Major Depressive Disorder and Chronic Fatigue Syndrome Show Characteristic Heart Rate Variability Profiles Reflecting Autonomic Dysregulations: Differentiation by Linear Discriminant Analysis.

Major depressive disorder (MDD) and chronic fatigue syndrome (CFS) have overlapping symptoms, and differentiation is important to administer the proper treatment. The present study aimed to assess the usefulness of heart rate variability (HRV) indices. Frequency-domain HRV indices, including high-frequency (HF) and low-frequency (LF) components, their sum (LF+HF), and their ratio (LF/HF), were measured in a three-behavioral-state paradigm composed of initial rest (Rest), task load (Task), and post-task rest (After) periods to examine autonomic regulation. It was found that HF was low at Rest in both disorders, but was lower in MDD than in CFS. LF and LF+HF at Rest were low only in MDD. Attenuated responses of LF, HF, LF+HF, and LF/HF to task load and an excessive increase in HF at After were found in both disorders. The results indicate that an overall HRV reduction at Rest may support a diagnosis of MDD. HF reduction was found in CFS, but with a lesser severity. Response disturbances of HRV to Task were observed in both disorders, and would suggest the presence of CFS when the baseline HRV has not been reduced. Linear discriminant analysis using HRV indices was able to differentiate MDD from CFS, with a sensitivity and specificity of 91.8% and 100%, respectively. HRV indices in MDD and CFS show both common and different profiles, and can be useful for the differential diagnosis.

TFAP4 Activates IGF2BP1 and Promotes Progression of Non-Small Cell Lung Cancer by Stabilizing TK1 Expression through m6A Modification.

Non-small cell lung cancer (NSCLC) is a well-known global health concern. TFAP4 has been reported to function as an oncogene. This study sought to investigate the molecular mechanism of TFAP4 in NSCLC development. Significantly highly-expressed gene IGF2BP1 was screened on online databases and its downstream gene TK1 was predicted. IGF2BP1 promoter sequence was identified. The binding site of TFAP4 and IGF2BP1 was predicted. The expression correlations among TFAP4, IGF2BP1, and TK1 were confirmed. The correlations between TFAP4, IGF2BP1, TK1, and NSCLC prognosis were predicted. NSCLC and paracancerous tissues were collected. The expressions of TFAP4, IGF2BP1, and TK1 were detected. NSCLC cell proliferation, migration, invasion, and apoptosis were detected. The binding of TFAP4 to the IGF2BP1 promoter was verified. m6A modification of TK1 mRNA was detected. The correlation between IGF2BP1 and TK1 was confirmed. A subcutaneous tumor xenograft model was established to validate the effect of TFAP4 in vivo. IGF2BP1 was highly expressed in NSCLC tissues and cells. IGF2BP1 knockdown repressed NSCLC cell proliferation, migration, and invasion and facilitated apoptosis. Mechanically, TFAP4 transcriptionally activated IGF2BP1. IGF2BP1 stabilized TK1 expression via m6A modification and promoted NSCLC cell proliferation, migration, and invasion. In vivo experiments confirmed that TFAP4 knockdown suppressed tumor growth by downregulating IGF2BP1/TK1. IMPLICATIONS: Our findings revealed that TFAP4 activated IGF2BP1 and facilitated NSCLC progression by stabilizing TK1 expression via m6A modification, which offered new insights into the diagnosis and treatment of NSCLC.

KBTBD7 promotes non-small cell lung carcinoma progression by enhancing ubiquitin-dependent degradation of PTEN.

The Kelch repeat and BTB domain containing 7 (KBTBD7) was first cloned in 2010. Its function as a transcriptional activator and a substrate adaptor during the ubiquitination process was soon found. KBTBD7 was shown to be involved in excessive inflammation after myocardial infarction, brain development, and neurofibromin stability. However, studies on the role of KBTBD7 in solid tumors, especially lung cancer, are still lacking. Therefore, in this study, we investigate the role of KBTBD7 in non-small cell lung cancer (NSCLC). Immunohistochemical staining of 104 paired NSCLC and peritumoral normal specimens indicated that KBTBD7 was highly expressed in NSCLC tissues and positively correlated with the histological type, P-TNM stage, lymph node metastasis, and tumor size. KBTBD7 was also well-expressed in NSCLC cell lines, and downregulation of KBTBD7 resulted in inhibition of NSCLC cell proliferation and invasion. Further investigation showed that KBTBD7 enhanced ubiquitin-dependent degradation of PTEN, thus activating EGFR/PI3K/AKT signaling and promoting NSCLC cell proliferation and invasion by regulating CCNE1, CDK4, P27, ZEB-1, Claudin-1, ROCK1, MMP-9, and E-cadherin protein levels. Our results indicate that KBTBD7 may be a potential therapeutic target for the treatment of NSCLC.

LINC01342 silencing upregulates microRNA-508-5p to inhibit progression of lung cancer by reducing cysteine-rich secretory protein 3.

Long noncoding RNAs (lncRNAs) are critical players during cancer progression. Nevertheless, the effect of most lncRNAs in lung cancer (LC) remains unclear. We aimed to explore the role of LINC01342 in LC development through the microRNA-508-5p (miR-508-5p)/cysteine-rich secretory protein 3 (CRISP3) axis. LINC01342, miR-508-5p, and CRISP3 expression in clinical samples and cell lines were determined, and their correlations in LC were analyzed. The prognostic role of LINC01342 in LC patients was evaluated. LC cells were screened and, respectively, transfected to alter the expression of LINC01342, miR-508-5p, and CRISP3. Then, proliferation, migration, invasion, and apoptosis of transfected LC cells were determined, and the in vivo tumor growth was observed as well. Binding relationships between LINC01342 and miR-508-5p, and between miR-508-5p and CRISP3 were identified. LINC01342 and CRISP3 were upregulated and miR-508-5p was downregulated in LC tissues and cells. High LINC01342 expression indicated a poor prognosis of LC patients. The LINC01342/CRISP3 silencing or miR-508-5p elevation inhibited proliferation, migration, and invasion of LC cells and promoted LC cell apoptosis, and also suppressed the in vivo tumor growth. LINC01342 bound to miR-508-5p and miR-508-5p targeted CRISP3. LINC01342 plays a prognostic role in LC and LINC01342 silencing upregulates miR-508-5p to inhibit the progression of LC by reducing CRISP3.

Endogenous thrombopoietin promotes non-small-cell lung carcinoma cell proliferation and migration by regulating EGFR signalling.

Thrombopoietin (TPO) is a haematopoietic cytokine mainly produced by the liver and kidneys, which stimulates the production and maturation of megakaryocytes. In the past decade, numerous studies have investigated the effects of TPO outside the haematopoietic system; however, the role of TPO in the progression of solid cancer, particularly lung cancer, has not been well studied. Exogenous TPO does not affect non-small-cell lung cancer (NSCLC) cells as these cells show no or extremely low TPO receptor expression; therefore, in this study, we focused on endogenous TPO produced by NSCLC cells. Immunohistochemical analysis of 150 paired NSCLC and adjacent normal tissues indicated that TPO was highly expressed in NSCLC tissues and correlated with clinicopathological parameters including differentiation, P-TNM stage, lymph node metastasis and tumour size. Suppressing endogenous TPO by small interfering RNA inhibited the proliferation and migration of NSCLC cells. Moreover, TPO interacted with the EGFR protein and delayed ligand-induced EGFR degradation, thus enhancing EGFR signalling. Notably, overexpressing TPO in EGF-stimulated NSCLC cells facilitated cell proliferation and migration, whereas no obvious changes were observed without EGF stimulation. Our results suggest that endogenous TPO promotes tumorigenicity of NSCLC via regulating EGFR signalling and thus could be a therapeutic target for treating NSCLC.

Analysis of Segmental Lymph Node Metastasis and Clinical Features in cT1N0M0 Lung Adenocarcinoma.

The progression of lung adenocarcinoma through lymph node metastasis has been well established; however, the process of segmental lymph node (LSN) metastasis in cT1N0M0 lung adenocarcinoma remains unclear. We aimed to elucidate the markers of lymph node metastasis to different segments in early-stage lung adenocarcinoma and identify new indications for segmentectomy. A total of 200 patients were enrolled in this study. These patients were diagnosed with cT1N0M0 lung adenocarcinoma after positron emission tomography/computed tomography and received lobectomy and lymph node dissection surgeries. Lymph nodes retrieved from each station were sorted. The metastatic status of the isolated (i) LSNs and several characteristics were analyzed. Patients with ground-glass nodules (GGNs) (P=0.025), AIS/MIA/lepidic adenocarcinoma (P=0.038), nodules with a maximum diameter ≤1 cm (P=0.017), maximum standardized uptake value (SUVmax) < 2.5 (P=0.029), serum carcinoembryonic antigen (CEA) levels ≤4.5 ng/ml (P=0.036), and no N1 lymph nodes metastasis (P=0.036) had significantly lower iLSN metastasis rates than those without these characteristics. Pure GGNs, CEA levels ≤4.5 ng/ml, SUVmax < 2.5, tumors with a maximum diameter of ≤1 cm, or those confirmed to be adenocarcinoma in situ, minimally invasive adenocarcinoma, or invasive lepidic-predominant adenocarcinoma by frozen section may indicate segmentectomy. However, segmentectomy is not suitable for patients with metastasis to the N1 lymph nodes.

Tumor-suppressive activity of sTRAIL on circulating CD44+ cells in patients with non-small cell lung cancer.

Circulating CD44+ cells have been identified as a prognostic marker for patients with non-small cell lung cancer (NSCLC). Serum tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) is involved in the pathophysiology of many cancers. However, no previous studies have shown the roles of sTRAIL in circulating CD44+ cells in the blood of NSCLC patients. We detected circulating CD44+ cells and sTRAIL levels in blood samples from NSCLC patients using flow cytometry and an enzyme-linked immunosorbent assay (ELISA). Anti-tumor roles of TRAIL in CD44+ cells were confirmed using a CCK-8 assay and mouse models. A higher number of circulating CD44+ cells were identified in NSCLC patients compared with healthy control individuals. In addition, we confirmed the anti-tumor roles and mechanisms of TRAIL in CD44+ cells both in vitro and in vivo. Our results indicate that (1) there is a negative correlation between sTRAIL and circulating CD44+ cells in NSCLC patients and (2) CD44+ cells have cancer stem cell properties and are more sensitive than CD44- cells to TRAIL.

Dengue Fever Detecting System Using Peak-detection of Data from Contactless Doppler Radar.

Infectious diseases, such as dengue fever and Middle East respiratory syndrome, have become prevalent worldwide in recent times. To conduct highly accurate and effective infection screening, we are working on the development of a contactless infection screening system using Doppler radar and thermography. In our previous work, three parameters (face temperature, heartbeat rate, and respiration rate) were used to judge whether a subject was infected. However, facial temperature measurements may be vastly different from temperatures measured at the axilla owing to influence from the immediate environment. In this study, heartbeat rate (HR), respiration rate (RR), and standard deviation of heartbeat interval (SDHI) were used to quantify the infection screening system without using facial temperature as a parameter. We found that respiratory sinus arrhythmia (RSA) diminished in patients who had dengue fever. We gathered data from 47 patients with dengue fever using a 10-GHz Doppler radar system at the National Hospital of Tropical Diseases (NHTD) in Hanoi, Vietnam. To evaluate the accuracy, the data of these patients were compared to that of 23 unaffected subjects. We observed that a linear discriminant analysis (LDA) was effective at detecting the dengue fever conditions, and the detection accuracy was approximately 97.6%.

Remote sensing of multiple vital signs using a CMOS camera-equipped infrared thermography system and its clinical application in rapidly screening patients with suspected infectious diseases.

BACKGROUND: Infrared thermography (IRT) is used to screen febrile passengers at international airports, but it suffers from low sensitivity. This study explored the application of a combined visible and thermal image processing approach that uses a CMOS camera equipped with IRT to remotely sense multiple vital signs and screen patients with suspected infectious diseases. METHODS: An IRT system that produced visible and thermal images was used for image acquisition. The subjects' respiration rates were measured by monitoring temperature changes around the nasal areas on thermal images; facial skin temperatures were measured simultaneously. Facial blood circulation causes tiny color changes in visible facial images that enable the determination of the heart rate. A logistic regression discriminant function predicted the likelihood of infection within 10s, based on the measured vital signs. Sixteen patients with an influenza-like illness and 22 control subjects participated in a clinical test at a clinic in Fukushima, Japan. RESULTS: The vital-sign-based IRT screening system had a sensitivity of 87.5% and a negative predictive value of 91.7%; these values are higher than those of conventional fever-based screening approaches. CONCLUSIONS: Multiple vital-sign-based screening efficiently detected patients with suspected infectious diseases. It offers a promising alternative to conventional fever-based screening.

A compact and hand-held infection-screening system for use in rapid medical inspection at airport quarantine stations: system design and preliminary validation.

To conduct mass screening and thereby reduce the spread of infection, a compact (13.5 cm × 8.5 cm × 2.5 cm), highly-mobile and hand-held infection-screening system was developed for rapid medical inspection in mass gathering places such as airports. The system is capable of non-contact vital-sign monitoring using two integrated sensors: a 24-GHz microwave radar for measuring heart and respiration rates and a thermopile array for capturing facial temperature. Subsequently, the system detects infected individuals using a linear discriminant function (LDA) from the derived vital-signs data. The system was tested on 10 subjects under two conditions (resting as normal and exercising as pseudo-infected, i.e. a 10-min bicycle ergometer at 100 W exercise); the normal and pseudo-infected conditions were classified successfully via LDA for all subjects (p < 0.01; classification error rate < 5%). The proposed non-contact system can be applied for preventing secondary exposure of medical doctors at the outbreak of highly pathogenic infectious diseases such as the Ebola virus.

An infectious disease/fever screening radar system which stratifies higher-risk patients within ten seconds using a neural network and the fuzzy grouping method.

OBJECTIVES: To classify higher-risk influenza patients within 10 s, we developed an infectious disease and fever screening radar system. METHODS: The system screens infected patients based on vital signs, i.e., respiration rate measured by a radar, heart rate by a finger-tip photo-reflector, and facial temperature by a thermography. The system segregates subjects into higher-risk influenza (HR-I) group, lower-risk influenza (LR-I) group, and non-influenza (Non-I) group using a neural network and fuzzy clustering method (FCM). We conducted influenza screening for 35 seasonal influenza patients and 48 normal control subjects at the Japan Self-Defense Force Central Hospital. Pulse oximetry oxygen saturation (SpO2) was measured as a reference. RESULTS: The system classified 17 subjects into HR-I group, 26 into LR-I group, and 40 into Non-I group. Ten out of the 17 HR-I subjects indicated SpO2 <96%, whereas only two out of the 26 LR-I subjects showed SpO2 <96%. The chi-squared test revealed a significant difference in the ratio of subjects showed SpO2 <96% between HR-I and LR-I group (p < 0.001). There were zero and nine normal control subjects in HR-I and LR-I groups, respectively, and there was one influenza patient in Non-I group. CONCLUSIONS: The combination of neural network and FCM achieved efficient detection of higher-risk influenza patients who indicated SpO2 96% within 10 s.

Rapid screening for influenza using a multivariable logistic regression model to save labor at a clinic in Iwaki, Fukushima, Japan.

To lighten the workload of health care professionals, we conducted a clinical test of a newly developed automated infection screening system using a multivariable logistic regression model. The system was tested with 44 influenza patients and 45 healthy control subjects based on 3 vital signs: facial temperature, heart rate and respiratory rate. The system showed a high accuracy for distinguishing influenza patients from control subjects within 15 seconds.

Design an easy-to-use infection screening system for non-contact monitoring of vital-signs to prevent the spread of pandemic diseases.

The outbreak of infectious diseases such as influenza, dengue fever, and severe acute respiratory syndrome (SARS) are threatening the global health. Especially, developing countries in the South-East Asia region have been at serious risk. Rapid and highly reliable screening of infection is urgently needed during the epidemic season at mass gathering places, such as airport quarantine facilities, public health centers, and hospital outpatients units, etc. To meet this need, our research group is currently developing a multiple vital-signs based infection screening system that can perform human medical inspections within 15 seconds. This system remotely monitors facial temperature, heart and respiration rates using a thermopile array and a 24-GHz microwave radar, respectively. In this work, we redesigned our previous system to make a higher performance with a user-friendly interface. Moreover, the system newly included a multivariable logistic regression model (MLRM) to determine the possibility of infection. We tested the system on 34 seasonal influenza patients and 35 normal control subjects at the Japan Self-Defense Forces Central Hospital. The sensitivity and specificity of the screening system using the MLRM were 85.3% and 88.6%, respectively.

Development of an infection screening system for entry inspection at airport quarantine stations using ear temperature, heart and respiration rates.

After the outbreak of severe acute respiratory syndrome (SARS) in 2003, many international airport quarantine stations conducted fever-based screening to identify infected passengers using infrared thermography for preventing global pandemics. Due to environmental factors affecting measurement of facial skin temperature with thermography, some previous studies revealed the limits of authenticity in detecting infectious symptoms. In order to implement more strict entry screening in the epidemic seasons of emerging infectious diseases, we developed an infection screening system for airport quarantines using multi-parameter vital signs. This system can automatically detect infected individuals within several tens of seconds by a neural-network-based discriminant function using measured vital signs, i.e., heart rate obtained by a reflective photo sensor, respiration rate determined by a 10-GHz non-contact respiration radar, and the ear temperature monitored by a thermography. In this paper, to reduce the environmental effects on thermography measurement, we adopted the ear temperature as a new screening indicator instead of facial skin. We tested the system on 13 influenza patients and 33 normal subjects. The sensitivity of the infection screening system in detecting influenza were 92.3%, which was higher than the sensitivity reported in our previous paper (88.0%) with average facial skin temperature.