Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy.

BACKGROUND: Breast cancer ranks first among malignant tumors, of which triple-negative breast cancer (TNBC) is characterized by its highly invasive behavior and the worst prognosis. Timely diagnosis and precise treatment of TNBC are substantially challenging. Abnormal tumor vessels play a crucial role in TNBC progression and treatment. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis, while effective NO delivery can normalize the tumor vasculature. Accordingly, we have proposed here a tumor vascular microenvironment remodeling strategy based on NO-induced vessel normalization and extracellular matrix collagen degradation with multimodality imaging-guided nanoparticles against TNBC called DNMF/PLGA. RESULTS: Nanoparticles were synthesized using a chemotherapeutic agent doxorubicin (DOX), a NO donor L-arginine (L-Arg), ultrasmall spinel ferrites (MnFe2O4), and a poly (lactic-co-glycolic acid) (PLGA) shell. Nanoparticle distribution in the tumor was accurately monitored in real-time through highly enhanced magnetic resonance imaging and photoacoustic imaging. Near-infrared irradiation of tumor cells revealed that MnFe2O4 catalyzes the production of a large amount of reactive oxygen species (ROS) from H2O2, resulting in a cascade catalysis of L-Arg to trigger NO production in the presence of ROS. In addition, DOX activates niacinamide adenine dinucleotide phosphate oxidase to generate and supply H2O2. The generated NO improves the vascular endothelial cell integrity and pericellular contractility to promote vessel normalization and induces the activation of endogenous matrix metalloproteinases (mainly MMP-1 and MMP-2) so as to promote extravascular collagen degradation, thereby providing an auxiliary mechanism for efficient nanoparticle delivery and DOX penetration. Moreover, the chemotherapeutic effect of DOX and the photothermal effect of MnFe2O4 served as a chemo-hyperthermia synergistic therapy against TNBC. CONCLUSION: The two therapeutic mechanisms, along with an auxiliary mechanism, were perfectly combined to enhance the therapeutic effects. Briefly, multimodality image-guided nanoparticles provide a reliable strategy for the potential application in the fight against TNBC.

Selection and Validation of Reference Genes for Gene Expression in Bactericera gobica Loginova under Different Insecticide Stresses.

Insecticide resistance has long been a problem in crop pest control. Bactericera gobica is a major pest on the well-known medicinal plants Lycium barbarum L. Investigating insecticide resistance mechanisms of B. gobica will help to identify pesticide reduction strategies to control the pest. Gene expression normalization by RT-qPCR requires the selection and validation of appropriate reference genes (RGs). Here, 15 candidate RGs were selected from transcriptome data of B. gobica. Their expression stability was evaluated with five algorithms (Delta Ct, GeNorm, Normfinder, BestKeeper and RefFinder) for sample types differing in response to five insecticide stresses and in four other experimental conditions. Our results indicated that the RGs RPL10 + RPS15 for Imidacloprid and Abamectin; RPL10 + AK for Thiamethoxam; RPL32 + RPL10 for λ-cyhalothrin; RPL10 + RPL8 for Matrine; and EF2 + RPL32 under different insecticide stresses were the most suitable RGs for RT-qPCR normalization. EF1α + RPL8, EF1α + ß-actin, ß-actin + EF2 and ß-actin + RPS15 were the optimal combination of RGs under odor stimulation, temperature, developmental stages and both sexes, respectively. Overall, EF2 and RPL8 were the two most stable RGs in all conditions, while α-TUB and RPL32 were the least stable RGs. The corresponding suitable RGs and one unstable RG were used to normalize a target cytochrome P450 CYP6a1 gene between adult and nymph stages and under imidacloprid stress. The results of CYP6a1 expression were consistent with transcriptome data. This study is the first research on the most stable RG selection in B. gobica nymphs exposed to different insecticides, which will contribute to further research on insecticide resistance mechanisms in B. gobica.

Selection and Verification of Standardized Reference Genes of Angelica dahurica under Various Abiotic Stresses by Real-Time Quantitative PCR.

In traditional Chinese medicine, Angelica dahurica is a valuable herb with numerous therapeutic applications for a range of ailments. There have not yet been any articles on the methodical assessment and choice of the best reference genes for A. dahurica gene expression studies. Real-time quantitative PCR (RT-qPCR) is widely employed as the predominant method for investigating gene expression. In order to ensure the precise determination of target gene expression outcomes in RT-qPCR analysis, it is imperative to employ stable reference genes. In this study, a total of 11 candidate reference genes including SAND family protein (SAND), polypyrimidine tract-binding protein (PTBP), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), actin (ACT), TIP41-like protein (TIP41), cyclophilin 2 (CYP2), elongation factor 1 α (EF1α), ubiquitin-protein ligase 9 (UBC9), tubulin ß-6 (TUB6), thioredoxin-like protein YLS8 (YLS8), and tubulin-α (TUBA) were selected from the transcriptome of A. dahurica. Subsequently, three statistical algorithms (geNorm, NormFinder, and BestKeeper) were employed to assess the stability of their expression patterns across seven distinct stimulus treatments. The outcomes obtained from these analyses were subsequently amalgamated into a comprehensive ranking using RefFinder. Additionally, one target gene, phenylalanine ammonia-lyase (PAL), was used to confirm the effectiveness of the selected reference genes. According to the findings of this study, the two most stable reference genes for normalizing the expression of genes in A. dahurica are TIP41 and UBC9. Overall, our research has determined the appropriate reference genes for RT-qPCR in A. dahurica and provides a crucial foundation for gene screening and identifying genes associated with the biosynthesis of active ingredients in A. dahurica.

Implementation considerations for a point-of-care Neisseria gonorrhoeae rapid diagnostic test at primary healthcare level in South Africa: a qualitative study.

BACKGROUND: South Africa maintains an integrated health system where syndromic management of sexually transmitted infections (STI) is the standard of care. An estimated 2 million cases of Neisseria gonorrhoeae (N. gonorrhoeae) occur in South Africa every year. Point-of-care diagnostic tests (POCT) may address existing STI control limitations such as overtreatment and missed cases. Subsequently, a rapid lateral flow assay with fluorescence-based detection (NG-LFA) with a prototype reader was developed for N. gonorrhoeae detection showing excellent performance and high usability; however, a better understanding is needed for device implementation and integration into clinics. METHODS: A qualitative, time-series assessment using 66 in-depth interviews was conducted among 25 trained healthcare workers involved in the implementation of the NG-LFA. Findings were informed by the Normalization Process Theory (NPT) as per relevant contextual (strategic intentions, adaptive execution, and negotiation capacity) and procedural constructs (coherence, cognitive participation, collective action, reflexive monitoring) to examine device implementation within primary healthcare levels. Interviews were audio-recorded, transcribed, and then analyzed using a thematic approach guided by NPT to interpret results. RESULTS: Overall, healthcare workers agreed that STI POCT could guide better STI clinical decision-making, with consideration for clinic integration such as space constraints, patient flow, and workload. Perceived NG-LFA benefits included enhanced patient receptivity and STI knowledge. Further, healthcare workers reflected on the suitability of the NG-LFA given current limitations with integrated primary care. Recommendations included sufficient STI education, and appropriate departments for first points of entry for STI screening. CONCLUSIONS: The collective action and participation by healthcare workers in the implementation of the NG-LFA revealed adaptive execution within the current facility environment including team compositions, facility-staff receptivity, and STI management experiences. User experiences support future clinic service integration, highlighting the importance of further assessing patient-provider communication for STI care, organizational readiness, and identification of relevant departments for STI screening.

Tanshinone IIA normalized hepatocellular carcinoma vessels and enhanced PD-1 inhibitor efficacy by inhibiting ELTD1.

BACKGROUND: Hepatocellular carcinoma responds poorly to immune checkpoint inhibitors, such as PD-1 inhibitors, primarily due to the low infiltration capacity of TILs in the TME. Abnormal vasculature is an important factor which limiting the infiltration of TILs. According to recent research, targeting ELTD1 expression may improve TILs delivery to reverse immunosuppression and boost tumor responses to immunotherapy. Research has demonstrated that Tanshinone IIA (TSA) improves blood vessel normalization, but the precise mechanism is yet unknown. PURPOSE: The purpose of this study is to investigate the molecular processes for TSA's pro-vascular normalization of HCC in vitro and in vivo. METHODS: We established a mouse H22-luc in situ liver tumor model to evaluate the role of TSA vascular normalization and the immunosuppressive microenvironment. The role of ELTD1 in vascular and immune crosstalk was evaluated by bioinformatic analysis of the TCGA database. By creating a transwell co-culture cell model, the effects of TSA on enhancing tumor endothelial cell activities and ELTD1 intervention were evaluated. RESULTS: We investigated the effect of Tanshinone IIA (TSA), a major component of Salvia miltiorrhiza Bge., on the normalization of vasculature in situ HCC models. Our results demonstrated that TSA elicited vascular normalization in a hepatocellular carcinoma model in situ. In addition, the combination of TSA with anti-PD-1 significantly inhibited tumor development due to increased infiltration of immune cells in the tumor. Mechanistically, we demonstrated that TSA improved the immunosuppressive microenvironment by inhibiting tumor growth by suppressing ELTD1 expression, inhibiting downstream JAK1 and JAK2, promoting the expression of ZO-1, occlaudin, Claudin 5, and Col IV, and promoting vascular integrity and perfusion in situ. CONCLUSIONS: This study reveals a new mechanism between TSA and ELTD1 for vascular normalization, suggesting that therapeutic or pharmacological intervention with ELTD1 may enhance the efficacy of PD-1 inhibitors in HCC.

[Research progress on anti-tumor effects by traditional Chinese medicine based on "soothing" or "blockage" regulation of tumor vessels].

Regulation of tumor vessels has become one of the most common strategies for clinical anti-tumor therapy. In recent years, studies have found that the anti-tumor effect of limotherapy, which routinely inhibits tumor angiogenesis, is not ideal and may even deteriorate the tumor microenvironment, causing tumor resistance and distal metastasis and increasing the risk of tumor metastasis and recurrence. However, the proper use of anti-angiogenic drugs can promote the normalization of tumor vessels, improve the structure and function of tumor vessels, increase the number of functional vessels in the tumor, and reduce the number of ineffective vessels. It is beneficial to promote the penetration of anti-tumor drugs into the tumor, improve the microenvironment of tumor hypoxia and immunosuppression, and enhance the anti-tumor effect. Traditional Chinese medicine(TCM) has a long history of understanding the etiology and pathogenesis of tumors and has accumulated rich experience in tumor treatment, with significant clinical advantages and broad application prospects. In this study, from the perspective of bidirectional "soothing" or "blockage" regulation of tumor vessels, the commonly used molecular targets were sorted out, and the research status of anti-tumor regulation of tumor vessels by monomer-single herb-compound(herb pair) of TCM in recent years was summarized. The research on the anti-tumor effects of TCM compounds and active ingredients by regulating tumor vessels combined with other therapies was analyzed and sorted out, so as to provide ideas for the clinical application of TCM in regulating functions and anti-tumor effects of tumor vessels.

Reference Genes Screening and Gene Expression Patterns Analysis Involved in Gelsenicine Biosynthesis under Different Hormone Treatments in Gelsemium elegans.

Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is an accurate method for quantifying gene expression levels. Choosing appropriate reference genes to normalize the data is essential for reducing errors. Gelsemium elegans is a highly poisonous but important medicinal plant used for analgesic and anti-swelling purposes. Gelsenicine is one of the vital active ingredients, and its biosynthesis pathway remains to be determined. In this study, G. elegans leaf tissue with and without the application of one of four hormones (SA, MeJA, ETH, and ABA) known to affect gelsenicine synthesis, was analyzed using ten candidate reference genes. The gene stability was evaluated using GeNorm, NormFinder, BestKeeper, ∆CT, and RefFinder. The results showed that the optimal stable reference genes varied among the different treatments and that at least two reference genes were required for accurate quantification. The expression patterns of 15 genes related to the gelsenicine upstream biosynthesis pathway was determined by RT-qPCR using the relevant reference genes identified. Three genes 8-HGO, LAMT, and STR, were found to have a strong correlation with the amount of gelsenicine measured in the different samples. This research is the first study to examine the reference genes of G. elegans under different hormone treatments and will be useful for future molecular analyses of this medically important plant species.

Efficacy and safety of XELOX combined with anlotinib and penpulimab vs XELOX as an adjuvant therapy for ctDNA-positive gastric and gastroesophageal junction adenocarcinoma: a protocol for a randomized, controlled, multicenter phase II clinical trial (EXPLORING study).

Background: The efficacy of current adjuvant chemotherapy for gastric adenocarcinoma/gastroesophageal junction adenocarcinoma (GA/GEJA) leaves much to be desired. ctDNA could serve as a potential marker to identify patients who are at higher risk of recurrence. Reinforcing standard adjuvant chemotherapy with immunotherapy has already been indicated to significantly improve clinical outcome, albeit such evidence is rare in GA/GEJA. Here, we intend to explore the clinical benefit of the reinforcement of adjuvant immunotherapy and antiangiogenics alongside with chemotherapy in patients who are deemed in high risk of recurrence by ctDNA analysis, which might shed light on further improvements in adjuvant therapy for GA/GEJA. Methods/Design: This study is designed as a prospective, multicenter, randomized, controlled phase II study in patients histologically or cytologically diagnosed with GA/GEJA who underwent D2 gastrectomy and achieved R0 or R1 resection. From February 2022, a total of 300 stage III patients will be enrolled and subjected according to ctDNA sequencing results, and those with positive results will subsequently be randomized 1:1 to arm A or B. Patients in arm A will receive anlotinib, penpulimab and XELOX for 6-8 cycles, maintained with anlotinib and penpulimab for up to 1 year, while patients in arm B will receive XELOX alone for 6-8 cycles. ctDNA-negative patients will be assigned to arm C, and patients who are ctDNA positive but failed in randomization will be assigned to arm D. Patients in arms C and D will receive the investigator's choice of therapy. The primary endpoint is the median disease-free survival (DFS) of arm A versus arm B determined via CT/MRI imaging. Secondary endpoints include the DFS of ctDNA positive patients versus ctDNA negative patients, the 2- and 3-year DFS rates, overall survival (OS), the impact of hallmark molecules on the treatment response, adverse events (AEs), and the impact of nutrition status or exercise on recurrence. Discussion: We expect that ctDNA would be a strong prognostic factor and ctDNA-positive patients are at higher risk of relapse than ctDNA-negative patients. The addition of anlotinib and penpulimab to XELOX, may contribute to delaying relapse in ctDNA-positive patients. Trial registration: https://www.clinicaltrials.gov, identifier NCT05494060.

[Preliminary Study on Microvasculature Normalization Induced by Peritumoral Electroacupuncture in Mice With Breast Cancer Xenografts].

Objective: To observe the effect of peritumoral electroacupuncture on the induction of vascular normalization in a mouse breast cancer model. Methods: A subcutaneous graft model of breast cancer was established with 4T1 breast cancer cell line in female BALB/c mice aged 6-8 weeks. The mice were randomly assigned to three groups, a tumor-bearing group (TG), peritumoral electroacupuncture tumor-bearing group (EATG), and bevacizumab tumor-bearing group (BTG), with 18 mice in each group. The TG mice did not receive any intervention, the EATG mice received peritumoral electroacupuncture for 30 minutes, and the BTG mice were intraperitoneally injected with bevacizumab at 10mg/kg. Immunofluorescence was performed to assess the expression of CD31/alpha smooth muscle actin (α-SMA) and hypoxia-inducible factor 1-alpha (HIF-1α) in the tumor tissue at various points of time, including before intervention and 3 days and 5 days after intervention. Then, 3 days after intervention, observation of morphological changes of the microvessels in the tumor tissue was performed through Hematoxylin and Eosin (HE) staining and scanning electron microscope. Results: There was no significant difference in the expression of CD31, α-SMA, and HIF-1α in the tumor tissues of all groups before experimental intervention ( P>0.05). On day 3 of the experimental interventions, the CD31 and HIF-1α expression levels in the tumor tissues of the EATG and BTG mice were significantly reduced ( P<0.01), while α-SMA expression levels were significantly increased ( P<0.01) in both groups. On day 5 of the experimental interventions, the CD31 and HIF-1α expression levels in the tumor tissues of the EATG and BTG mice were still significantly lower than those in the TG mice ( P<0.01), while the α-SMA expression level was significantly higher than that in the TG group ( P<0.05). On day 3 of the experimental interventions, H&E staining showed visible microvessels in the tumor tissues of all 3 groups. In addition, scanning electron microscopic observation showed that the tumor microvessel walls of the TG mice were rough and defective, and that obvious deformities appeared in the lumen. In contrast, the walls of the microvessels of the EATG and BTG mice were generally intact and there was no obvious deformities in the lumen. Conclusion: Peritumoral electroacupuncture may induce microvasculature normalization by decreasing microvascular density and increasing pericyte coverage of the neovasculature, thereby improving hypoxic microenvironment of breast cancer in mice.

Selection and Validation of Optimal RT-qPCR Reference Genes for the Normalization of Gene Expression under Different Experimental Conditions in Lindera megaphylla.

Lindera megaphylla, a broad-leaved evergreen that is used as a landscape ornamental plant and medicinal plant, is an ecologically important and dominant tree species. However, little is known about the molecular mechanisms of its growth, development, and metabolism. The selection of suitable reference genes is critical for molecular biological analyses. To date, no research on reference genes as a foundation for gene expression analysis has been undertaken in L. megaphylla. In this study, 14 candidate genes were selected from the transcriptome database of L. megaphylla for RT-qPCR assay under different conditions. Results showed that helicase-15 and UBC28 were most stable in different tissues of seedlings and adult trees. For different leaf developmental stages, the best combination of reference genes was ACT7 and UBC36. UBC36 and TCTP were the best under cold treatment, while PAB2 and CYP20-2 were the best under heat treatment. Finally, a RT-qPCR assay of LmNAC83 and LmERF60 genes were used to further verify the reliability of selected reference genes above. This work is the first to select and evaluate the stability of reference genes for the normalization of gene expression analysis in L. megaphylla and will provide an important foundation for future genetic studies of this species.

Vascular Normalization Caused by Short-Term Lenvatinib Could Enhance Transarterial Chemoembolization in Hepatocellular Carcinoma.

We describe the clinical effects of short-term lenvatinib administration prior to conventional transarterial chemoembolization (cTACE) on tumor vasculature. Two patients with unresectable hepatocellular carcinoma underwent high-resolution digital subtraction angiography (DSA) and perfusion four-dimensional computed tomography during hepatic arteriography (4D-CTHA) before and after administration of lenvatinib treatment. The doses and periods of lenvatinib administration were, respectively, 12 mg/day for 7 days and 8 mg/day for 4 days. In both cases, high-resolution DSA revealed a decrease in dilatation and tortuosity of the tumor vessels. Furthermore, the tumor staining became more refined, and newly formed tiny tumor vessels were observed. Perfusion 4D-CTHA revealed a decrease in arterial blood flow to the tumor by 28.6% (from 487.9 to 139.5 mL/min/100 mg) and 42.5% (from 288.2 to 122.6 mL/min/100 mg) in the two cases, respectively. The cTACE procedure resulted in good lipiodol accumulation and complete response. Patients have remained recurrence-free for 12 and 11 months after the cTACE procedure, respectively. The administration of short-term lenvatinib in these two cases resulted in the normalization of tumor vessels, which likely led to improved lipiodol accumulation and a favorable antitumor effect.

Panax notoginseng saponins normalises tumour blood vessels by inhibiting EphA2 gene expression to modulate the tumour microenvironment of breast cancer.

BACKGROUND: Panax notoginseng saponins (PNS), the main active component of Panax notoginseng, can promote vascular microcirculation. PNS exhibits antitumor effects in various cancers. However, the molecular basis of the relationship between PNS and tumor blood vessels remains unclear. PURPOSE: To study the relationship between PNS inhibiting the growth and metastasis of breast cancer and promoting the normalization of blood vessels. METHODS: We performed laser speckle imaging of tumor microvessels and observed the effects of PNS on tumor growth and metastasis of MMTV-PyMT (FVB) spontaneous breast cancer in a transgenic mouse model. Immunohistochemical staining of Ki67 and CD31 was performed for tumors, scanning electron microscopy was used to observe tumor vascular morphology, and flow cytometry was used to detect tumor tissue immune microenvironment (TME). RNA-seq analysis was performed using the main vessels of the tumor tissues of the mice. HUVECs were cultured in tumor supernatant in vitro to simulate tumor microenvironment and verify the sequencing differential key genes. RESULTS: After treatment with PNS, we observed that tumor growth was suppressed, the blood perfusion of the systemic tumor microvessels in the mice increased, and the number of lung metastases decreased. Moreover, the vascular density of the primary tumor increased, and the vascular epidermis was smoother and flatter. Moreover, the number of tumor-associated macrophages in the tumor microenvironment was reduced, and the expression levels of IL-6, IL-10, and TNF-α were reduced in the tumor tissues. PNS downregulated the expression of multiple genes associated with tumor angiogenesis, migration, and adhesion. In vitro tubule formation experiments revealed that PNS promoted the formation and connection of tumor blood vessels and normalized the vessel morphology primarily by inhibiting EphA2 expression. In addition, PNS inhibited the expression of tumor vascular marker proteins and vascular migration adhesion-related proteins in vivo. CONCLUSION: In this study, we found that PNS promoted the generation and connection of tumor vascular endothelial cells, revealing the key role of EphA2 in endothelial cell adhesion and tumor blood vessel morphology. PNS can inhibit the proliferation and metastasis of breast cancer by inhibiting EphA2, improving the immune microenvironment of breast cancer and promoting the normalization of tumor blood vessels.

Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy.

Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies, on account of its good safety and long-term memory ability. Discouragingly, low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside. However, it has become evident that, although the immunosuppressive tumor microenvironment (TME) plays a pivotal role in facilitating tumor progression and metastasis, it also provides various potential targets for remodeling the immunosuppressive TME, which can consequently bolster the effectiveness of antitumor response and tumor suppression. Additionally, the particular characteristics of TME, in turn, can be exploited as avenues for designing diverse precise targeting nanomedicines. In general, it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME, thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy. Herein, we will illustrate several formation mechanisms of immunosuppressive TME. More importantly, a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients' immune systems, will be reviewed. Ultimately, we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy. Hopefully, the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.

Systematic Identification and Validation of Suitable Reference Genes for the Normalization of Gene Expression in Prunella vulgaris under Different Organs and Spike Development Stages.

The quantitative real-time PCR (qRT-PCR) is an efficient and sensitive method for determining gene expression levels, but the accuracy of the results substantially depends on the stability of the reference gene (RG). Therefore, choosing an appropriate reference gene is a critical step in normalizing qRT-PCR data. Prunella vulgaris L. is a traditional Chinese medicine herb widely used in China. Its main medicinal part is the fruiting spike which is termed Spica Prunellae. However, thus far, few studies have been conducted on the mechanism of Spica Prunellae development. Meanwhile, no reliable RGs have been reported in P. vulgaris. The expression levels of 14 candidate RGs were analyzed in this study in various organs and at different stages of Spica Prunellae development. Four statistical algorithms (Delta Ct, BestKeeper, NormFinder, and geNorm) were utilized to identify the RGs' stability, and an integrated stability rating was generated via the RefFinder website online. The final ranking results revealed that eIF-2 was the most stable RG, whereas VAB2 was the least suitable as an RG. Furthermore, eIF-2 + Histon3.3 was identified as the best RG combination in different periods and the total samples. Finally, the expressions of the PvTAT and Pv4CL2 genes related to the regulation of rosmarinic acid synthesis in different organs were used to verify the stable and unstable RGs. The stable RGs in P. vulgaris were originally identified and verified in this work. This achievement provides strong support for obtaining a reliable qPCR analysis and lays the foundation for in-depth research on the developmental mechanism of Spica Prunellae.

Alignment and Analysis of a Disparately Acquired Multibatch Metabolomics Study of Maternal Pregnancy Samples.

Untargeted liquid chromatography-mass spectrometry metabolomics studies are typically performed under roughly identical experimental settings. Measurements acquired with different LC-MS protocols or following extended time intervals harbor significant variation in retention times and spectral abundances due to altered chromatographic, spectrometric, and other factors, raising many data analysis challenges. We developed a computational workflow for merging and harmonizing metabolomics data acquired under disparate LC-MS conditions. Plasma metabolite profiles were collected from two sets of maternal subjects three years apart using distinct instruments and LC-MS procedures. Metabolomics features were aligned using metabCombiner to generate lists of compounds detected across all experimental batches. We applied data set-specific normalization methods to remove interbatch and interexperimental variation in spectral intensities, enabling statistical analysis on the assembled data matrix. Bioinformatics analyses revealed large-scale metabolic changes in maternal plasma between the first and third trimesters of pregnancy and between maternal plasma and umbilical cord blood. We observed increases in steroid hormones and free fatty acids from the first trimester to term of gestation, along with decreases in amino acids coupled to increased levels in cord blood. This work demonstrates the viability of integrating nonidentically acquired LC-MS metabolomics data and its utility in unconventional metabolomics study designs.

Remodeling of tumor microenvironment for enhanced tumor chemodynamic/photothermal/chemo-therapy.

The anticancer treatment is largely affected by the microenvironment of the tumors, which not only resists the tumors to the thermo/chemo-therapy, but also promotes their growth and invasion. In this work, the angiogenesis factor is balanced by combining with the breathing hyperoxygen, for regulating the tumor microenvironment and also for relieving hypoxia and high tissue interstitial pressure, which promote drug delivery to tumor tissues by increasing the in vivo perfusion and reversing the immunosuppressive tumor. In addition, the designed multifunctional nanoparticles have a great potential for applications to the tumor dual-mode imaging including magnetic resonance (MR) and photoacoustic (PA) imaging. This work proposes a promising strategy to enhance the thermo/chemo-therapy efficacy by remodeling the tumor microenvironment, which would provide an alternative to prolong the lifetime of tumor patients.

Aerial gamma-ray spectrometric survey data as a guide for probable hydrocarbon accumulations at Abu-Zeneima/Al-Tur area, Southwestern Sinai, Egypt.

A method using surface and aerial gamma-ray spectral measurements to explore the hydrocarbon accumulations in Abu-Zeneima/Al-Tur area of Southwestern Sinai, Egypt, was selected due to both its structural setting and its location in close proximity to the Gulf of Suez, which represents one of the important sites of oil production in Egypt. Examination of the normalized potassium map (KD %) shows low concentrations above Abu-Alaqah, Thebes, and Kariem formations, while normalized equivalent uranium map (eUD %) shows a high concentration above these formations. The Deviation of Radio-Active Derivative (DRAD) map shows some of the delineated high positive DRAD anomalies, which are elongated in the NW-SE direction and related to Abu-Alaqah, Thebes, and Kariem formations. Data from every formation and rock unit as well as each flight line were extracted in XYZ format and evaluated with simple statistical applications. The DRAD arithmetic means plus three standard deviations (x + 3s) and plus two standard deviations (x + 2s) for the data set all over the study area were computed and reached the values of 2.5 and 2.1, respectively. Any single point that possesses a value greater than these two values should have a probability of 99.7% and 95%, respectively, of possible petroleum accumulations and represents a sure anomaly. The use of these criteria helped identify Abu-Alaqah, Thebes, and Kariem formations. Moreover, five zones along four flight lines correlating geologically with Abu-Alaqah, Thebes, and Kariem formations have sure anomalies. This might indicate a prospective possibility of feasible subsurface petroleum accumulations in Abu-Zeneima/Al-Tur area, Southwestern Sinai, Egypt.

Wireless electrical stimulation at the nanoscale interface induces tumor vascular normalization.

Pathological angiogenesis frequently occurs in tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating tumor progression. However, traditional vascular normalization strategies are not fully effective and limited by the development of resistance. Herein, inspired by the intervention of endogenous bioelectricity in vessel formation, we propose a wireless electrical stimulation therapeutic strategy, capable of breaking bioelectric homeostasis within cells, to achieve tumor vascular normalization. Polarized barium titanate nanoparticles with high mechano-electrical conversion performance were developed, which could generate pulsed open-circuit voltage under low-intensity pulsed ultrasound. We demonstrated that wireless electrical stimulation significantly inhibited endothelial cell migration and differentiation in vitro. Interestingly, we found that the angiogenesis-related eNOS/NO pathway was inhibited, which could be attributed to the destruction of the intracellular calcium ion gradient by wireless electrical stimulation. In vivo tumor-bearing mouse model indicated that wireless electrical stimulation normalized tumor vasculature by optimizing vascular structure, enhancing blood perfusion, reducing vascular leakage, and restoring local oxygenation. Ultimately, the anti-tumor efficacy of combination treatment was 1.8 times that of the single chemotherapeutic drug doxorubicin group. This work provides a wireless electrical stimulation strategy based on the mechano-electrical conversion performance of piezoelectric nanoparticles, which is expected to achieve safe and effective clinical adjuvant treatment of malignant tumors.

[Nomenclature standardization of Chinese medicine extracts and components].

Chinese medicine extracts are the important pharmaceutical materials of Chinese medicinal preparations, but their nomenclature still needs improvement in the field of traditional Chinese medicine(TCM). By the analysis of the evolution rules of names of Chinese medicine extracts recorded in the Chinese Pharmacopoeia, this study proposed a three-level nomenclature of "Chinese medicine name+chemical information+extract" based on the standardization problems involved in the existing nomenclature, striving to accurately suggest the material basic information on extract names. Meanwhile, the basic elements of Chinese medicine components, the special case from Chinese medicine extracts, were clarified, and the core connotations of the professional names were discriminated to arouse attention and discussions of researchers, facilitate the standardization of Chinese medicine terminology, and promote the scienti-fic development of Chinese medicinal preparations, and the modernization and internationalization of Chinese medicine.

Evaluation of effectiveness of eye massage therapy via classification of periocular images.

This paper proposes a method to evaluate the effectiveness of the eye message therapy. The existing methods are via the diagnoses conducted by the medical professions based on the measurements acquired by the optical instruments. However, this approach is very expensive. To address this issue, this paper performs the classification between the periocular images taken before performing the eye massage therapy and those after performing the eye massage therapy to address the above difficulty. First, the median filtering is used to suppress the solitary point noise with preserving the edges of the image without causing the significant blurring. Then, the Canny operator is employed to accurately locate the edges. Next, the circle Hough transform (CHT) is used for performing the iris segmentation. Finally, various classifiers are used to perform the classification. The computer numerical simulation results show that our proposed method can achieve the high classification accuracies. This implies that there is a significant difference on the iris before performing the eye massage therapy and after performing the eye massage therapy. In addition, the comparisons with the state of art Daugman method have been performed. It is found that the classification performance achieved by the CHT based method is better than those achieved by the Daugman method.