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Background Apolipoprotein (Apo) A1 and Apo B are strongly associated with the risk of atherosclerotic cardiovascular disease (ASCVD). However, the relationship between the Apo B/A1 ratio and the morphology of coronary vulnerable plaques has not been fully elucidated in patients with ASCVD. Methods A total of 320 patients with ASCVD undergoing percutaneous coronary intervention were enrolled and assigned into acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) group. The morphology of culprit plaque was analyzed by intravascular optical coherence tomography. Association between the Apo B/A1 ratio and coronary vulnerable plaques were evaluated using logistic regression models and receiver operator characteristic (ROC) curve analyses. Results The Apo B/A1 ratio was higher in ACS patients than CCS patients (0.77 ± 0.28 vs. 0.64 ± 0.22, P Conclusions The Apo B/A1 ratio is an independent predictor for plaque rupture, erosion, and thrombus in patients with ASCVD.

Background: Utilities of blood-based biomarkers in Alzheimer’s disease (AD) clinical trials remain unknown. Objective: To evaluate the ability of plasma neurofilament light chain (NfL) to predict future declines in cognition and activities of daily living (ADL) outcomes in 26 older adults with mild-to-moderate AD dementia from the FIT-AD Trial. Methods: Plasma NfL was measured at baseline and 3 and 6 months. Cognition and ADL were assessed using the AD Assessment Scale-Cognition (ADAS-Cog) and AD Uniform Dataset Instruments and Disability Assessment for Dementia (DAD), respectively, at baseline, 3, 6, 9, and 12 months. Linear mixed effects models were used to examine the associations between baseline or change in plasma NfL and changes in outcomes. Results: Higher baseline plasma NfL was associated with greater rate of decline in ADAS-Cog from baseline to 6 months (standardized estimate of 0.00462, p = 0.02853) and in ADL from baseline to 12 months (standardized estimate of –0.00284, p = 0.03338). Greater increase in plasma NfL in short term from baseline to 3 months was associated with greater rate of decline in memory and ADL from 3 to 6 months (standardized estimate of –0.04638 [0.003], p = 0.01635; standardized estimate of –0.03818, p = 0.0435) and greater rate of decline in ADL from 3 to 12 month (standardized estimate of –0.01492, p = 0.01082). Conclusion: This study demonstrated that plasma NfL might have the potential to predict cognitive and function decline up to 12 months. However, future studies with bigger sample sizes need to confirm the findings.

Objectives To explore the correlations among social isolation and symptoms of anxiety and depression among patients with breast cancer in China and to further verify the mediating role of social support in social isolation and symptoms of depression or anxiety. Design A cross‐sectional survey. Settings The cluster sampling method was conducted for 456 female inpatients diagnosed with breast cancer at the Tumor Hospital Affiliated of Harbin Medical University from April 2019–September 2019. Methods Pearson correlation analysis was used for identifying correlations among all the variables. Mediation effect analysis was used to examine the role of social support in social isolation and symptoms of depression or anxiety. Results The results showed a prevalence of 73.26% and 70.44% for anxiety and depression symptoms in patients with breast cancer, respectively. Anxiety was significantly negatively correlated with social support (r = −.334, p

Although p21 activated kinase 5 (PAK5) is related to the progression of multiple cancers, its biological function in breast cancer remains unclear. Apoptosis-inducing factor (AIF) is a vital apoptosis factor in mitochondria, which can be released from mitochondria and enter the nucleus, causing caspase-independent apoptosis. In this study, we reveal that PAK5 inhibits apoptosis by preventing the nuclear translocation of AIF. PAK5 inhibits the release of AIF from mitochondria in breast cancer cells by decreasing the mitochondria membrane permeability and increasing the membrane potential. Furthermore, PAK5 phosphorylates AIF at Thr281 site to inhibit the formation of AIF/importin α3 complex, leading to decrease AIF nuclear translocation. Functionally, we demonstrate that PAK5-mediated AIF phosphorylation promotes the proliferation of breast cancer cells and accelerates the growth of breast cancer in vivo. Significantly, PAK5 and AIF expression in breast cancer are positively correlated with poor patient prognosis. PAK5 expression is negatively correlated with AIF nuclear translocation. These results suggest that PAK5-AIF signaling pathway may play an essential role in mammary tumorigenesis, providing a new therapeutic target for the treatment of breast cancer.

The biological function of nuclear PAK4 in ERα-positive breast cancer osteolytic bone destruction remains unclear. Here, we find that the nuclear PAK4 promotes osteoclastogenesis and tumor-induced osteolysis via phosphorylating RUNX1. We show that nuclear PAK4 interacts with and phosphorylates RUNX1 at Thr-207, which induces its localization from the nucleus to the cytoplasm and influences direct interaction with SIN3A/HDAC1 and PRMT1. Furthermore, we reveal that RUNX1 phosphorylation by PAK4 at Thr-207 promotes osteolytic bone destruction via targeting downstream genes related to osteoclast differentiation and maturation. Importantly, we verify changes in RUNX1 subcellular localization when nuclear PAK4 is positive in breast cancer bone metastasis tissues. Functionally, we demonstrate that RUNX1 phosphorylation promotes osteolytic bone maturation and ERα-positive breast cancer-induced osteolytic bone damage in the mouse model of orthotopic breast cancer bone metastasis. Our results suggest PAK4 can be a therapeutic target for ERα-positive breast cancer osteolytic bone destruction.

The development of blood-based biomarkers of Alzheimer’s disease (AD) pathology as tools for screening the general population, and as the first step in a multistep process to determine which non-demented individuals are at greatest risk of developing AD dementia, is essential. Proteins that are reflective of AD pathology, such as amyloid beta 42 (Aβ42), tau proteins [total tau (T-tau) and phosphorylated tau (P-tau)], and neurofilament light chain (NfL), are detectable in the blood. However, a major challenge in measuring these blood-based proteins is that their concentrations are much lower in plasma or serum than in the cerebrospinal fluid. Single molecule array (SiMoA) is an ultrasensitive technology that can detect proteins in blood at sub-femtomolar concentrations (i.e., 10−16 M). In this review, we focus on the utility of SiMoA assays for the measurement of plasma or serum Aβ42, P-tau, T-tau, and NfL levels and discuss future directions.

Radiolabeled epidermal growth factor receptor (EGFR) targeted antibody could be used for imaging EGFR expressing cancer. In this study, the SPECT probe 125I-Necitumumab were synthesized and evaluated for SPECT imaging of non-small cell lung cancer (NSCLC). In vivo biodistribution study indicated that 125I-Necitumumab was cleared rapidly in most organs and tissues. Though the tumor expressed a relatively high level of EGFR, however SPECT images showed no obvious uptake in the tumors. Therefore, we considered that 125I-Necitumumab was not suitable for EGFR-targeted NSCLC SPECT imaging.

Background: Remote ischemic pre-conditioning (RIPC) alleviated the myocardial ischemia-reperfusion injury, yet the underlying mechanisms remain to be fully elucidated, especially at the late phase. Searching a key component as a transfer carrier may provide a novel insight into RIPC-mediated cardioprotection in the condition of myocardial ischemia-reperfusion.Objective: To investigate the cardioprotective effect of plasma exosomes at the late phase of RIPC and its potential signaling pathways involved.Methods and Results: Exosomes were isolated from the plasma of rats 48 h after the RIPC or control protocol. Although the total plasma exosomes level had no significant change at the late phase of RIPC (RIPC-exosome) compared with the control exosomes (Control-exosome), the RIPC-exosome afforded remarkable protection against myocardial ischemia-reperfusion (MI/R) injury in rats and hypoxia-reoxygenation (H/R) injury in cells. The miRNA array revealed significant enrichment of miR-126a-3p in RIPC-exosome. Importantly, both miR-126a-3p inhibitor and antagonist significantly blunted the cardioprotection of RIPC-exosome in H/R cells and MI/R rats, respectively, while miR-126a-3p mimic and agomir showed significant cardioprotection against H/R injury in cells and MI/R injury in rats. Mechanistically, RIPC-exosome, especially exosomal miR-126a-3p, activated the reperfusion injury salvage kinase (RISK) pathway by enhancing the phosphorylation of Akt and Erk1/2, and simultaneously inhibited Caspase-3 mediated apoptotic signaling.Conclusions: Our findings reveal a novel myocardial protective mechanism that plasma exosomes at the late phase of RIPC attenuate myocardial ischemia-reperfusion injury via exosomal miR-126a-3p.

Excess mental stress may harm health, and even accelerate cancer initiation and progression. One fourth of breast cancer patients suffer mental stress including anxiety, sadness, or depression, which negatively affect prognosis and survival. However, the regulatory mechanism is yet to be determined. Herein, we applied unpredictable stress stimuli to the breast tumor-bearing mice to establish a xenograft model of breast cancer suffering mental stress, followed by behavioral tests, tumor growth tracking, immune analysis, miRNA screening, and tumor cell proliferation analysis as well. As a result, increased stress hormone levels in serum, decreased percentage of T and NK cells in both blood and tumor samples and accelerated tumor growth in vivo were observed in the mice exposed to mental stress. Promoted cell proliferation was observed in both primary tumor cells derived from the stressed mice and 4T1 breast cancer cells treated with stress hormone corticosterone. In addition, a subset of miRNAs including miR-326, 346, 493, 595, 615, and 665 were identified through a miRNA screening with downregulation in tumors of the stressed mice. CCND1 was identified as a common target gene of miR-346 and miR-493, the top two most significantly downregulated miRNAs by stress exposure. The stress-miRNA-CCND1 signaling regulation of the tumor cell proliferation was further validated in 4T1 cells treated with corticosterone in vitro. GO terms and KEGG pathways analyses on the target genes of miR-346 and miR-493 revealed their involvement in the regulation of human cancer and neuron system, indicating the importance of non-coding genome in mediating the mental stress-induced cancer regulation. In conclusion, this study not only explored immune and nonimmune mechanisms through which mental stress exposure contributes to tumor growth in breast cancer, but also suggested a new therapeutic strategy for cancer patients suffering mental stress.

Cancer stem cells (CSCs) contribute to the cancer initiation, metastasis and drug resistance in non-small cell lung cancer (NSCLC). Herein, we identified a miR-221/222 cluster as a novel regulator of CSCs in NSCLC. Targeted overexpression or knockdown of miR-221/222 in NSCLC cells revealed the essential roles of miR-221/222 in regulation of lung cancer cell proliferation, mammosphere formation, subpopulation of CD133+ CSCs and the expression of stemness genes including OCT4, NANOG and h-TERT. The in vivo animal study showed that overexpression of miR-221/222 significantly enhanced the capacity of lung cancer cells to develop tumor and grow faster, indicating the importance of miR-221/222 in tumorigenesis and tumor growth. Mechanistically, Reck was found to be a key direct target gene of miR-221/222 in NSCLC. Overexpression of miR-221/222 significantly suppressed Reck expression, activated Notch1 signaling and increased the level of NICD. As an activated form of Notch1, NICD leads to enhanced stemness in NSCLC cells. In addition, knockdown of Reck by siRNA not only mimicked miR-221/222 effects, but also demonstrated involvement of Reck in the miR-221/222-induced activation of Notch1 signaling, verifying the essential roles of the miR-221/222-Reck-Notch1 axis in regulating stemness of NSCLC cells. These findings uncover a novel mechanism by which lung CSCs are significantly manipulated by miR-221/222, and provide a potential therapeutic target for the treatment of NSCLC.

It is unclear whether cerebrospinal fluid (CSF) phosphatidylcholines (PCs) are associated with neuroimaging measures of amyloid deposition and neurodegeneration (glucose metabolism, cortical thickness, and hippocampal volume), cognitive decline, or risk of mild cognitive impairment (MCI) among cognitively unimpaired older adults. This study investigated the associations of 19 individual CSF PC concentrations and their total sum with cross-sectional and longitudinal measures of amyloid deposition and neurodegeneration, global and domain-specific cognitive z-scores, and risk of MCI among 655 cognitively unimpaired participants, mean age of 71 years, enrolled in the Mayo Clinic Study of Aging. Neither the CSF total PC concentration nor individual CSF PCs were cross-sectionally or longitudinally associated with neuroimaging measures, cognition, or risk of MCI.

Although clinically associated with the progression of multiple cancers, the biological function of p21-activated kinase 5 (PAK5) in breast cancer remains largely unknown. Here, we reveal that the PAK5-aspartyl aminopeptidase (DNPEP)-ubiquitin-specific protease 4 (USP4) axis is involved in breast cancer progression. We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. Functionally, we demonstrate that DNPEP overexpression suppresses breast cancer cell proliferation and invasion and restricts breast cancer growth and metastasis in mice. Furthermore, we identify USP4 as a downstream target of the PAK5-DNPEP pathway; DNPEP mediates USP4 downregulation. Importantly, we verify that DNPEP expression is frequently downregulated in breast cancer tissues and is negatively correlated with PAK5 and USP4 expression. PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway. Consistently, analyses of clinical breast cancer specimens revealed significantly increased PAK5 and USP4 levels and an association between higher PAK5 and USP4 expression and worse breast cancer patient survival. These findings suggest a pivotal role for PAK5-elicited signaling in breast cancer progression.

Plasma phosphatidylcholines (PCs) have been examined in the context of Alzheimer's disease dementia. However, their association with longitudinal changes in amyloid deposition remains unknown. This study investigated the associations of 8 plasma PC levels (PC aa [14:0_14:0], PC aa [16:0_16:0], PC aa [16:0_18:2], PC aa [16:0_22:6], PC aa [18:0_18:0], PC aa [18:0_18:1], PC aa [18:0_20:4], PC aa [18:1_18:1]) with cross-sectional and longitudinal measures of amyloid deposition, Alzheimer's disease–associated neurodegeneration (glucose metabolism and cortical thickness), and cognition (global- and domain-specific) of 1440 cognitively unimpaired participants (47% female, aged 50.7–95.3 years) in the Mayo Clinic Study of Aging. Longitudinally, higher baseline levels of PC aa [16:0_18:2], PC aa [18:0_18:1], and PC aa [18:1_18:1] were associated with slower decline in performance on tests of global cognition and specific cognitive domains. Furthermore, higher baseline levels of plasma PC aa (14:0_14:0) were associated with slower amyloid deposition and cortical thinning after multiple covariable adjustment (age, sex, education, medical comorbidity, dyslipidemia, statin use, and APOE4 allele presence). Our study findings support an independent association between plasma PC aa (14:0_14:0) with slower amyloid deposition and cortical thinning among cognitively unimpaired older adults.

Introduction/Objective Elevated parathyroid hormone-related peptide (PTHrP) is a biomarker often associated with hypercalcemia of malignancy. However, elevations of PTHrP can be seen in non-malignant patients with normal calcium status, notably renal failure. We investigate whether a LC-MS/MS test that specifically measures a peptide in the middle region of PTHrP fragments is immune to false elevations of PTHrP. Furthermore, we examine if PTHrP/PTH ratio or renal status can be used to further characterize PTHrP elevations in a cohort of normocalcemic patients. Methods/Case Report We conducted a retrospective study on adult patients that had at least one PTHrP laboratory test (i.e., ARUP PTHrP by LC-MS/MS) within the past 10 years (01/01/2011 to 04/29/2021) at a large academic center. We further stratified this cohort by demographics and additional laboratory markers including calcium status, parathyroid hormone (PTH) (i.e., by Siemens Centaur assay (Malvern, PA)), renal status, and known malignancies. Results (if a Case Study enter NA) We identified a total of 941 patients (585 female and 356 male). 33% of patients (30% [70/233] female and 36% [84/236] male) with elevated PTHrP were normocalcemic (i.e., did not have an elevation in calcium, ionized calcium, or diagnosis of hypercalcemia). 95% (21/22) of normocalcemic males and 100% (17/17) of normocalcemic females with an elevated PTHrP and elevated PTH had a PTHrP/PTH ratio below the normal sex specific reference ranges of 1.07 and 1.86, respectively. A subset of normocalcemic patients with elevated PTHrP had an estimated glomerular filtration rate (eGFR) recorded. Of these patients, 100% (58/58) of females and 94% (65/59) of males had an eGFR below 90 mL/min/1.73 m2 had an eGFR less than 30 mL/min/1.73 m2. and 50% (29/58) of females and 38% (26/69) of males Conclusion Our study supports the hypothesis that elevated PTHrP in the setting of normal calcium may occur due to renal insufficiency.

An accurate assessment of HER2 status in patients with colorectal cancer is very important, because only the patients overexpressing HER2 can benefit most from the anti-HER2 targeted therapy. In this study, we investigated the feasibility of detecting HER2 expression in colon cancer by SPECT imaging using 125I-Herceptin, which showed high labeling rate, good in vitro stability and high binding specificity for HER2. HER2-positive mouse colon adenocarcinoma cell line (MC 38) was chosen as the colon caner cell model, and used for the establishment of colon cancer-bearing nude mice model. SPECT/CT imaging suggested that the tumors can be visualized at 12 h after the injection of 125I-Herceptin, and the uptake of tracer in tumors reached the peak at 24 h after injection, and can be attenuated significantly by pretreatment with an excess of nonlabeled Herceptin. These results indicates that 125I-Herceptin can be considered as an effective SPECT probe for the non-invasive detection of HER2 expression in colon cancer.

Significant 68Ga-PSMA-11 activity is commonly observed in the lacrimal and salivary glands on PSMA PET/CT. An 80-year-old man after radical prostatectomy was evaluated with 68Ga-PSMA-11 PET/CT. There was no obvious PSMA uptake in the bilateral lacrimal, parotid, and submandibular glands. Subsequently, based on laboratory examination results and 99mTcO4 salivary gland scintigraphy, this patient was diagnosed with Sjogren syndrome, which accounted for the absence of uptake by the glands. This case showed the potential of 68Ga-PSMA-11 PET/CT in the evaluation of the lacrimal glands and major salivary glands.

BackgroundGastric cancer (GC) still represents the third leading cause of cancer-related death worldwide. Peritoneal relapse (PR) is the most frequent metastasis occurring among patients with advanced gastric cancer. Increasingly more evidence have clarified the tumor immune microenvironment (TIME) may predict survival and have clinical significance in GC. However, tumor-transcriptomics based immune signatures derived from immune profiling have not been established for predicting the peritoneal recurrence of the advanced GC.MethodsIn this study, we depict the immune landscape of GC by using transcriptome profiling and clinical characteristics retrieved from GSE62254 of Gene Expression Omnibus (GEO). Immune cell infiltration score was evaluated via single-sample gene set enrichment (ssGSEA) analysis algorithm. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to select the valuable immune cells and construct the final model for the prediction of PR. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to check the accuracy of PRIs. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore the molecular pathways associated with PRIs.ResultsA peritoneal recurrence related immune score (PRIs) with 10 immune cells was constructed. Compared to the low-PRIs group, the high-PRIs group had a greater risk. The upregulation of the focal adhesion signaling was observed in the high-PRIs subtype by GSEA and KEGG. Multivariate analysis found that both in the internal training cohort and the internal validation cohort, PRIs was a stable and independent predictor for PR. A nomogram that integrated clinicopathological features and PRIs to predict peritoneal relapse was constructed. Subgroup analysis indicated that the PRIs could obviously distinguish peritoneal recurrence in different molecular subtypes, pathological stages and Lauren subtypes, in which PRIs of Epithelial-Mesenchymal Transitions (EMT) subtype, III-IV stage and diffuse subtype are higher respectively.ConclusionOverall, we performed a comprehensive evaluation of the immune landscape of GC and constructed a predictive PR model based on the immune cell infiltration. The PRIs represents novel promising feature of predicting peritoneal recurrence of GC and sheds light on the improvement of the personalized management of GC patients after surgery.

The most common cause of hyperglycemia is diabetes mellitus, which has become a worldwide epidemic. This chapter concerns the definition, diagnosis, causes, and evaluation of hyperglycemia, diabetes, and related conditions (e.g., the metabolic syndrome). Emphasis is placed on the broad causes of diabetes that range from the common conditions of type 1 and type 2 diabetes to the emerging field of monogenic diabetes. The reader is referred to the second edition of this textbook for an extensive discussion of the metabolic syndrome although the salient clinical features of the metabolic syndrome are described in this chapter.

Primary liver tumor with hepatocellular carcinoma accounting for 75–80% of all such tumors, is one of the global leading causes of cancer-related death, especially in cirrhotic patients. Liver tumors are highly hypervascularized via the hepatic artery, while normal liver tissues are mainly supplied by the portal vein; consequently, intra-arterially delivered treatment, which includes transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), is deemed as a palliative treatment. With the development of nuclear technology and radiochemistry, TARE has become an alternative for patients with hepatic cancer, especially for patients who failed other therapies, or for patients who need tumor downstaging treatment. In practice, some radionuclides have suitable physicochemical characteristics to act as radioactive embolism agents. Among them, 90Y emits β rays only and is suitable for bremsstrahlung single photon emission computed tomography (BS SPECT) and positron emission tomography (PET); meanwhile, some others, such as 131I, 153Sm, 166Ho, 177Lu, 186Re, and 188Re, emit both β and γ rays, enabling embolism beads to play a role in both therapy and single photon emission computed tomography (SPECT) imaging. During TARE, concomitant imaging provide additive diagnostic information and help to guide the course of liver cancer treatment. Therefore, we review the theranostic radionuclides that have been used or could potentially be used in TARE for liver cancer and focus on the clinical benefits of diagnostic applications, including real-time monitoring of embolism beads, evaluating irradiation dose, predicting therapy effects, and corresponding adjustments to TARE.

Gametogenesis, the formation of gametes from gametocytes, an essential step for malaria parasite transmission, is targeted by transmission-blocking drugs and vaccines. We identified a conserved protein (PBANKA_0305900) in Plasmodium berghei, which encodes a protein of 22 kDa (thus named Pb22) and is expressed in both asexual stages and gametocytes. Its homologues are present in all Plasmodium species and its closely related, Hepatocystis, but not in other apicomplexans. Pb22 protein was localised in the cytosols of schizonts, as well as male and female gametocytes. During gamete-to-ookinete development, Pb22 became localised on the plasma membranes of gametes and ookinetes. Compared to the wild-type (WT) parasites, P. berghei with pb22 knockout (KO) showed a significant reduction in exflagellation (~89%) of male gametocytes and ookinete number (~97%) during in vitro ookinete culture. Mosquito feeding assays showed that ookinete and oocyst formation of the pb22-KO line in mosquito midguts was almost completely abolished. These defects were rescued in parasites where pb22 was restored. Cross-fertilisation experiments with parasite lines defective in either male or female gametes confirmed that the defects in the pb22-KO line were restricted to the male gametes, whereas female gametes in the pb22-KO line were fertile at the WT level. Detailed analysis of male gametogenesis showed that 30% of the male gametocytes in the pb22-KO line failed to assemble the axonemes, whereas ~48.9% of the male gametocytes formed flagella but failed to egress from the host erythrocyte. To explore its transmission-blocking potential, recombinant Pb22 (rPb22) was expressed and used to immunise mice. in vitro assays showed that the rPb22-antisera significantly inhibited exflagellation by ~64.8% and ookinete formation by ~93.4%. Mosquitoes after feeding on rPb22-immunised mice also showed significant decreases in infection prevalence (83.3-93.3%) and oocyst density (93.5-99.6%). Further studies of the Pb22 orthologues in human malaria parasites are warranted.

Summary Due to the lack of effective early diagnostic measures and treatment methods, bladder cancer has become a malignant tumor that seriously threatens people's lives and health. Here, we reported that LINC00162, a super-enhancer long noncoding RNA, was highly expressed in bladder cancer cells and tissues. And LINC00162 was negatively correlated with neighboring PTTG1IP expression. Knocking down LINC00162 expression can inhibit the proliferative activity of bladder cancer cells and the growth of transplanted tumors in vivo, while knocking down the expression of PTTG1IP could restore the proliferative activity of bladder cancer cells. In addition, both LINC00162 and PTTG1IP were found to be able to bind to THRAP3, a transcription-related protein. And THRAP3 can regulate PTTG1IP expression. Finally, we demonstrated a mechanism that LINC00162 could regulate PTTG1IP expression through binding THRAP3. This study provided a potential target molecule for clinical treatment of bladder cancer., Graphical Abstract, Highlights • Expression of LINC00162 is increased in bladder cancer • LINC00162 promotes bladder cancer progress in vitro and in vivo • LINC00162 regulates neighboring PTTG1IP expression to promote bladder cancer • LINC00162 inhibits PTTG1IP expression by interacting THRAP3, Molecular Biology; Cancer

Background Alzheimer’s disease (AD) is an epidemic with tremendous public health impacts because there are currently no disease-modifying therapeutics. Randomized controlled trials (RCTs) for prevention of AD dementia often use clinical endpoints that take years to manifest (e.g., cognition) or surrogate endpoints that are costly or invasive (e.g., magnetic resonance imaging [MRI]). Blood biomarkers represent a clinically applicable alternative surrogate endpoint for RCTs that would be both cost-effective and minimally invasive, but little is known about their value as surrogate endpoints for treatment responses in the prevention of AD dementia. Methods The objective of this study is to investigate blood neuropathological, neurodegenerative, and neurotrophic biomarkers as surrogate endpoints for treatment responses to three interventions in older adults with amnestic mild cognitive impairment (aMCI, a prodromal stage of AD): aerobic exercise, cognitive training, and combined aerobic exercise and cognitive training (ACT). We chose these three sets of biomarkers for their unique mechanistic associations with AD pathology, neurodegeneration and neurogenesis. This study is built on the ACT Trial (1R01AG055469), a single-blinded, multi-site, 2 × 2 factorial phase II RCT that examines the synergistic effects of a 6-month ACT intervention on cognition and MRI biomarkers (AD-signature cortical thickness and hippocampal volume) (n = 128). In this ACT Trial blood biomarkers study, we will enroll 120 ACT Trial participants with aMCI and measure blood biomarkers at baseline and at 3, 6, 12, and 18 months. The goals are to (1) determine the effect of interventions on blood biomarkers over 6 months, (2) evaluate blood biomarkers as surrogate endpoints for predicting cognitive responses to interventions over 18 months, and (3, exploratory) examine blood biomarkers as surrogate endpoints for predicting brain MRI biomarker responses to interventions over 18 months. Discussion This study aims to identify new blood biomarkers that can track cognitive decline or AD-related brain atrophy among patients with aMCI subjected to a regimen of aerobic exercise and cognitive training. Findings from this study will drive the further use of blood biomarkers in developing effective prevention and treatment strategies for AD dementia. Trial registration ClinicalTrials.gov, NCT03313895. Registered on 18 October 2017.

Cisplatin has been widely used in the treatment of a various types of cancers including triple-negative breast cancer (TNBC) by damaging DNA and inducing apoptosis. However, its anti-cancer effects are often limited due to chemo-resistance, which is one of the main reasons causing cancer relapse and metastasis. To overcome resistance, cisplatin is often used in combination with other drugs or molecules. Our study found that the targeted inhibition of miR-221/222 in MDA-MB-231 cells promoted cisplatin-induced cell apoptosis, and increased the cell sensitivity to cisplatin in vitro. Much higher expression levels of miR-221/222 were detected in the cisplatin-resistant MDA-MB-231 cells and in cisplatin-resistant breast cancer patients. The combination chemotherapy of cisplatin with anti-miR-221/222 showed much higher efficiency in suppressing tumor growth in the mice transplanted with MDA-MB-231 cells. In addition, anti-miR-221 and anti-miR-222 showed synergetic effects on improving sensitivity to cisplatin in MDA-MB-231 cells. Suppression of SOCS1-STAT3-Bcl-2 pathway and activation of p53-Pten signaling both contribute to anti-miR-221/222-induced sensitivity to cisplatin in MDA-MB-231 cells. These findings suggest the potential of a novel approach for the combination chemotherapy of cisplatin with small non-coding RNA in treatment of human TNBC.

The precise detection of PD-1/PD-L1 biomarkers helps to predict the prognosis of corresponding immunotherapy. 125I-labeled nivolumab targeting activated immune cells infiltrating the tumorous tissues was developed to evaluate the expression of PD-1 immune checkpoints. SPECT images indicated that 125I–nivolumab preferentially targeted to tumor-surrounded immune cells. This radiotracer can dynamically and quantitatively characterize the in vivo expression of immune checkpoints for colorectal cancer, thereby potentially enabling the early screening of patients, monitoring the efficacy of treatment, and assessing potential immunotoxicity.

Peripheral inflammatory biomarkers may play an important role in the cognitive decline of aging and incidence of Alzheimer's disease (AD); however, data from epidemiological studies present conflicting findings. The purpose of the current review was to systematically determine the current state of the science on the association between peripheral inflammatory biomarkers and cognitive decline. Articles published from January 1, 2006 to October 28, 2016 were searched using the Medline and Embase databases. Nine studies met inclusion criteria (two examined participants with AD dementia and seven examined participants without dementia). Although a wide range of peripheral inflammatory biomarkers was examined, C-reactive protein and interleukin 6 were the most studied. Findings show conflicting results for the association between peripheral inflammatory biomarkers and cognitive decline. Peripheral inflammation may harm and help the brain, and therefore, the challenge of modulating immunity will be to find ways of fine tuning inflammation to delay, prevent, or treat AD. [ Journal of Gerontological Nursing, 43 (12), 53–60.]

Multiple drug resistance (MDR) and metastasis are two major factors that contribute to the failure of cancer treatment. However, the relationship between MDR and metastasis has not been characterized. Additionally, the role of the E3 ubiquitin ligase Cbl-b in metastasis of MDR gastric and breast cancer is not well known. In the present study, we found that MDR gastric and breast cancer cells possess a typical mesenchymal phenotype and enhanced cell migration capacity. Additionally, Cbl-b is poorly expressed in MDR gastric and breast cancer cells. In MDR gastric adenocarcinoma tissues, gastric cancer patients with low Cbl-b expression were more likely to have tumor invasion ( P =.016) and lymph node metastasis ( P =.007). Moreover, overexpression of Cbl-b reduced cell migration in MDR cell cultures both in vitro and in vivo . Cbl-b overexpression also prevented EMT by inducing ubiquitination and degradation of EGFR, leading to inhibition of the EGFR-ERK/Akt-miR-200c-ZEB1 axis. However, further overexpression of EGFR on a background of Cbl-b overexpression restored both the mesenchymal phenotype and cell migration capacity of MDR gastric and breast cancer cells. These results suggest that Cbl-b is an important factor for maintenance of the epithelial phenotype and inhibition of cell migration in MDR gastric and breast cancer cells.

Background The prognostic value of postoperative 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) to patients with gastric cancer remains unclear. This study aims to investigate the prognostic value of whole body (WB) metabolic tumor burden (MTBWB) on postsurgical 18F-FDG PET/CT to patients with gastric cancer. Methods A total of 376 patients with surgeries-confirmed gastric cancer were enrolled. Clinicopathologic information, overall survival (OS) and MTBWB parameters on postsurgical PET/CT, in terms of WB maximum standardized uptake value (SUVWBmax), WB metabolic tumor volume (MTVWB), and WB total lesion glycolysis (TLGWB) were collected. In-between differences of patient clinicopathologic characteristics, OS and MTBWB measurements were compared using chi-square test, Fisher’s exact test, Student’s t test or the Kaplan-Meier survival analysis. The optimal cutoffs of MTBWB measurements were calculated through the receiver operating characteristic (ROC) curve analysis. Univariable and multivariable Cox proportional hazard regression were performed to test the predictive value of the clinicopathologic factors and MTBWB measurements to patient survival. Results The PET-positive patients had significantly decreased OS based on either Kaplan-Meier survival analysis (P 8.6, MTVWB > 91.5 cm3, and TLGWB > 477.6 cm3 were significantly different (P = 0.001, P

Background The malaria burden of Myanmar still remains high within the Greater Mekong Subregion of Southeast Asia. An important indicator of progress towards malaria elimination is the prevalence of parasite infections in endemic populations. Information about malaria epidemiology is mostly derived from reports of confirmed acute malaria cases through passive case detection, whereas the prevalence of baseline subclinical malaria infections is much less known. Methods In this study, cross-sectional surveys were conducted during the rainy season of 2017 in four townships (Bilin, Thabeikkyin, Banmauk and Paletwa) of Myanmar with divergent annual malaria incidences. A total of 1991 volunteers were recruited from local villages and Plasmodium subclinical infections were estimated by light microscopy (LM), rapid diagnostic tests (RDTs) and nested PCR. The nested PCR analysis was performed with a modified pooling strategy that was optimized based on an initial estimate the infection prevalence. Results The overall malaria infection prevalence based on all methods was 13.9% (277/1991) and it differed drastically among the townships, with Paletwa in the western border having the highest infection rate (22.9%) and Thabeikkyin in central Myanmar having the lowest (3.9%). As expected, nested PCR was the most sensitive and identified 226 (11.4%) individuals with parasite infections. Among the parasite species, Plasmodium vivax was the most prevalent in all locations, while Plasmodium falciparum also accounted for 32% of infections in the western township Paletwa. Two RDTs based on the detection of the hrp2 antigen detected a total of 103 P. falciparum infections, and the ultrasensitive RDT detected 20% more P. falciparum infections than the conventional RDT. In contrast, LM missed the majority of the subclinical infections and only identified 14 Plasmodium infections. Conclusions Cross-sectional surveys identified considerable levels of asymptomatic Plasmodium infections in endemic populations of Myanmar with P. vivax becoming the predominant parasite species. Geographical heterogeneity of subclinical infections calls for active surveillance of parasite infections in endemic areas. The pooling scheme designed for nested PCR analysis offers a more practical strategy for large-scale epidemiological studies of parasite prevalence. Such information is important for decision-makers to put forward a more realistic action plan for malaria elimination. Electronic supplementary material The online version of this article (10.1186/s13071-019-3330-1) contains supplementary material, which is available to authorized users.

Introduction Phospholipids are altered in brains of patients with dementia and some studies suggest their plasma levels may be useful in the detection of mild cognitive impairment (MCI) and dementia. Methods We measured 188 plasma metabolites in participants who underwent a detailed neuropsychological assessment and classified as normal (n = 153), MCI (n = 145), or dementia (n = 143) by expert adjudication. Results Among 10 phospholipids recently implicated as altered in dementia, higher concentration of PC aa C36:6 was significantly associated with decreased prevalence of dementia (odds ratio = 0.71, 95% confidence interval = 0.50–1.00 per 1−SD increase). Adding these phospholipids to a model including multiple predictors of dementia led to only minimal improvement in detection (C statistic changed from 0.702 to 0.71). Discussion Some phospholipids and metabolites were altered in MCI and dementia but cross‐sectional association was relatively weak and did not improve detection of MCI and dementia beyond information provided by clinical variables.

The establishment of malaria immune memory is slow, incomplete, and short-lived. The mechanisms underpinning the generation and maintenance of anti-malarial immune memory remain unclear. This study evaluated the possible role of programmed cell death-1 (PD-1) in the establishment of malaria immune memory. Following infection by Plasmodium berghei ANKA (Pb ANKA) we compared natural immunity, acquired immunity, and immune memory between WT and mice lacking PD-1 via monoclonal antibody treatment. We found that parasitemia levels were significantly lower in the PD-1 knockdown group. After PD-1 elimination, dendritic cells, Th1, and T-follicular helper cells increased significantly. In addition, memory T, long-lived plasma cells, and serum antibody production also increased significantly. Therefore, PD-1 elimination induced stronger natural and acquired immune responses and enhanced immune memory against the parasite.

Manganese (Mn), an essential micronutrient, has the potential to induce apoptosis. The NT3/TrkC ligand/receptor pair known as part of the classic neurotrophic theory plays a critical role in neuronal survival. However, whether the NT3/TrkC-mediated signaling pathways are involved in Mn-induced apoptosis of cortical neurons remains unknown. The present study was designed to investigate the interactions between NT3/TrkC-mediated signaling pathways and Mn-induced apoptosis in cortical neurons. This study showed that subacute Mn exposure significantly increased the levels of pro-apoptotic Bax while decreasing the levels of anti-apoptotic Bcl 2 in the cortex compared with the corresponding control. Markedly reduced NT3 and TrkC levels along with decreased Ras/MAPK and PI3/Akt signaling in the cortex were observed following subacute Mn exposure. We further found increased levels of Bax, cleaved caspase-3, and the total apoptosis rate, and decreased levels of Bcl 2, NT3, TrkC, and Ras/MAPK and PI3/Akt signaling in Mn-treated primary cortical neurons. Pretreatment with hNT3 or Z-VAD-FAM ameliorated Mn-induced apoptosis by increasing the levels of NT3 and TrkC and its Ras/MAPK and PI3/Akt signaling pathways. Taken together, our findings clearly indicate that NT3/TrkC and mediated Ras/MAPK and PI3/Akt signaling pathways play a crucial role in Mn-induced neurotoxicity.

IntroductionThe objective of this study was to investigate whether 10 phospholipids/metabolites previously identified as prospectively predictive of mild cognitive impairment (MCI) or dementia in whites would also be predictive in a mostly African-American cohort.MethodsWe repeatedly measured 188 phospholipids/metabolites in plasma samples of 221 participants of the Atherosclerosis Risk in Communities study, 97% African American, who were followed between 2004–2006 and 2011–2013.ResultsAfter a mean follow-up of 7.3 years, 77 were classified as having MCI and 18 as having dementia. Our study failed to replicate previous findings in this mostly African American cohort, in that the 10 phospholipids/metabolites only achieved a C statistic/AUC of 0.609 in predicting development of MCI or dementia (compared to 0.96) and 0.607 in distinguishing normal from MCI or dementia at the follow-up visit.ConclusionA panel of 10 phospholipids/metabolites previously associated with incident dementia was not predictive of MCI or dementia in an independent cohort.

Assays used for discovery of biomarkers should be robust and high-throughput, capable of analyzing a sufficiently large number of samples over a sufficiently long period of time with good precision.We evaluated the analytical performance of the Bio-Plex Pro™ Human Cancer Biomarker Panel 1, a 16-plex multiplex immunoassay, in serum for composite profiling of angiogenic factors. Because prostate cancer progression and metastasis are pathological events closely linked to angiogenesis, serum angiogenic factors are ideal candidates as prognostic biomarkers.Our 5-day evaluation indicated that all 16 assays in the panel had good reproducibility (total precisions over 5 independent plates in 5 days of20%), adequate sensitivity (LOQs of majority of the assays less than 100 pg/ml), and wide dynamic ranges (linearity of majority of the assays spanning across 3 logs in concentrations).Applying the panel to sera from prostate cancer patients with Gleason scores of 6, 7, 8-10, tumor stages that correlated with clinical outcome, we identified that the levels of sTIE-2, a soluble form of the transmembrane tyrosine kinase receptor for angiopoietins, were increased in patients with Gleason score of 8-10. Future studies are necessary to determine whether sTIE-2 could be used as a prognostic biomarker for identifying aggressive prostate cancer.

Au nanoparticles (3.8 ± 0.6 nm) are assembled to sub-micrometer Au particles (186.3 ± 20.4 nm) and covered with adhesive polydopamine (PDA) as embolism beads (198.8 ± 23.2 nm). Radioactive iodine-125 is labeled to Au@PDA to introduce the function of intra-irradiation. For the therapeutic effects of Au@PDA-125 I, Au particles sensitize the radiation to MHCC97H hepatoma cells and tumor-bearing mice. At the cellular level, after being treated with a relatively low-dose (5 Gy) γ-ray, Au-sensitized radiotherapy (RT) leads to an immediate increase of intracellular reactive oxygen species, accompanying with an increase of cell apoptosis. Due to the intra-irradiation, self-healing of RT-leaded DNA double-strand breakage is suppressed, inducing a further increase of cell apoptosis after RT treatment. Likewise, 3 cycles of sensitized RT leads to a valid control of tumor volume growth, but Au@PDA-125 I has no harm or radioactive residual on or in the radiosensitive organs, including the thyroid, heart, lungs, liver, and spleen. Additionally, photons emitted from 125 I and high X-ray absorption of the Au element makes the beads suitable for single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Therefore, as theranostic embolism beads, Au@PDA-125 I can both enhance the therapeutic effects of external RT, and provide a real-time SPECT/CT monitoring of therapeutic time window.

Despite considerable advances in chemotherapy, radiotherapy, target therapy, and biological therapy, the prognosis for those with resected non-small-cell lung cancer (NSCLC) has not substantially improved. It was recently reported that two receptors, Notch-1 and c-Met, correlate directly or indirectly with the initiation and development of malignant tumors, such as lung cancer; however, the prognostic value of coexpression of these receptors and their relationship in resected NSCLC was not clear. In this study, the expression levels of Notch-1 and c-Met in 117 patients with resected NSCLC were assessed using immunohistochemistry (IHC). The results showed that the positive expression rate of Notch-1 in total patients was 59.8 %. The positive expression rate of c-Met in the all population was 69.2 %. In addition, a significant positive association was shown between Notch-1 and c-Met (P < 0.001). Simultaneously, patients with coexpression of both receptors had a significantly poorer prognosis than those without coexpression (P < 0.001). Multivariate analysis showed that T stage (P = 0.016) and c-Met expression (P < 0.001) were independent prognostic factors. In conclusion, coexpression of both receptors correlates with poorer prognosis in patients with resected NSCLC. Targeting both receptors simultaneously may prove a more effective antitumor strategy. Patients with coexpression of both receptors might benefit from cotargeting Notch-1 and c-Met.

Despite considerable advances in gastrectomy and chemotherapy, the prognosis of gastric cancer (GC) has not noticeably improved due to lymph node or distant metastases. P21-activated serine/threonine kinase 4 (Pak4) plays an important role in cell morphology and cytoskeletal reorganization-both prerequisite steps for cell migration. However, it is still unclear if activated Pak4 (p-Pak4) is related to prognosis in GC patients. In our study, the level of p-Pak4 in 95 GC tissue specimens was examined by immunohistochemistry (IHC). We observed significant correlation between the level of p-Pak4 and grosstype (advanced stage GC vs. early stage GC, P = 0.04). Moreover, GC patients with higher p-Pak4 levels had a poorer prognosis than those with lower p-Pak4 levels (17 vs. 38 months, P = 0.001). Multivariate analysis showed that high phosphorylation level of Pak4, advanced stage GC, and lymph node metastasis were independent prognostic factors for GC patients (p-Pak4, P = 0.026; advanced stage GC, P = 0.030; lymph node metastasis, P = 0.016). In addition, in vitro assays indicated that knockdown of Pak4 accompanied with decreased p-Pak4, inhibited cell migration via downregulation of the traditional downstream signaling pathways of Pak4, LIMK1, and cofilin. In conclusion, this report reveals that high level of p-Pak4 correlates with poor prognosis in GC, thereby suggesting that p-Pak4 might be a potential prognostic marker for GC.

Background: Parapneumonic pleural effusion (PPE) is a common complication of pneumonia. The accurate diagnosis of PPE remains a challenge. Recent studies suggest that procalcitonin (PCT) emerges as a potential biomarker for PPE. Our study aimed to determine the diagnostic value of PCT for PPE by a clinical study and summarize the overall diagnostic performance of PCT through a meta-analysis. Methods: Demographic and clinical data of the patients with PPE and controls were collected in our clinical study. The diagnostic performances of serum PCT (s-PCT) were analyzed via receiver operating characteristic (ROC) curve analysis, using area under the curve (AUC) as a measure of accuracy. Literature databases were systematically searched for the studies examining the accuracy of PCT for diagnosing PPE. Data on sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR) were pooled. Summary ROC curves and AUC were used to evaluate overall test performance. Results: In our clinical study, 47 patients with PPE and 101 controls were included. The s-PCT levels were significantly increased in the setting of PPE (5.44 ± 9.82 ng/mL) compared with malignant PE (0.15 ± 0.19 ng/mL), tuberculous PE (0.18 ± 0.16 ng/mL), and transudates (0.09 ± 0.03 ng/mL) (P

Background: Multiple drug resistance (MDR) and metastasis are two major unfavorable factors causing failure of cancer treatment. However, the relationship between MDR and metastasis is not characterized. Additionally, the role of the E3 ubiquitin ligase Cbl-b in metastasis of MDR gastric and breast cancer is little known. Methods: The effect of Cbl-b on tumor invasion and metastasis was analyzed in P-gp-positive gastric adenocarcinoma tissues. Transfections of Cbl-b WT and epidermal growth factor receptor (EGFR) WT plasmid were used to assess Cbl-b and EGFR involvement in epithelial-mesenchymal transition (EMT) and tumor metastasis. Results: MDR gastric and breast cancer cells possess a typical mesenchymal phenotype and an enhanced cell migration capacity. Additionally, Cbl-b is poorly expressed in MDR gastric and breast cancer cells. We performed immunohistochemical analysis on P-gp-positive gastric adenocarcinoma tissues and identified associations between Cbl-b expression and clinical pathological parameters. Gastric cancer patients with low Cbl-b expression were more likely to have tumor invasion (P=0.016) and lymph node metastasis (P=0.007). Moreover, over-expression of Cbl-b reduced cell migration in MDR cell cultures both in vitro and in vivo. Cbl-b over-expression also prevented EMT by inducing ubiquitination and degradation of EGFR, leading to inhibition of the EGFR- ERK/Akt-miR-200c-ZEB1 axis. However, further over-expression of EGFR on a background of Cbl-b over-expression restored both the mesenchymal phenotype and the cell migration capacity of MDR gastric and breast cancer cells. Conclusions: These results suggest that Cbl-b is an important factor for maintenance of the epithelial phenotype and inhibition of cell migration in MDR gastric and breast cancer cells. Note: This abstract was not presented at the meeting. Citation Format: Ling Xu, Xiujuan Qu, Ye Zhang, Xiaofang Che, Tianshu Guo, Ying Cai, Aodi Li, Danni Li, Ce Li, Ti Wen, Yibo Fan, Kezuo Hou, Yanju Ma, Xuejun Hu, Yunpeng Liu. E3 ubiquitin ligase Cbl-b prevents tumor metastasis by maintaining the epithelial phenotype in multiple drug-resistant gastric and breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4916. doi:10.1158/1538-7445.AM2017-4916

Subclinical ovulatory disturbances (anovulation or short luteal phases within normal-length menstrual cycles) indicate lower progesterone-to-estrogen levels. Given that progesterone plays a bone formation role, subclinical ovulatory disturbances may be associated with bone loss or less than expected bone gain. Our purpose was to perform a meta-analysis of prospective studies in healthy premenopausal women to determine the overall relationship of subclinical ovulatory disturbances to change in bone mineral density. Two reviewers independently identified from serial literature searches 6 studies meeting inclusion criteria: a 2-year study in 114 young adult women, 2006-2009, Vancouver, Canada; a 2-year study in 189 premenopausal women, 2000-2005, Toronto, Canada; a single-cycle study in 14 young women, 1996-1997, Melbourne, Australia; an 18-month study in 53 women, 1990-1995, Santa Clara, California; a 4-year study in 27 women, 1988-1995, Vancouver, Canada; and a 1-year study in 66 women, 1985-1988, Vancouver, Canada. This meta-analysis included a combined sample size of 473 observations in 436 premenopausal women studied over 1-4 years and aged 14-47 years. The percentage of women with ovulatory disturbances varied significantly from 13% to 82%. Women with more frequent ovulatory disturbances had more negative percentage changes in spine bone mineral density (weighted mean difference = -0.86; P = 0.040) for random-effects analysis. There was significant heterogeneity among these 6 studies (I(2) = 80%). In summary, these data show that regularly menstruating women with more frequent ovulatory disturbances experience more negative changes in bone (approximately -0.9% per year). These cycles with silent estrogen/progesterone imbalance may be clinically important.

The current landscape of cancer biomarkers is changing rapidly, with new and exciting developments. With the advances of proteomic technologies, many potential cancer biomarkers have been discovered. However, the number of new cancer biomarkers cleared or approved by the US FDA is rather limited. Although technological advances are important, clearly defining intended use, good study design and appropriate patient specimens are critical for the success of FDA approval. While obtaining FDA clearance/approval for newly developed and clinically useful cancer biomarkers has been slow, the reward for patient care could be enormous.