Caveolin-1 Promotes the Imbalance of Th17/Treg in Chronic Obstructive Pulmonary Disease by Regulating Hsp70 Expression.

Objective: To investigate whether the expression of Hsp70 is associated with Cav-1 in promoting the imbalance of Th17/Treg cells in COPD. Methods: The plasma Cav-1, Hsp70 expression were quantified by enzyme-linked immunosorbent assay (ELISA). The frequencies of circulating Th17, Treg cells and Th17/Treg ratio were determined by flow cytometry. Peripheral blood mononuclear cells (PBMCs) from subjects were transfected with Cav-1 or control plasmids and Hsp70 plasmid. Results: We found that Cav-1 expression was lower but the levels of Hsp70 and Th17 cells were higher in COPD than in healthy control (HC). Hsp70 expressions were positively correlated with Cav-1 levels, Th17 cells, and Th17/Treg ratio in COPD but not in HC. Cav-1 over-expression resulted in an increase in Hsp70 and Th17 levels. Suppressing Hsp70 expressing by small interfering RNA (siRNA), the decline of Th17 frequency was observed in Cav-1-overexpressed PBMCs. Conclusion: Collectively, our results illuminate that Cav-1 contributes to the imbalance of Th17/Treg through potentially regulating Hsp70 expression.

Identification of Immune-Related Prognostic Markers in Gastric Cancer.

Gastric cancer (GC) is a malignant tumor with a high fatality rate. Poor prognosis is the main cause of death caused by GC. In this study, the gene expression difference between GC and the control group was analyzed. Differentially expressed genes (DEGs) related to immunity were screened for enrichment analysis. The differences in immune cell infiltration and immune function between GC and normal were identified. Cox regression analysis and survival analysis were used to determine the prognostic genes of GC in TCGA and GSE62254. The potential prognostic role of genes was further evaluated by risk score. Difference genes in GC were analyzed in TCGA. Candidate genes in TCGA and GSE62254 are analyzed, and prognostic genes are determined. The potential prognostic role of genes was further evaluated by risk score. The immune-related prognostic markers in GC were determined. FABP4, LBP, LCN1, CMA1, INHBA, ANGPTL1, ACKR1, GHR, and OGN may be used as markers for monitoring the prognosis of GC in the future.

CircFAM64A enhances cellular processes in triple-negative breast cancer by targeting the miR-149-5p/CDT1 axis.

Triple-negative breast cancer (TNBC) is a breast cancer subtype without targeted treatment options. Accumulating evidence has demonstrated the roles of circular RNAs in cancer. This study aimed to investigate the expression and function of circFAM64A in TNBC. The GSE101124 dataset from the GEO database was examined to identify the differentially expressed circular RNAs in TNBC. RT-qPCR and western blot analyses were performed to measure gene expression. TNBC cell proliferation, migration, invasion, and cell cycle were assessed using cell counting kit-8, EdU, flow cytometry, wound healing, and transwell invasion experiments. Bioinformatics analysis, RIP, RNA pulldown, and luciferase reporter assays were used to investigate the regulatory mechanism of circFAM64A. In this study, CircFAM64A expression was significantly upregulated in TNBC tissues and cells compared with normal tissues and cells. Overexpression of circFAM64A increased the proliferative, migratory, and invasive capacities of TNBC cells and promoted cell cycle progression. Mechanistically, circFAM64A acted as a molecular sponge for miR-149-5p, and miR-149-5p directly targeted the Cdc10-dependent transcript 1 (CDT1) 3'UTR. Moreover, the high expression of CDT1 is associated with a poor prognosis in patients with breast cancer. Rescue experiments demonstrated that circFAM64A sponged miR-149-5p to increase CDT1 expression, thereby promoting cellular processes in TNBC. Overall, CircFAM64A plays an oncogenic role in TNBC by interacting with miR-149-5p to increase CDT1 expression.

Motif-dependent immune co-receptor interactome profiling by photoaffinity chemical proteomics.

Identification of the tyrosine phosphorylation (pY)-dependent interactome of immune co-receptors is crucial for understanding signal pathways involved in immunotherapy. However, identifying the motif-specific interactome for each pY commonly found on these multi-phosphorylated membrane proteins remains challenging. Here, we describe a photoaffinity-based chemical proteomic approach to dissect the motif-specific cytoplasmic interactomes of the critical immune co-receptor CD28. Various full-length CD28 cytoplasmic tails (CD28cyto) with defined pY and selectively replaced photo-methionine were synthesized and applied to explore three pY-motif-dependent CD28cyto interactomes. We identified a stand-alone interaction of phospholipase PLCG1 with the Y191 motif with enhanced affinity for the sequence neighboring the transmembrane domain. Importantly, taking advantage of native top-down mass spectrometry with a 193-nm laser, we discovered the direct association of a previously undefined pY218 motif with the kinase PKCθ through its C2 domain. This synthetic CD28cyto-based photoaffinity proteomic approach is generically applicable to the study of other immune co-receptors with multiple pY sites on their linear cytoplasmic tail.

Neoantigen-reactive T cells exhibit effective anti-tumor activity against colorectal cancer.

Neoantigens play a crucial role in cancer immunotherapy. However, the effectiveness and safety of neoantigen-based immunotherapies in patients with colorectal cancer (CRC), particularly in the Chinese population, have not been well studied. This study explored the feasibility and effectiveness of neoantigens in the treatment of CRC. Whole-exome sequencing (WES) and transcriptome sequencing were used to identify somatic mutations, RNA expression, and human leukocyte antigen (HLA) alleles. Neoantigen candidates were predicted, and immunogenicity was assessed. The neoantigens TSHZ3-L523P, RARA-R83H, TP53-R248W, EYA2-V333I, and NRAS-G12D from Patient 4 (PW4); TASP1-P161L, RAP1GAP-S215R, MOSPD1-V63I, and NAV2-D1973N from Patient 10 (PW10); and HAVCR2-F39V, SEC11A-R11L, SMPDL3B-T452M, LRFN3-R118Q, and ULK1-S248L from Patient 11 (HLA-A0201+PW11) induced a heightened neoantigen-reactive T cell (NRT) response as compared with the controls in peripheral blood lymphocytes (PBLs) isolated from patients with CRC. In addition, we identified neoantigen-containing peptides SEC11A-R11L and ULK1-S248L from HLA-A0201+PW11, which more effectively elicited specific CTL responses than the corresponding native peptides in PBLs isolated from HLA-A0201+PW11 as well as in HLA-A2.1/Kb transgenic mice. Importantly, adoptive transfer of NRTs induced by vaccination with two mutant peptides could effectively inhibit tumor growth in tumor-bearing mouse models. These data indicate that neoantigen-containing peptides with high immunogenicity represent promising candidates for peptide-mediated personalized therapy.Abbreviations: CRC: colorectal cancer; DCs: dendritic cells; ELISPOT: enzyme-linked immunosorbent spot; E:T: effector:target; HLA: human leukocyte antigen; MHC: major histocompatibility complex; Mut: mutant type; NGS: next-generation sequencing; NRTs: neoantigen-reactive T cells; PBMCs: peripheral blood mononuclear cells; STR: short tandem repeat; PBLs: peripheral blood lymphocytes; PBS: phosphate-buffered saline; PD-1: programmed cell death protein 1; TILs: tumor-infiltrating lymphocytes; RNA-seq: RNA sequencing; Tg: transgenic; TMGs: tandem minigenes; WES: whole-exome sequencing; WT: wild-type.

DSP-free remote antenna unit in a coherent radio over fiber mobile fronthaul for 5G mm-wave mobile communication.

We propose a novel coherent analog radio over fiber (A-RoF) scheme to realize the generation, separation, and detection of four-independent mm-wave signals with the same carrier frequency on a single-wavelength for 5th generation (5G) mobile communication, and no digital signal processing (DSP) algorithms are required in remote antenna unit (RAU). In baseband unit (BBU), four-independent mm-wave signals are modulated on the two orthogonal polarization states of a single wavelength based on a dual-polarization IQ modulator using the dual single-sideband (SSB) modulation and polarization division multiplexing (PDM) technique. In RAU, a novel carrier polarization rotation module based on the self-polarization stabilization technique is proposed, and thus the four-independent mm-wave signals can be detected by self-coherent detection. Besides, the power fading effect induced by the chromatic dispersion could be overcome thanks to the optical SSB modulation, contributing to the increased coverage. By these means, no DSP algorithms are required in RAU, and the latency of signal processing could be significantly reduced. The experimental results show our proposed scheme could support 38.4 Gbps 16-ary quadrature amplitude modulation (16QAM) signals at 14 GHz over 30 km standard single-mode fiber (SSMF) transmission without DSP, satisfying 3rd Generation Partnership Project (3GPP) requirements. Besides, the measured error vector magnitude (EVM) value of 800 MBaud 16QAM signals at 28 GHz over 50 km SSMF transmission is 12.99%. This research provides a potential solution for the 5G mobile fronthaul.

Asymmetric dual-SSB modulation for photonic co-frequency mm-wave signals generation and DSP-free receiver.

An asymmetric dual-single-sideband (SSB) modulation scheme for photonic co-frequency millimeter (mm)-wave signals generation and digital signal processing (DSP)-free receiver is experimentally demonstrated for the first time, to the best of our knowledge. To effectively avoid the sideband crosstalk in the traditional symmetric dual-SSB modulation scheme, not only two vector-modulated signals but also two unmodulated sidebands are modulated on the two asymmetric sides of an optical carrier in this scheme. An optical delay line interferometer could easily separate these two asymmetric dual-SSB signals simultaneously in the receiver, and thus the photonic frequency up-conversion is realized. Besides, this scheme is free of dispersion-induced RF power fading thanks to the SSB modulation. By this means, no digital compensation algorithms such as carrier phase recovery, fiber dispersion compensation, and channel equalization are required, contributing to the DSP-free receiver. In our experiment, two 32 GHz 3.2 Gb/s 16-ary quadrature amplitude modulation mm-wave signals are produced using two RF signals with the carrier frequencies of 12 GHz and 20 GHz. The error vector magnitude (EVM) performances of these two mm-wave signals after 25.5 km standard single-mode fiber transmission are better than 3rd Generation Partnership Project requirements without using any digital compensation algorithms.

Rectosigmoid-Junction Squamous Cell Carcinoma With pMMR/MSS Achieved a Partial Response Following PD-1 Blockade Combined With Chemotherapy: A Case Report.

Colorectal squamous cell carcinoma (SCC) is extremely rare and associated with a poor prognosis. And the pMMR/MSS colorectal cancer is related to a limited response to programmed death ligand-1 (PD-1) blockade monotherapy. However, the clinical activity of PD-1 blockade monotherapy or combination therapy in colorectal SCC is unknown. One patient with rectosigmoid-junction SCC was treated with PD-1 blockade combined with chemotherapy. After 3 months of PD-1 blockade and chemotherapy, the computed tomography imaging showed that this patient achieved a partial response. The next generation sequencing and immunohistochemistry analysis showed that the patient had tumors with proficient mismatch repair (pMMR) and microsatellite stability (MSS), strong PD-L1 expression, and tumor mutational burden-high (TMB-High), respectively. This case suggests that PD-1 blockade combined with chemotherapy might be an effective therapy for colorectal SCC with pMMR/MSS status. Moreover, the PD-L1 expression and TMB might be the potential predictors of PD-1 blockade response for colorectal SCC patients.

Depleting long noncoding RNA HOTAIR attenuates chronic myelocytic leukemia progression by binding to DNA methyltransferase 1 and inhibiting PTEN gene promoter methylation.

Long noncoding RNAs (lncRNAs) are known to play a key role in chronic myelocytic leukemia (CML) development, and we aimed to identify the involvement of the lncRNA HOX antisense intergenic RNA (HOTAIR) in CML via binding to DNA methyltransferase 1 (DNMT1) to accelerate methylation of the phosphatase and tensin homolog (PTEN) gene promoter. Bone marrow samples from CML patients and normal bone marrow samples from healthy controls were collected. HOTAIR, DNMT1, DNMT3A, DNMT3B, and PTEN expression was detected. The biological characteristics of CML cells were detected. The relationship among HOTAIR, DNMT1, and PTEN was verified. Tumor volume and weight in mice injected with CML cells were tested. We found that HOTAIR and DNMT1 expression was increased and PTEN expression was decreased in CML. We also investigated whether downregulated HOTAIR or DNMT1 reduced proliferation, colony formation, invasion, and migration and increased the apoptosis rate of CML cells. Moreover, we tested whether low expression of HOTAIR or DNMT1 reduced the volume and weight of tumors in mice with CML. Collectively, the results of this studied showed that depleted HOTAIR demonstrated reduced binding to DNMT1 to suppress CML progression, which may be related to methylation of the PTEN promoter.

Successful recovery of a patient with multiple myeloma from severe coronavirus disease 2019 (COVID-19) pneumonia during the first chemotherapy cycle: A case report.

A continuing outbreak of pneumonia associated with the 2019 novel coronavirus (2019-nCoV) was initially described in Wuhan, China in December 2019. Weak and elderly individuals, and those with chronic diseases such as hematological malignancies are prone to develop severe pneumonia. The humoral immunity of patients with multiple myeloma is prevalently low, and their inferior immunity further deteriorates during chemotherapy. For patients with onco-hematological malignancies infected with 2019-nCoV during the first chemotherapy cycle, the clinical treatment experience is lacking. The present study is a report of a 61-year-old patient newly diagnosed with multiple myeloma in the key 2019-nCoV outbreak area, who suffered severe 2019-nCoV pneumonia during the first chemotherapy cycle. The present case report demonstrated that a rapidly progressive and severe form of pneumonia was a specific clinical feature of COVID-19, especially in immunocompromised patients with cancer. The treatment strategy combining timely suspending chemotherapy, early intervention using intravenous immunoglobulin, interferon α inhalation and oral antiviral drugs was effective. Therefore, in the pandemic environment, it is strongly recommend that the risk of 2019-nCoV infection is assessed prior to chemotherapy.

Long Noncoding RNAs: New Regulators of Resistance to Systemic Therapies for Gastric Cancer.

Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant disease, with approximately 951,000 new cases diagnosed and approximately 723,000 cases of mortality each year. The highest mortality rate of GC is in East Asia, and the lowest is in North America. A large number of studies have demonstrated that GC patients are characterized by higher morbidity, metastasis rates, and mortality and lower early diagnosis rates, radical resection rates, and 5-year survival rates. All cases of GC can be divided into two important stages, namely, early- and advanced-stage GC, and the stage mainly determines the treatment strategy for and the therapeutic effect in GC patients. Patients with early-stage GC undergo radical surgery followed by chemotherapy, and the 5-year survival rate can be as high as 90%. However, patients with advanced-stage GC cannot undergo radical surgery because they are at risk for metastasis; therefore, they can choose only radiotherapy or chemotherapy and have a poor prognosis. Based on the lack of specific clinical manifestations and detection methods, most GC patients (>70%) are diagnosed in the advanced stage; therefore, continued efforts toward developing treatments have been focused on advanced-stage GC patients and include molecular targeted therapy, immunotherapy, and small molecular therapy. Nevertheless, in recent years, accumulating evidence has indicated that small molecules, especially long noncoding RNAs (lncRNAs), are involved in the occurrence, development, and progression of GC, and their abundantly dysregulated expression has been identified in GC tissues and cell lines. Therefore, lncRNAs are considered easily detectable molecules and ideal biomarkers or target-specific agents for the future diagnosis or treatment of GC. In this review, we primarily discuss the status of GC, the role of lncRNAs in GC, and the emerging systemic treatments for GC.

Low-complexity equalization scheme for suppressing FFE-enhanced in-band noise and ISI in 100 Gbps PAM4 optical IMDD system.

The commonly used feed-forward equalizer (FFE) in an intensity modulation and direct-detection (IMDD) system is seriously restrained by the enhanced in-band noise in the high-frequency region. In this Letter, a low-complexity equalization scheme including FFE, post-filter (PF), and a newly designed interference cancellation (IC) algorithm is proposed to cope with the FFE-enhanced noise and serious inter-symbol interference (ISI) simultaneously. In our experiment, the achieved bit error rate value of 100 Gb/s optical double-sideband (ODSB) four-level pulse amplitude modulation (PAM4) signal transmission over 10 km standard single-mode fiber (SSMF) can go below the 20% overhead soft-decision forward error correction threshold of ${2.7} \times {{10}^{ - 2}}$2.7×10-2 when the FFE is replaced by the proposed equalizer. Even a 100 Gb/s optical single-sideband (OSSB) PAM4 signal can be successfully transmitted over 80 km SSMF. The results show that the proposed ${\rm FFE}+{\rm PF}+{\rm IC}$FFE+PF+IC algorithm can effectively suppress the FFE-enhanced noise and ISI with a quite low increase in complexity. Moreover, compared to the joint FFE, PF, and maximum likelihood sequence detection (MLSD) algorithm, the proposed ${\rm FFE}+{\rm PF}+{\rm IC}$FFE+PF+IC algorithm has 1.2 dB and 0.4 dB power penalties after 10 km SSMF in ODSB and 80 km SSMF in OSSB cases, respectively. However, the complexity of this IC algorithm is approximately 3% that of the MLSD.

SFPQ Is an FTO-Binding Protein that Facilitates the Demethylation Substrate Preference.

The fat mass and obesity-associated protein (FTO) is the first identified demethylase of the internal RNA modification N6-methyladenosine (m6A), which also exhibits demethylation activity toward N6,2'-O-dimethyladenosine (m6Am) and N1-methyladenosine (m1A). Demethylation of m6A at specific sites on target transcripts is a key enzymatic function of FTO that modulates diverse physiological and/or pathological processes. However, how FTO selects target RNA and whether additional interaction proteins facilitate this process remain elusive. Herein, via the genetically encoded and site-specific photocrosslinking strategy, we identified the major RNA-binding protein SFPQ as a direct interaction partner of FTO. Our study showed that FTO and SFPQ were located in close proximity throughout the transcriptome and that overexpression of SFPQ led to the demethylation of adjacent m6As, likely through recruiting FTO to these specific RNA sites. These results uncovered a new layer of regulation mechanism that may assist FTO to gain substrate specificity.

LncRNA, a novel target biomolecule, is involved in the progression of colorectal cancer.

Colorectal cancer is one of the most commonly diagnosed malignancies among males and females worldwide. Although China is a country with a low incidence of colorectal cancer, with the improvement of China's economy and lifestyle changes, the incidence rate in China has generally increased in recent years, and the morbidity and mortality of colorectal cancer rank fifth among those of all malignant tumours. Furthermore, despite recent improvements in screening strategies and treatments for colorectal cancer, the prognosis of advanced colorectal cancer is still poor, mainly due to the recurrence or distant metastasis of this disease. Thus, colorectal cancer still seriously threatens the health and life of people and is a major public health problem worthy of further study. Recently, accumulating evidence has revealed that colorectal carcinogenesis might be a multistep process driven by progressive genetic abnormalities, including changes in lncRNA expression. Moreover, a large number of studies have discovered and studied the abnormal expression of lncRNAs in colorectal cancer, providing a promising target for the diagnosis and treatment of colorectal cancer, which will promote human understanding of the pathogenesis of colorectal cancer and improve diagnosis and treatment. Therefore, in the present review, we mainly summarize the present status of colorectal cancer, the characteristics, functions and clinical perspectives of lncRNAs, and the current therapeutic methods used for colorectal cancer, especially the application of lncRNAs in the treatment of colorectal cancer. It is hoped that this review will give readers a new understanding of the roles of lncRNAs in colorectal cancer.

Columnar cell papillary thyroid carcinoma prognosis: findings from the SEER database using propensity score matching analysis.

BACKGROUND: Columnar cell papillary thyroid carcinoma (CCPTC) is a rare variant of papillary thyroid carcinoma (PTC), whose prognosis, as defined by the American Thyroid Association (ATA) guidelines, is considered poor, although available evidence is insufficient for reliable assessment. This study aimed to investigate the CCPTC prognosis using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Data of thyroid cancer patients, recorded from 2004 to 2013, were extracted to assess the CCPTC prognosis. All-cause and cancer-specific mortality rates associated with thyroid cancer types were evaluated using the Kaplan-Meier method and Cox proportional hazards regression. Propensity score matching analysis was used to adjust for potential confounders. RESULTS: Cancer-specific mortality per 1000 person-years was higher for CCPTC than for classic papillary thyroid cancer (CPTC) and follicular thyroid cancer (FTC). The multivariate Cox regression model revealed that the cancer-specific and all-cause mortality rates were higher for CCPTC than for CPTC but not FTC. However, propensity score matching analysis demonstrated a significantly lower survival for CCPTC than for both CPTC and FTC. CONCLUSIONS: Our findings provide evidence to support the poor prognosis associated with CCPTC. These findings may serve to improve the diagnosis of CCPTC, provide reliable reference data for clinical use, and increase the comprehensiveness of current guidelines.

Amplifier-free 4×96 Gb/s PAM8 transmission enabled by modified Volterra equalizer for short-reach applications using directly modulated lasers.

By using four O-band directly modulated lasers (DMLs), for the first time a 384 Gb/s (4 × 96 Gbit/s) 8-level pulse amplitude modulation (PAM8) signal is successfully transmitted over a 15 km standard single mode fiber (SSMF) with no optical amplifier. The nonlinear Volterra equalizer is usually used to cope with the distortions induced by the nonlinearity of DML and the bandwidth-limited components. However, the Volterra equalizer would also enhance the noise at high frequency, which is harmful, especially to PAM8 signal because it is more sensitive to noise. Thus, the Volterra equalizer is modified in our scheme by adding a decision feedback process behind. With the help of the modified Volterra equalizer, the enhanced noise at high frequency is effectively eliminated, and a power gain of 0.5 dB and 3.3 dB for 4 × 64 Gbit/s PAM4 signal transmission over 30 km SSMF and 4 × 96 Gbit/s PAM8 signal transmission over 15 km SSMF at the HD-FEC limit can be obtained, respectively. Moreover, the computation complexity of the modified Volterra equalizer could be reduced by 38% compared with the conventional Volterra equalizer.

Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers.

The incidence of aggressive neuroendocrine prostate cancers (NEPC) related to androgen-deprivation therapy (ADT) is rising. NEPC is still poorly understood, such as its neuroendocrine differentiation (NED) and angiogenic phenotypes. Here we reveal that NED and angiogenesis are molecularly connected through EZH2 (enhancer of zeste homolog 2). NED and angiogenesis are both regulated by ADT-activated CREB (cAMP response element-binding protein) that in turn enhances EZH2 activity. We also uncover anti-angiogenic factor TSP1 (thrombospondin-1, THBS1) as a direct target of EZH2 epigenetic repression. TSP1 is downregulated in advanced prostate cancer patient samples and negatively correlates with NE markers and EZH2. Furthermore, castration activates the CREB/EZH2 axis, concordantly affecting TSP1, angiogenesis and NE phenotypes in tumor xenografts. Notably, repressing CREB inhibits the CREB/EZH2 axis, tumor growth, NED, and angiogenesis in vivo. Taken together, we elucidate a new critical pathway, consisting of CREB/EZH2/TSP1, underlying ADT-enhanced NED and angiogenesis during prostate cancer progression.

Overexpression of TACC3 in Breast Cancer Associates With Poor Prognosis.

Increasing evidences suggest that transforming acidic coiled-coil protein 3 (TACC3) is associated with various types of human cancer. However, the expression of TACC3 in breast cancer tissues remains largely unknown. To identify whether TACC3 can serve as a biomarker for the diagnosis and prognosis of breast cancer, quantitative polymerase chain reaction, western blotting, and immunohistochemistry staining were utilized to detect the expression of TACC3. The mRNA and protein levels of TACC3 in breast cancer samples were novelty higher compared with nontumorous breast tissues. Immunohistochemistry results revealed TACC3 expression was significantly correlated to lymphoid nodal metastasis (P=0.035) and HER-2 status (P=0.021). The patients with high expression of TACC3 had a significantly poor prognosis compared with patients with low expression (P=0.017), especially in the patients with pathological tumor size 2-4 status (P=0.028). Furthermore, multivariate analysis indicated that TACC3 expression was an independent prognostic factor for breast cancer patients (P=0.029). This study, first, suggested TACC3 might be an important molecular marker for diagnosis and prognosis of breast cancer.