Wavelength-modulated photoacoustic spectroscopic instrumentation system for multiple greenhouse gas detection and in-field application in the Qinling mountainous region of China.

We present a sensitive and compact quantum cascade laser-based photoacoustic greenhouse gas sensor for the detection of CO2, CH4 and CO and discuss its applicability toward on-line real-time trace greenhouse gas analysis. Differential photoacoustic resonators with different dimensions were used and optimized to balance sensitivity with signal saturation. The effects of ambient parameters, gas flow rate, pressure and humidity on the photoacoustic signal and the spectral cross-interference were investigated. Thanks to the combined operation of in-house designed laser control and lock-in amplifier, the gas detection sensitivities achieved were 5.6 ppb for CH4, 0.8 ppb for CO and 17.2 ppb for CO2, signal averaging time 1 s and an excellent dynamic range beyond 6 orders of magnitude. A continuous outdoor five-day test was performed in an observation station in China's Qinling National Botanical Garden (E longitude 108°29', N latitude 33°43') which demonstrated the stability and reliability of the greenhouse gas sensor.

Development and validation of an interpretable model integrating multimodal information for improving ovarian cancer diagnosis.

Ovarian cancer, a group of heterogeneous diseases, presents with extensive characteristics with the highest mortality among gynecological malignancies. Accurate and early diagnosis of ovarian cancer is of great significance. Here, we present OvcaFinder, an interpretable model constructed from ultrasound images-based deep learning (DL) predictions, Ovarian-Adnexal Reporting and Data System scores from radiologists, and routine clinical variables. OvcaFinder outperforms the clinical model and the DL model with area under the curves (AUCs) of 0.978, and 0.947 in the internal and external test datasets, respectively. OvcaFinder assistance led to improved AUCs of radiologists and inter-reader agreement. The average AUCs were improved from 0.927 to 0.977 and from 0.904 to 0.941, and the false positive rates were decreased by 13.4% and 8.3% in the internal and external test datasets, respectively. This highlights the potential of OvcaFinder to improve the diagnostic accuracy, and consistency of radiologists in identifying ovarian cancer.

Development and validation of ultrasound-based radiomics model to predict germline BRCA mutations in patients with breast cancer.

BACKGROUND: Identifying breast cancer (BC) patients with germline breast cancer susceptibility gene (gBRCA) mutation is important. The current criteria for germline testing for BC remain controversial. This study aimed to develop a nomogram incorporating ultrasound radiomic features and clinicopathological factors to predict gBRCA mutations in patients with BC. MATERIALS AND METHODS: In this retrospective study, 497 women with BC who underwent gBRCA genetic testing from March 2013 to May 2022 were included, including 348 for training (84 with and 264 without a gBRCA mutation) and 149 for validation(36 patients with and 113 without a gBRCA mutation). Factors associated with gBRCA mutations were identified to establish a clinicopathological model. Radiomics features were extracted from the intratumoral and peritumoral regions (3 mm and 5 mm) of each image. The least absolute shrinkage and selection operator regression algorithm was used to select the features and logistic regression analysis was used to construct three imaging models. Finally, a nomogram that combined clinicopathological and radiomics features was developed. The models were evaluated based on the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness. RESULTS: Age at diagnosis, family history of BC, personal history of other BRCA-related cancers, and human epidermal growth factor receptor 2 status were independent predictors of the clinicopathological model. The AUC of the imaging radiomics model combining intratumoral and peritumoral 3 mm areas in the validation set was 0.783 (95% confidence interval [CI]: 0.702-0.862), which showed the best performance among three imaging models. The nomogram yielded better performance than the clinicopathological model in validation sets (AUC: 0.824 [0.755-0.894] versus 0.659 [0.563-0.755], p = 0.007). CONCLUSION: The nomogram based on ultrasound images and clinicopathological factors performs well in predicting gBRCA mutations in BC patients and may help to improve clinical decisions about genetic testing.

Nicotinamide mononucleotide induces autophagy and ferroptosis via AMPK/mTOR pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignancy worldwide. Herein, we investigated the role of nicotinamide mononucleotide (NMN) in HCC progression. HCC cells were treated with NMN (125, 250, and 500 µM), and then nicotinamide adenine dinucleotide (NAD+ ) and NADH levels in HCC cells were measured to calculate NAD+ /NADH ratio. Cell proliferation, apoptosis, autophagy and ferroptosis were determined. AMPK was knocked down to confirm the involvement of AMPK/mTOR signaling. Furthermore, tumor-inhibitory effect of NMN was investigated in xenograft models. Exposure to NMN dose-dependently increased NAD+ level and NAD+ /NADH ratio in HCC cells. After NMN treatment, cell proliferation was inhibited, whereas apoptosis was enhanced in both cell lines. Additionally, NMN dose-dependently enhanced autophagy/ferroptosis and activated AMPK/mTOR pathway in HCC cells. AMPK knockdown partially rescued the effects of NMN in vitro. Furthermore, NMN treatment restrained tumor growth in nude mice, activated autophagy/ferroptosis, and promoted apoptosis and necrosis in tumor tissues. The results indicate that NMN inhibits HCC progression by inducing autophagy and ferroptosis via AMPK/mTOR signaling. NMN may serve as a promising agent for HCC treatment.

Deep Learning-assisted Diagnosis of Breast Lesions on US Images: A Multivendor, Multicenter Study.

Purpose: To evaluate the diagnostic performance of a deep learning (DL) model for breast US across four hospitals and assess its value to readers with different levels of experience. Materials and Methods: In this retrospective study, a dual attention-based convolutional neural network was built and validated to discriminate malignant tumors from benign tumors by using B-mode and color Doppler US images (n = 45 909, March 2011-August 2018), acquired with 42 types of US machines, of 9895 pathologic analysis-confirmed breast lesions in 8797 patients (27 men and 8770 women; mean age, 47 years ± 12 [SD]). With and without assistance from the DL model, three novice readers with less than 5 years of US experience and two experienced readers with 8 and 18 years of US experience, respectively, interpreted 1024 randomly selected lesions. Differences in the areas under the receiver operating characteristic curves (AUCs) were tested using the DeLong test. Results: The DL model using both B-mode and color Doppler US images demonstrated expert-level performance at the lesion level, with an AUC of 0.94 (95% CI: 0.92, 0.95) for the internal set. In external datasets, the AUCs were 0.92 (95% CI: 0.90, 0.94) for hospital 1, 0.91 (95% CI: 0.89, 0.94) for hospital 2, and 0.96 (95% CI: 0.94, 0.98) for hospital 3. DL assistance led to improved AUCs (P < .001) for one experienced and three novice radiologists and improved interobserver agreement. The average false-positive rate was reduced by 7.6% (P = .08). Conclusion: The DL model may help radiologists, especially novice readers, improve accuracy and interobserver agreement of breast tumor diagnosis using US.Keywords: Ultrasound, Breast, Diagnosis, Breast Cancer, Deep Learning, Ultrasonography Supplemental material is available for this article. © RSNA, 2023.

Reprogramming the lipid metabolism of dendritic cells in tumor immunomodulation and immunotherapy.

Dendritic cells (DCs) are the most potent antigen-presenting cells in the human body. They detect and process environmental signals and communicate with T cells to bridge innate and adaptive immunity. Cell activation, function, and survival are closely associated with cellular metabolism. An increasing number of studies have revealed that lipid metabolism affects DC activation as well as innate and acquired immune responses. Combining lipid metabolic regulation with immunotherapy can strengthen the ability of antigen-presentation and T-cell activation of DCs, improve the existing anti-tumor therapy, and overcome the defects of DC-related therapies in the current stage, which has great potential in cancer therapy. This review summarizes the lipid metabolism of DCs under physiological conditions, analyzes the role of reprogramming the lipid metabolism of DCs in tumor immune regulation, and discusses potential immunotherapeutic strategies.

VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway.

Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases.

Long non-coding RNAs in virus-related cancers.

Some viral infections lead to tumourigenesis explained by a variety of underlying molecular mechanisms. Long non-coding RNAs (lncRNAs) have the potential to be added to this list due to their diverse mechanisms in biological functions and disease processes via gene alternation, transcriptional regulation, protein modification, microRNA sponging and interaction with RNA/DNA/proteins. In this review, we summarise the dysregulation and mechanism of lncRNAs in virus-related cancers focussing on Hepatitis B virus, Epstein-Barr virus, Human Papillomavirus. We will also discuss the potential implications of lncRNAs in COVID-19.

LIF, a mitogen for choroidal endothelial cells, protects the choriocapillaris: implications for prevention of geographic atrophy.

In the course of our studies aiming to discover vascular bed-specific endothelial cell (EC) mitogens, we identified leukemia inhibitory factor (LIF) as a mitogen for bovine choroidal EC (BCE), although LIF has been mainly characterized as an EC growth inhibitor and an anti-angiogenic molecule. LIF stimulated growth of BCE while it inhibited, as previously reported, bovine aortic EC (BAE) growth. The JAK-STAT3 pathway mediated LIF actions in both BCE and BAE cells, but a caspase-independent proapoptotic signal mediated by cathepsins was triggered in BAE but not in BCE. LIF administration directly promoted activation of STAT3 and increased blood vessel density in mouse eyes. LIF also had protective effects on the choriocapillaris in a model of oxidative retinal injury. Analysis of available single-cell transcriptomic datasets shows strong expression of the specific LIF receptor in mouse and human choroidal EC. Our data suggest that LIF administration may be an innovative approach to prevent atrophy associated with AMD, through protection of the choriocapillaris.

Compact QEPAS humidity sensor in SF6 buffer gas for high-voltage gas power systems.

In SF6 insulated high-voltage gas power systems, H2O is the most problematic impurity which not only decreases insulation performance but also creates an acidic atmosphere that promotes corrosion. Corrosion damages electrical equipment and leads to leaks, which pose serious safety hazards to people and the environment. A QEPAS-based sensor system for the sub-ppm level H2O detection in SF6 buffer gas was developed by use of a near-infrared commercial DFB diode laser. Since the specific physical constants of SF6 are strongly different from that of N2 or air, the resonant frequency and Q-factor of the bare quartz tuning fork (QTF) had changed to 32,763 Hz and 4173, respectively. The optimal vertical detection position was 1.2 mm far from the QTF opening. After the experimental optimization of acoustic micro-resonator (AmR) parameters, gas pressures, and modulation depths, a detection limit of 0.49 ppm was achieved for an averaging time of 1 s, which provided a powerful prevention tool for the safety monitoring in power systems.

Near-infrared laser photoacoustic gas sensor for simultaneous detection of CO and H2S.

A ppb-level H2S and CO photoacoustic spectroscopy (PAS) gas sensor was developed by using a two-stage commercial optical fiber amplifier with a full output power of 10 W. Two near-infrared diode lasers with the central wavenumbers of 6320.6 cm-1 and 6377.4 cm-1 were employed as the excitation laser source. A time-division multiplexing method was used to simultaneously detect CO and H2S with an optical switch. A dual-resonator structural photoacoustic cell (PAC) was theoretically simulated and designed with a finite element analysis. A µV level background noise was achieved with the differential and symmetrical PAC. The performance of the multi-component sensor was evaluated after the optimization of frequency, pressure and modulation depth. The minimum detection limits of 31.7 ppb and 342.7 ppb were obtained for H2S and CO at atmospheric pressure.

3-D Res-CapsNet convolutional neural network on automated breast ultrasound tumor diagnosis.

PURPOSE: We propose a 3-D tumor computer-aided diagnosis (CADx) system with U-net and a residual-capsule neural network (Res-CapsNet) for ABUS images and provide a reference for early tumor diagnosis, especially non-mass lesions. METHODS: A total of 396 patients with 444 tumors (226 malignant and 218 benign) were retrospectively enrolled from Sun Yat-sen University Cancer Center. In our CADx, preprocessing was performed first to crop and resize the tumor volumes of interest (VOIs). Then, a 3-D U-net and postprocessing were applied to the VOIs to obtain tumor masks. Finally, a 3-D Res-CapsNet classification model was executed with the VOIs and the corresponding masks to diagnose the tumors. Finally, the diagnostic performance, including accuracy, sensitivity, specificity, and area under the curve (AUC), was compared with other classification models and among three readers with different years of experience in ABUS review. RESULTS: For all tumors, the accuracy, sensitivity, specificity, and AUC of the proposed CADx were 84.9 %, 87.2 %, 82.6 %, and 0.9122, respectively, outperforming other models and junior reader. Next, the tumors were subdivided into mass and non-mass tumors to validate the system performance. For mass tumors, our CADx achieved an accuracy, sensitivity, specificity, and AUC of 85.2 %, 88.2 %, 82.3 %, and 0.9147, respectively, which was higher than that of other models and junior reader. For non-mass tumors, our CADx achieved an accuracy, sensitivity, specificity, and AUC of 81.6 %, 78.3 %, 86.7 %, and 0.8654, respectively, outperforming the two readers. CONCLUSION: The proposed CADx with 3-D U-net and 3-D Res-CapsNet models has the potential to reduce misdiagnosis, especially for non-mass lesions.

Highly sensitive broadband differential infrared photoacoustic spectroscopy with wavelet denoising algorithm for trace gas detection.

Enhancement of trace gas detectability using photoacoustic spectroscopy requires the effective suppression of strong background noise for practical applications. An upgraded infrared broadband trace gas detection configuration was investigated based on a Fourier transform infrared (FTIR) spectrometer equipped with specially designed T-resonators and simultaneous differential optical and photoacoustic measurement capabilities. By using acetylene and local air as appropriate samples, the detectivity of the differential photoacoustic mode was demonstrated to be far better than the pure optical approach both theoretically and experimentally, due to the effectiveness of light-correlated coherent noise suppression of non-intrinsic optical baseline signals. The wavelet domain denoising algorithm with the optimized parameters was introduced in detail to greatly improve the signal-to-noise ratio by denoising the incoherent ambient interference with respect to the differential photoacoustic measurement. The results showed enhancement of sensitivity to acetylene from 5 ppmv (original differential mode) to 806 ppbv, a fivefold improvement. With the suppression of background noise accomplished by the optimized wavelet domain denoising algorithm, the broadband differential photoacoustic trace gas detection was shown to be an effective approach for trace gas detection.

Inhibition of protein glycosylation is a novel pro-angiogenic strategy that acts via activation of stress pathways.

Endothelial cell (EC) metabolism is thought to be one of the driving forces for angiogenesis. Here we report the identification of the hexosamine D-mannosamine (ManN) as an EC mitogen and survival factor for bovine and human microvascular EC, with an additivity with VEGF. ManN inhibits glycosylation in ECs and induces significant changes in N-glycan and O-glycan profiles. We further demonstrate that ManN and two N-glycosylation inhibitors stimulate EC proliferation via both JNK activation and the unfolded protein response caused by ER stress. ManN results in enhanced angiogenesis in a mouse skin injury model. ManN also promotes angiogenesis in a mouse hindlimb ischemia model, with accelerated limb blood flow recovery compared to controls. In addition, intraocular injection of ManN induces retinal neovascularization. Therefore, activation of stress pathways following inhibition of protein glycosylation can promote EC proliferation and angiogenesis and may represent a therapeutic strategy for treatment of ischemic disorders.

Identification of osteogenic progenitor cell-targeted peptides that augment bone formation.

Activation and migration of endogenous mesenchymal stromal cells (MSCs) are critical for bone regeneration. Here, we report a combinational peptide screening strategy for rapid discovery of ligands that not only bind strongly to osteogenic progenitor cells (OPCs) but also stimulate osteogenic cell Akt signaling in those OPCs. Two lead compounds are discovered, YLL3 and YLL8, both of which increase osteoprogenitor osteogenic differentiation in vitro. When given to normal or osteopenic mice, the compounds increase mineral apposition rate, bone formation, bone mass, and bone strength, as well as expedite fracture repair through stimulated endogenous osteogenesis. When covalently conjugated to alendronate, YLLs acquire an additional function resulting in a "tri-functional" compound that: (i) binds to OPCs, (ii) targets bone, and (iii) induces "pro-survival" signal. These bone-targeted, osteogenic peptides are well suited for current tissue-specific therapeutic paradigms to augment the endogenous osteogenic cells for bone regeneration and the treatment of bone loss.

Automated Breast Ultrasound: Interobserver Agreement, Diagnostic Value, and Associated Clinical Factors of Coronal-Plane Image Features.

OBJECTIVE: To evaluate the interobserver agreement, diagnostic value, and associated clinical factors of automated breast ultrasound (ABUS) coronal features in differentiating breast lesions. MATERIALS AND METHODS: This study enrolled 457 pathologically confirmed lesions in 387 female (age, 46.4 ± 10.3 years), including 377 masses and 80 non-mass lesions (NMLs). The unique coronal features, including retraction phenomenon, hyper- or hypoechoic rim (continuous or discontinuous), skipping sign, and white wall sign, were defined and recorded. The interobserver agreement on image type and coronal features was evaluated. Furthermore, clinical factors, including the lesion size, distance to the nipple or skin, palpability, and the histological grade were analyzed. RESULTS: Among the 457 lesions, 296 were malignant and 161 were benign. The overall interobserver agreement for image type and all coronal features was moderate to good. For masses, the retraction phenomenon was significantly associated with malignancies (p < 0.001) and more frequently presented in small and superficial invasive carcinomas with a low histological grade (p = 0.027, 0.002, and < 0.001, respectively). Furthermore, continuous hyper- or hypoechoic rims were predictive of benign masses (p < 0.001), whereas discontinuous rims were predictive of malignancies (p < 0.001). A hyperechoic rim was more commonly detected in masses more distant from the nipple (p = 0.027), and a hypoechoic rim was more frequently found in large superficial masses (p < 0.001 for both). For NMLs, the skipping sign was a predictor of malignancies (p = 0.040). CONCLUSION: The coronal plane of ABUS may provide useful diagnostic value for breast lesions.

Value of Hand-held Ultrasound in the Differential Diagnosis and Accurate Breast Imaging Reporting and Data System Subclassification of Complex Cystic and Solid Breast Lesions.

To explore the value of hand-held ultrasound (HHUS) for diagnosing complex cystic and solid breast lesions, 472 pathologically proven lesions were analyzed. The lesions were divided into four types based on ultrasound features. Positive predictive values (PPVs) for lesion types and risk factor performances were assessed. Furthermore, HHUS and mammography (MAM) performances were compared: 27 lesions missed in MAM were detected in HHUS. Ultrasound feature analysis revealed higher PPVs for type III and IV lesions than for type I and II lesions. In patients older than 51 y, a type III or IV lesion with a diameter greater than 18 mm, an irregular shape, a non-parallel orientation, an uncircumscribed margin, calcification, vascularity and abnormal axillary lymph nodes were suggestive of malignancy; the area under the curve reached 0.869. Thus, ultrasound is useful in diagnosing complex cystic and solid breast lesions, which should be categorized as Breast Imaging Reporting and Data System (BI-RADS) 4B or 4C.

Adenoid cystic carcinoma of the breast: a study of five cases.

Adenoid cystic carcinoma of the breast is a rare type of breast cancer. Most patients present with a bilateral palpable mass. Ultrasound and mammography are non-specific and can sometimes lead to misdiagnosis because of their variable imaging features. Pathological examination is the standard reference. Surgery is the mainstay of treatment for patients. Although adenoid cystic carcinoma has an excellent prognosis, metastatic cases have been reported. This report aims to discuss the clinical and imaging features of one case of adenoid cystic carcinoma with a poor prognosis and four cases with a good prognosis at our center.

Novel multi-targeted inhibitors suppress ocular neovascularization by regulating unique gene sets.

Neovascular diseases, such as many cancers and ocular disorders, are life threatening and devastating. Although anti-vascular endothelial growth factor A (VEGF-A) therapy is available, many patients are not responsive and drug resistance can develop. To try to overcome these problems, combination therapy targeting VEGF-A and platelet-derived growth factor B (PDGF-B) was tested. However, one obvious drawback was that the other VEGF and PDGF family members were not inhibited and therefore could compensate. Indeed, this was, at least to some extent, demonstrated by the disappointing outcomes. To this end, we designed novel multi-targeted inhibitors that can block most of the VEGF and PDGF family members simultaneously by making a fusion protein containing the ligand-binding domains of vascular endothelial growth factor receptor 1 (VEGFR1), vascular endothelial growth factor receptor 2 (VEGFR2) and platelet-derived growth factor receptor beta (PDGFRß), which can therefore act as a decoy blocker for most of the VEGF and PDGF family members. Indeed, in cultured cells, the novel inhibitors suppressed the migration and proliferation of both vascular endothelial cells and smooth muscle cells, and abolished VEGFR2 and PDGFRß activation. Importantly, in a choroidal neovascularization model in vivo, the novel inhibitor inhibited ocular neovascularization more efficiently than the mono-inhibitors against VEGFR or PDGFR alone respectively. Mechanistically, a genome-wide microarray analysis unveiled that the novel inhibitor regulated unique sets of genes that were not regulated by the mono-inhibitors, further demonstrating the functional uniqueness and superiority of the novel inhibitor. Together, we show that the multi-targeted inhibitors that can block VEGFR1, VEGFR2 and PDGFRß simultaneously suppress pathological angiogenesis more efficiently than monotherapy, and may therefore have promising therapeutic value for the treatment of neovascular diseases.

VEGF-B is a potent antioxidant.

VEGF-B was discovered a long time ago. However, unlike VEGF-A, whose function has been extensively studied, the function of VEGF-B and the mechanisms involved still remain poorly understood. Notwithstanding, drugs that inhibit VEGF-B and other VEGF family members have been used to treat patients with neovascular diseases. It is therefore critical to have a better understanding of VEGF-B function and the underlying mechanisms. Here, using comprehensive methods and models, we have identified VEGF-B as a potent antioxidant. Loss of Vegf-b by gene deletion leads to retinal degeneration in mice, and treatment with VEGF-B rescues retinal cells from death in a retinitis pigmentosa model. Mechanistically, we demonstrate that VEGF-B up-regulates numerous key antioxidative genes, particularly, Gpx1 Loss of Gpx1 activity largely diminished the antioxidative effect of VEGF-B, demonstrating that Gpx1 is at least one of the critical downstream effectors of VEGF-B. In addition, we found that the antioxidant function of VEGF-B is mediated mainly by VEGFR1. Given that oxidative stress is a crucial factor in numerous human diseases, VEGF-B may have therapeutic value for the treatment of such diseases.