC may mimic epidermotropic T-cells.