A hot and cold tumor­related prognostic signature for stage II colorectal cancer.

Globally, colorectal cancer (CRC) is one of the most lethal and prevalent malignancies. Based on the presence of immune cell infiltration in the tumor microenvironment, CRC can be divided into immunologically 'hot' or 'cold' tumors, which in turn leads to the differential efficacy of immunotherapy. However, the immune characteristics of hot and cold CRC tumors remain largely elusive, prompting further investigation of their properties regarding the tumor microenvironment. In the present study, a predictive model was developed based on the differential expression of proteins between cold and hot CRC tumors. First, the differentially expressed proteins (DEPs) were identified using digital spatial profiling and mass spectrometry-based proteomics analysis, and the pathway features of the DEPs were analyzed using functional enrichment analysis. A novel eight-gene signature prognostic risk model was developed (IDO1, MAT1A, NPEPL1, NT5C, PTGR2, RPL29, TMEM126A and TUBB4B), which was validated using data obtained from The Cancer Genome Atlas. The results revealed that the risk score of the eight-gene signature acted as an independent prognostic indicator in patients with stage II CRC (T3-4N0M0). It was also found that a high-risk score in the eight-gene signature was associated with high immune cell infiltration in patients with CRC. Taken together, these findings revealed some of the differential immune characteristics of hot and cold CRC tumors, and an eight-gene signature prognostic risk model was developed, which may serve as an independent prognostic indicator for patients with stage II CRC (T3-4N0M0).

Wide-Angle Optical Metasurface for Vortex Beam Generation.

In this work, we have achieved an advancement by integrating wide-angle capacity into vortex beams with an impressive topological charge (TC) of 12. This accomplishment was realized through the meticulous engineering of a propagation-phase-designed metasurface. Comprising gallium nitride (GaN), meta-structures characterized by their high-aspect ratio, this metasurface exhibits an average co-polarization transmission efficiency, reaching a remarkable simulated value of up to 97%. The intricate spiral patterns, along with their respective quantification, have been meticulously investigated through tilt-view scanning electron microscopy (SEM) and were further analyzed through the Mach-Zehnder interferometer. A captivating revelation emerged, a distinctive petal-like interference pattern manifests prior to the metasurface's designed focal distance. The occurrence of this petal-like pattern at a specific z-axis position prompts a deliberate manipulation of the helicity of the spiral branches. This strategic helicity alteration is intrinsically tied to the achievement of a minimized donut diameter at the designed focal length. In regard to the angular capability of the device, the captured images continuously showcase prominent attributes within incident angles spanning up to 30 degrees. However, as incident angles surpass the 30-degree threshold, the measured values diverge from their corresponding theoretical projections, resulting in a progressive reduction in the completeness of the donut-shaped structure.

α-SMA+ cancer-associated fibroblasts increased tumor enhancement ratio on contrast-enhanced multidetector-row computed tomography in stages I-III colon cancer.

BACKGROUND AND AIM: Our prior research revealed that the tumor enhancement ratio (TER) on triphasic abdominal contrast-enhanced MDCT (CE-MDCT) scans was a prognostic factor for patients with stages I-III colon cancer. Building upon this finding, the present study aims to investigate the proteomic changes in colon cancer patients with varying TER values. METHODS: TER was analyzed on preoperative triphasic CE-MDCT scans of 160 stages I-III colon cancer patients. The survival outcomes of those in the low-TER and high-TER groups were compared. Proteomic analysis on colon cancer tissues was performed by mass spectrometry (MS) and verified by immune-histological chemistry (IHC) assays. In vivo, mouse xenograft models were employed to test the function of target proteins identified through the MS. CE-MDCT scans were conducted on mice xenografts, and the TER values were compared. RESULTS: Patients in the high-TER group had a significantly worse prognosis than those in the low-TER group. Proteomic analysis of colon cancer tissues revealed 153 differentially expressed proteins between the two groups. A correlation between TER and the abundance of α-SMA protein in tumor tissue was observed. IHC assays further confirmed that α-SMA protein expression was significantly increased in high-TER colon cancer, predominantly in cancer-associated fibroblasts (CAFs) within the cancer stroma. Moreover, CAFs promoted the growth of CRC xenografts in vivo and increased TER. CONCLUSIONS: Our study identified the distinct protein changes in colon cancer with low and high TER for the first time. The presence of CAFs may promote the growth of colon cancer and contribute to an increased TER.

Technological process optimization and measurement of image quality of the electrically bifocal metalens.

This Letter describes the design procedure and process optimization of the electrically bifocal metalens. In our design, horizontal and vertical polarization is manipulated by applying a suitable voltage to a twisted nematic liquid crystal (TN-LC) cell. Each nanostructure is designed to be a rectangular prism, making different polarizations of light experience various phase delays, thus causing bi-focus. We selected lithographical methods to fabricate our metalens because of the minimum physical size, which can be as small as 50 nm, and the maximum aspect ratio, which is as high as 15. Furthermore, to increase the tolerance and make the sidewall vertical and smooth, we coated different characteristics of photoresist sensitivity to the upper and lower layers. After the development, the mushroom-type photoresist makes Ni easier to strip while in the lift-off process, thus increasing the quality of the whole metalens. Our experiment shows that the focal lengths and focusing efficiencies corresponding to the two polarizations are similar to the simulation results. The proposed electrically modulated bifocal metalens can be utilized in different applications and combined with other optical components.

Molecular characterization of colorectal mucinous adenocarcinoma and adenocarcinoma, not otherwise specified, identified by multiomic data analysis.

Adenocarcinoma not otherwise specified (AC) and mucinous adenocarcinoma (MC) have different biological behaviors and clinical features. We utilized our previous proteomic data and public transcriptome, single-cell transcriptome, and spatial transcriptome databases to profile the molecular atlas of the tumor microenvironments of MC, AC, and normal colon tissues. By exploring the general and specific molecular features of AC and MC, we found that AC was immune-active but exposed to a hypoxic microenvironment. MC cells could protect against DNA damage, and the microenvironment was unfavorable to leukocyte transendothelial migration. We identified several potential molecular and cellular targets of AC and MC for future research. We also highlighted that the major difference between AC and MC was not the variety of cell types and functions but possibly cell interactions. Stromal and epithelial cell interactions play important roles in both MC and AC, but different regulatory pathways were involved.

FOSL2 promotes intertumoral infiltration of T cells and increases pathological complete response rates in locally advanced rectal cancer patients.

The outcome of neoadjuvant chemoradiotherapy (nCRT) remains highly unpredictable for individuals with locally advanced rectal cancer (LARC). We set out to characterize effective biomarkers that promote a pathological complete response (pCR). We quantified the abundances of 6483 high-confidence proteins in pre-nCRT biopsies of 58 LARC patients from two hospitals with pressure cycling technology (PCT)-assisted pulse data-independent acquisition (PulseDIA) mass spectrometry. Compared with non-pCR patients, pCR patients achieved long-term disease-free survival (DFS) and had higher tumor immune infiltration, especially CD8+ T cell infiltration, before nCRT. FOSL2 was selected as the candidate biomarker for predicting pCR and was found to be significantly upregulated in pCR patients, which was verified in another 54 pre-nCRT biopsies of LARC patients by immunohistochemistry. FOSL2 expression was able to predict pCR by multiple reaction monitoring (MRM) with high efficiency (Area under curve (AUC) = 0.939, specificity = 1.000, sensitivity = 0.850), and high FOSL2 expression was associated with long-term DFS (p = 0.044). When treated with simulated nCRT, FOSL2 sufficiency resulted in more significant inhibition of cell proliferation, and more significant promotion of cell cycle arrest and cell apoptosis. Moreover, CXCL10 secretion with abnormal cytosolic dsDNA accumulation was found in FOSL2-wildtype (FOSL2-WT) tumor cells over nCRT, which might elevate CD8+ T-cell infiltration and CD8+ T-cell-mediated cytotoxicity to promote nCRT-induced antitumor immunity. Our study revealed proteomic profiles in LARC patients before nCRT and highlighted immune activation in the tumors of patients who achieved pCR. We identified FOSL2 as a promising biomarker to predict pCR and promote long-term DFS by contributing to CD8+ T-cell infiltration.

GaN vortex metasurface for interference and broadband characteristics.

We experimentally demonstrate a highly efficient metasurface-based optical vortex beam (OVB) composed of high-aspect-ratio gallium nitride (GaN) meta-structures with an exceptional simulated absolute polarization conversion efficiency (APCE) of up to 98%. A flower-like interference pattern emerges at the converging distance of the device with the helicity switching in spiral and dislocation interference patterns beyond this point, as confirmed through meticulous Mach-Zehnder interferometer analysis. The device also performs broadband capabilities across visible wavelengths. Experimentally demonstrated, the annular shape adeptly expands its diameter with increasing incident wavelengths. This phenomenon is rooted in the fascinating anomalous refractive and reflective characteristics inherent to subwavelength-period metasurfaces.

Embryonal tumors with multilayered rosettes, C19MC-altered or not elsewhere classified: Clinicopathological characteristics, prognostic factors, and outcomes of 17 children from 2018 to 2022.

Objective: Embryonal tumors with multilayered rosettes (ETMRs) are a histologically heterogeneous entity and gather embryonal tumors with abundant neuropil and true rosettes (ETANTRs), ependymoblastoma, and medulloepithelioma. ETMRs are highly aggressive and associated with poorer clinical courses. However, cases of this entity are rare, and advances in molecular genetics and therapy are minor. The purpose of our study was to retrospectively analyze the clinical, pathological features, and prognostic factors of ETMRs. Methods: Our cohort consisted of 17 patients diagnosed with ETMRs in our hospital from 2018 to 2022, and two of them were lost to follow-up. Clinical data were retrieved, and immunohistochemistry and genetic analyses were performed. Results: Among 17 cases, 16 were ETANTRs, and one was medulloepithelioma. Morphologically, tumor cells of ETANTRs could transform into anaplasia and lose the biphasic architecture during tumor progression. Immunohistochemistry of LIN28A revealed positive expression in 17 cases, and the expression of LIN28A was more intense and diffuse in the recurrent lesions than in primaries. The increased N-MYC copy numbers were detected in the primary tumor and recurrence of patient 8. Moreover, the incidence of metastatic disease was 100% in patients aged > 4 years and 18% in the younger group. For patients receiving chemotherapy, the median overall survival time was 7.4 months, while that of those who didn't receive it was 1.2 months. Nevertheless, surgical approaches, radiotherapy, age at presentation, gender, tumor location, and metastatic status were not associated with independent prognosis. Conclusion: ETANTR might not present as the typical morphologies during tumor progression, so analyses of C19MC amplification and Lin28A antibody are indispensable for diagnosing ETMRs accurately. Children aged > 4 years tend to have a higher rate of metastasis in ETMRs. Chemotherapy is the only prognostic factor for ETMRs patients with a favorable prognosis. The biological nature and clinical patterns for recurrent diseases need to be further demonstrated to predict prognosis and guide treatment.

Bilateral Thalamic Gliomas Harboring Alterations of EGFR and H3K27M: An Integrated Clinicopathological Characteristics Case Series.

BACKGROUND: Bilateral thalamic gliomas (BTGs) are rare central nervous system tumors, and the outcome is usually dismal. BTG often harbors an EGFR mutation; however, a mutation in H3K27M is rare. We described 5 cases of BTGs harboring concomitant alterations of EGFR and H3K27M and retrospectively analyzed the clinicopathological features and prognosis of this rare entity. METHODS: Clinical data of patients were retrieved, and immunohistochemistry and molecular analyses were performed. In addition, a systematic review of literature was conducted using PubMed. RESULTS: Median patient age was 6 years (range, 3-9 years). The male-to-female ratio was 3:2. Tremors and disturbed speech were the main clinical manifestations. All lesions were located at bilateral thalami, and in 3 of 4 patients, the more significant thalamic lesion was on the left. Two patients harbored insertion mutations in exon 20 of EGFR, 1 missense mutation in exon 7 of EGFR, and 2 EGFR amplifications. After a median overall survival of 8 months, 3 patients died as a result of tumor progression. CONCLUSIONS: Concomitant alterations of EGFR and H3K27M might indicate a new subtype of diffuse midline glioma, H3K27M-altered. In addition, EGFR alterations could provide potential molecular therapeutic strategies to improve the dismal prognosis of BTGs. Due to the rarity of these tumors, more cases must be collected to study the pathogenesis, treatment, and clinical outcomes of BTGs with double alteration phenotypes.

Artificial intelligence defines protein-based classification of thyroid nodules.

Determination of malignancy in thyroid nodules remains a major diagnostic challenge. Here we report the feasibility and clinical utility of developing an AI-defined protein-based biomarker panel for diagnostic classification of thyroid nodules: based initially on formalin-fixed paraffin-embedded (FFPE), and further refined for fine-needle aspiration (FNA) tissue specimens of minute amounts which pose technical challenges for other methods. We first developed a neural network model of 19 protein biomarkers based on the proteomes of 1724 FFPE thyroid tissue samples from a retrospective cohort. This classifier achieved over 91% accuracy in the discovery set for classifying malignant thyroid nodules. The classifier was externally validated by blinded analyses in a retrospective cohort of 288 nodules (89% accuracy; FFPE) and a prospective cohort of 294 FNA biopsies (85% accuracy) from twelve independent clinical centers. This study shows that integrating high-throughput proteomics and AI technology in multi-center retrospective and prospective clinical cohorts facilitates precise disease diagnosis which is otherwise difficult to achieve by other methods.

Pollution level and health risk assessment of the total petroleum hydrocarbon in marine environment and aquatic products: a case of China.

To evaluate the pollution level and health risk of total petroleum hydrocarbon (TPH), seawater, sediments, and aquatic organisms were sampled from the southern sea area of Zhejiang Province (Yangtze River Delta, China) between 2017 and 2019. TPH was widely present in the aquatic environment and products, and its concentration was highly variable. The average value of pollution index (PI) exceeded 1 from 2017 to 2018, and 45.46-69.19% of seawater samples and 56.87-50.00% of sediment samples were polluted. The results showed significant differences in the TPH concentration in various species of aquatic organisms. The average TPH value in aquatic organisms could be ranked in the order as follows: bivalve > shrimp > crab > fish, further reflecting that the ability to accumulate and metabolize TPH existed differently among aquatic organisms within the same pond aquaculture environment. It was relatively safe to eat aquatic products since the exposure risk index was found to be far below the threshold value in this study. Therefore, it would be prudent to undertake regular monitoring of TPH to ensure effective ecosystem functioning and seafood safety in the southern Zhejiang ocean.

Mass Spectrometry-Based Targeted Serum Monomethylated Ribonucleosides Profiling for Early Detection of Breast Cancer.

RNA methylation plays a significant regulatory role in various of physiological activities and it has gradually become a hotspot of epigenetics in the past decade. 2'-O-methyladenosine (Am), 2'-O-methylguanosine (Gm), 2'-O-methylcytidine (Cm), 2'-O-methyluridine (Um), N 6-methyladenosine (m6A), N 1-methylguanosine (m1G), 5-methylcytidine (m5C), and 5-methyluridine (m5U) are representative 2'-O-methylation and base-methylation modified epigenetic marks of RNA. Abnormal levels of these ribonucleosides were found to be related to various diseases including cancer. Serum is an important source of biofluid for the discovery of biomarkers, and novel tumor biomarkers can be explored by measuring these ribonucleoside modifications in human serum. Herein, we developed and applied a hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC-MS/MS) method to determine the content of monomethylated ribonucleosides in human serum. The developed method enabled sensitive and accurate determination of these monomethylated ribonucleosides. By applying this robust method, we demonstrated the presence of Gm and Um in human serum for the first time, and we successfully quantified m6A, Gm, m1G, Cm, Um and m5U in serum samples collected from 61 patients with breast cancer and 69 healthy controls. We discovered that the levels of Gm, m1G, Cm, Um and m5U in serum were all significantly decreased in breast cancer patients whereas m6A was increased. We performed receiver operating characteristic (ROC) curve analysis, and obtained highest area under curve (AUC) value when combining these six monomethylated ribonucleosides together. These results suggest that m6A, Gm, m1G, Cm, Um and m5U might have great potential to be novel biomarkers for detection of breast cancer in the early stage. In addition, this study may stimulate future investigations about the regulatory roles of monomethylated ribonucleosides on the initiation and development of breast cancer.

A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer.

Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment.

HomeoboxC6 promotes metastasis by orchestrating the DKK1/Wnt/ß-catenin axis in right-sided colon cancer.

Patients with right-sided colon cancer (RCC) generally have a poorer prognosis than those with left-sided colon cancer (LCC). We previously found that homeobox C6 (HOXC6) was the most significantly upregulated gene in RCC compared to LCC. However, it remains unclear whether HOXC6 plays a role in tumor proliferation and metastasis. Our study aimed to explore the potential oncogenic role and the detailed molecular mechanism of HOXC6 in RCC. In this study, HOXC6 was validated to be overexpressed in RCC and associated with poor prognosis. Furthermore, overexpression of HOXC6 promoted the migration and invasion of colon cancer cells through inducing EMT by activating the Wnt/ß-catenin signaling pathway and inhibition of DKK1 secretion. Lastly, we preliminary explored the translational effect of HOXC6 and found that silencing of HOXC6 made HCT116 and HT29 cells more sensitive to irinotecan.

Plastomes of two Rehmannia species： comparative genomic and phylogenetic analyses.

Phylogenetic relationships within Rehmannia have not been well solved. Here, we assembled and reported two new complete plastomes of R. glutinosa and R. chingii by de novo assembly. The complete plastomes of R. glutinosa and R. chingii were 153,797 and 153,328 bp in length, respectively. These two plastomes had 98.8% sequence identity and a total of 401 SNPs, 137 indels and 6 inversions. They were highly conserved in GC content (43.1%), gene order, and gene content (133 genes), including 88 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. The phylogenomic analysis confirmed the monophyly of Rehmannieae and supported R. chingii as the basal taxon of Rehmannia.

[Assessment of nasal specific symptoms and psychological dysfunction in patients with chronic rhinosinusitis before and after surgery].

Objective:To investigate the effects of nasal specific symptoms on chronic rhinosinusitis（CRS） with anxiety, depression and other psychological dysfunction and endoscopic surgery for the improvement of psychological dysfunction in patients with CRS. Method:The Hamilton Anxiety Scale（HAMA）, Hamilton Depression Scale（HAMD） and the 22-Item Sino-Nasal Outcome Test（SNOT-22） were completed in 44 patients with CRS within one week before and 6 months after surgery. They were used to assess mental function and nasal specific symptoms. Result:According to the SNOT-22 score, patients with anxiety and depression mental dysfunction had more severe symptoms of dizziness, head and face pain and sleep disorders（P<0.01 or P<0.05）. After endoscopic sinus surgery, the scores of HAMD, HAMA and SNOT-22 in CRS patients were improved compared with preoperative（P<0.01）. Conclusion:Patients with CRS have more common anxiety and depression. The specific symptoms of dizziness and head and face pain are significantly related to the psychological dysfunction of patients with CRS. Endoscopic sinus surgery can significantly alleviate the specific symptoms and mental dysfunction.

DPHL: A DIA Pan-human Protein Mass Spectrometry Library for Robust Biomarker Discovery.

To address the increasing need for detecting and validating protein biomarkers in clinical specimens, mass spectrometry (MS)-based targeted proteomic techniques, including the selected reaction monitoring (SRM), parallel reaction monitoring (PRM), and massively parallel data-independent acquisition (DIA), have been developed. For optimal performance, they require the fragment ion spectra of targeted peptides as prior knowledge. In this report, we describe a MS pipeline and spectral resource to support targeted proteomics studies for human tissue samples. To build the spectral resource, we integrated common open-source MS computational tools to assemble a freely accessible computational workflow based on Docker. We then applied the workflow to generate DPHL, a comprehensive DIA pan-human library, from 1096 data-dependent acquisition (DDA) MS raw files for 16 types of cancer samples. This extensive spectral resource was then applied to a proteomic study of 17 prostate cancer (PCa) patients. Thereafter, PRM validation was applied to a larger study of 57 PCa patients and the differential expression of three proteins in prostate tumor was validated. As a second application, the DPHL spectral resource was applied to a study consisting of plasma samples from 19 diffuse large B cell lymphoma (DLBCL) patients and 18 healthy control subjects. Differentially expressed proteins between DLBCL patients and healthy control subjects were detected by DIA-MS and confirmed by PRM. These data demonstrate that the DPHL supports DIA and PRM MS pipelines for robust protein biomarker discovery. DPHL is freely accessible at https://www.iprox.org/page/project.html?id=IPX0001400000.

Application of exosomes as liquid biopsy in clinical diagnosis.

Liquid biopsy refers to the sampling and molecular analysis of the biofluids of circulating tumor cells, extracellular vesicles, nucleic acids, and so forth. Exosomes are small extracellular vesicles with sizes between 30-150 nm. They are secreted by multivesicular bodies through exocytosis in live cells and can participate in intercellular communication due to their contents, including nucleic acids, proteins, and lipids. Herein, we investigate publication frequencies on exosomes over the past 10 years, and review recent clinical studies on liquid biopsy of exosomes in the fields of oncology, pregnancy disorders, cardiovascular diseases, and organ transplantation. We also describe the advantages of exosomes as an effective liquid biopsy tool and the progression of exosome extraction methods. Finally, we depict the commercial development of exosome research and discuss the future role of exosomes in liquid biopsy.