Upconversion dual-photosensitizer-expressing bacteria for near-infrared monochromatically excitable synergistic phototherapy.

Synergistic phototherapy stands for superior treatment prospects than a single phototherapeutic modality. However, the combined photosensitizers often suffer from incompatible excitation mode, limited irradiation penetration depth, and lack of specificity. We describe the development of upconversion dual-photosensitizer-expressing bacteria (UDPB) for near-infrared monochromatically excitable combination phototherapy. UDPB are prepared by integrating genetic engineering and surface modification, in which bacteria are encoded to simultaneously express photothermal melanin and phototoxic KillerRed protein and the surface primary amino groups are derived to free thiols for biorthogonal conjugation of upconversion nanoparticles. UDPB exhibit a near-infrared monochromatic irradiation-mediated dual-activation characteristic as the photothermal conversion of melanin can be initiated directly, while the photodynamic effect of KillerRed can be stimulated indirectly by upconverted visible light emission. UDPB also show living features to colonize hypoxic lesion sites and inhibit pathogens via bacterial community competition. In two murine models of solid tumor and skin wound infection, UDPB separately induce robust antitumor response and a rapid wound healing effect.

Fumarate Hydratase Enhances the Therapeutic Effect of PD-1 Antibody in Colorectal Cancer by Regulating PCSK9.

Despite the notable achievements of programmed death 1 (PD-1) antibodies in treating various cancers, the overall efficacy remains limited in the majority of colorectal cancer (CRC) cases. Metabolism reprogramming of tumors inhibits the tricarboxylic acid (TCA) cycle, leading to down-regulation of fumarate hydratase (FH), which is related to poor prognosis in CRC patients. By establishing a tumor-bearing mouse model of CRC with Fh1 expression deficiency, we confirmed that the therapeutic effect of PD-1 antibodies alone was suboptimal in mice with low Fh1 expression, which was improved by combination with a protein invertase subtilisin/kexin 9 (PCSK9) inhibitor. Mechanistically, FH binds to Ras-related nucleoprotein (RAN), which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. On the contrary, the expression of PCSK9 increased in CRC cells with low FH expression, which antagonized the effects of immunotherapy. Overall, CRC patients with low FH expression may benefit from combinatorial therapy with PD-1 antibodies and PCSK9 inhibitors to enhance the curative effect.

The clinical relevance of adjuvant chemotherapy in locally advanced rectal cancer patients achieving near pathological complete response following neoadjuvant chemoradiotherapy: Insights from ypT stage.

BACKGROUND: Near-pathological complete response (Near-pCR) patients constitute a distinct subgroup with limited research attention. The clinical relevance of adjuvant chemotherapy (ACT) in this patient cohort remains uncertain. METHODS: We conducted a retrospective analysis of 245 patients with locally advanced rectal cancer (LARC) who achieved near-pCR following neoadjuvant chemoradiotherapy (NCRT) between 2011 and 2018. Based on their receipt of ACT or not (non-ACT), patients were divided into two groups. We examined their characteristics, treatment modalities, and survival outcomes, particularly focusing on 5-year disease-free survival (DFS) and 5-year overall survival (OS). RESULTS: Among the 245 near-pCR patients, 191 (77.96%) received ACT, and 42 (17.14%) experienced disease recurrence. All 54 (22.04%) Patients in the non-ACT group exhibited a lower 5-year DFS rate (72.2% vs. 85.9%, P = 0.014) and a similar 5-year OS rate (87.0% vs. 91.1%, P = 0.351). Interestingly, those with ypT3-T4 stage tumors demonstrated a worse DFS (76.8% vs. 89.9%, P = 0.010) and OS (87.5% vs. 97.0%, P = 0.004) compared to their counterparts with ypT1-T2 stage tumors. Patients with Non-Downstage tumors showed inferior DFS (76.9% vs. 88.3%, P = 0.025) and OS (87.2% vs. 93.0%, P = 0.166) in comparison to patients with Downstage tumors. The ACT subgroup in patients with Downstage demonstrated statistically better 5-year DFS (93.0% vs. 71.4%, P = 0.001) but analogous survival rates for 5-year OS (OS: 94.0% vs. 89.3%, P = 0.402). Pathological T stage 3-4, perineural invasion (PNI) (positive) and ACT were independent factors influencing 5-year DFS in multivariate analysis. Both univariate and multivariate analysis demonstrated a link between serum carcinoembryonic antigen (CEA) before treatment ≥5 ng/ml and shorter 5-year OS. Notably, near-pCR patients with positive lymph nodes experienced notably diminished 5-year DFS in the absence of ACT post-surgery (61.1% vs. 93.2%, P < 0.001). CONCLUSIONS: ACT demonstrated a significant positive impact on the prognosis of select near-pCR patients, particularly those with ypT1-T2 stage tumors and positive lymph nodes. ypT staging may emerge as a valuable criterion for precise post-surgical ACT guidance in near-pCR patients.

Fast and Stable Antibacterial Coating of Photosensitive Aggregation-Induced Emission Luminogens for Disinfection on Medical Devices.

Aggregation-induced emission luminogens (AIEgens) are promising photosensitizers that have exhibited excellent antibacterial ability with abundant reactive oxygen species (ROS) generation. TTCPy-PF6 and TTCPy-Br are deposited on the surface of diverse solid substrates through plasma-assistant electrostatic self-assembly. The AIEgens-covered coating can effectively eliminate different pathogenic Gram-positive (G+) bacteria and even their multidrug-resistant (MDR) mutants with negligible side effects such as cytotoxicity, hemolysis, and inflammation. Moreover, the AIEgen-coated surface can maintain high stability for long-time antibacterial usage, which is dependent on the ROS-mediated disruption of the attached bacteria. The AIEgen-based coatings with broad surface applicability have many advantages in high antibacterial ability, great biocompatibility, and low possibility of antibiotic pollution. The robust antibacterial ability and excellent biological safety of the AIEgen-based coatings would be helpful for the disinfection of medical devices.

Overview of role of survivin in cancer: expression, regulation, functions, and its potential as a therapeutic target.

Survivin holds significant importance as a member of the inhibitor of apoptosis protein (IAP) family due to its predominant expression in tumours rather than normal terminally differentiated adult tissues. The high expression level of survivin in tumours is closely linked to chemotherapy resistance, heightened tumour recurrence, and increased tumour aggressiveness and serves as a negative prognostic factor for cancer patients. Consequently, survivin has emerged as a promising therapeutic target for cancer treatment. In this review, we delve into the various biological characteristics of survivin in cancers and its pivotal role in maintaining immune system homeostasis. Additionally, we explore different therapeutic strategies aimed at targeting survivin.

Clinicopathological and molecular characteristics of colorectal adenosquamous carcinoma in an Asian population.

BACKGROUND: Adenosquamous carcinoma is a rare sub-type of colorectal cancer with a poor prognosis. Little is known about its clinicopathological and molecular characteristics in Asian populations. This study aimed to investigate these features in a cohort of patients with adenosquamous carcinoma in the colorectum. METHODS: Tumor cases pathologically diagnosed with colorectal adenosquamous carcinoma were retrieved from the Sixth Affiliated Hospital, Sun Yat-sen University tissue archive between December 2012 and June 2020. Clinicopathological features, molecular characteristics, and oncology outcomes were analyzed. RESULTS: Among 18,139 cases of colorectal cancer, 11 were diagnosed with adenosquamous carcinoma, providing an incidence rate of 0.061%. The median overall survival (OS) was 14 months, and the expected 3-year OS rate was 29.6%. As of October 14, 2022, four cases had local recurrence and five had distant metastasis. KRAS gene mutations were found in four of seven patients (57.1%), and three out of eleven (27.3%) patients had mismatch repair-deficient (dMMR) tumors. CONCLUSIONS: Adenosquamous carcinoma is associated with a poor prognosis. Compared to other sub-types of colorectal cancer, a higher proportion of patients with dMMR and KRAS mutations were observed. These findings suggested that more patients with adenosquamous carcinoma could benefit from targeted therapies, such as immunotherapy.

Mitochondrial DNA copy number plays opposing roles in T-lymphocyte infiltration of colorectal cancer based on mismatch repair status: new directions for immunotherapy?

BACKGROUND: Researchers have previously reported that mitochondrial DNA copy number (mtDNA-CN) can play different roles in microsatellite instable/mismatch repair-deficient (MSI/dMMR) and microsatellite stable/mismatch repair-proficient (MSS/pMMR) colorectal cancer (CRC). To support malignancy, dMMR CRC relies on glycolysis, while pMMR CRC favors oxidative phosphorylation. However, it is unclear whether mtDNA-CN changes are related to T cell infiltration in CRC. METHODS: The mtDNA-CN was detected by qRT-PCR in 532 patients, and the expression of CD3 and CD8 in 485 patients was detected by immunohistochemistry. The correlation between mtDNA-CN and the prognosis of CRC patients was further analyzed, and the correlation between mtDNA-CN and T lymphocyte infiltration was also analyzed. Biopsy specimens from the immune checkpoint inhibitors (ICIs) treatment cohort were obtained to verify the correlation between mtDNA-CN and the efficacy of ICIs. The effects of mtDNA-CN and MMR status on gene expression were analyzed by RNA-seq. RESULTS: Our results show that mtDNA-CN has inverse relationships to CRC prognosis in cases with different MMR statuses, potentially inducing the U-shaped association in CRC. The opposing correlations between mtDNA-CN and T lymphocyte infiltration in cases of dMMR CRC and pMMR CRC further suggest that mtDNA-CN might play an important role in CRC development. More importantly, cases of pMMR CRC with lower mtDNA-CN and of dMMR CRC with higher mtDNA-CN can benefit more dramatically from ICIs. Furthermore, RNA-seq revealed a link between the level of mtDNA-CN and T lymphocyte infiltration in CRC cases with different MMR statuses. CONCLUSION: Our study found a potential relationship between mtDNA-CN and CRC development that differs by MMR status, potentially providing a rationale for the use of mtDNA-CN as both a predictive biomarker and a therapeutic target for ICIs.

Inflammatory stress response after transanal vs laparoscopic total mesorectal excision: a cohort study based on the TaLaR trial.

BACKGROUND: Transanal total mesorectal excision (taTME) is a novel approach to radical surgery for low rectal cancer; however, it is not clear whether taTME causes a more severe inflammatory stress response than laparoscopic total mesorectal excision (laTME). Therefore, the authors conducted this study to address this question, with the secondary objective of analyzing the predictive effect of inflammatory indexes on postoperative infective complications between laTME and taTME. METHODS: A total of 545 cases of laTME and 544 cases of taTME from the TaLaR randomized controlled trial were included. Inflammatory stress response was assessed via C-reactive protein (CRP), white blood cell count, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, and prognostic nutritional index. Inflammatory indexes were measured and calculated preoperatively (t1) and on postoperative days one (t2) and seven (t3). The accuracy of inflammatory indexes as predictor of infective complications was evaluated by areas under the receiver operating characteristic curve. RESULTS: Preoperative blood parameters were comparable between the two surgical methods. There were no significant differences in CRP, white blood cell count, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, or prognostic nutritional index between the two surgical methods at any time point ( P >0.05). Among the inflammatory indexes at three time points, CRP on the first postoperative day was the most accurate predictor of infective complications, which is suitable for two surgical methods. The AUC was 0.7671 ( P <0.0001) with a cutoff of 39.84 mg/l, yielding 94% sensitivity and 47% specificity. CONCLUSIONS: Compared with laTME, taTME surgery has no obvious disadvantage with respect to the postoperative inflammatory stress response. In addition, inflammatory indexes were favorable in predicting infective complications, with the best results for CRP on the first postoperative day. Defining the specific predictors for laTME and taTME is unnecessary.

Iterative Reconstruction Algorithms in Magneto-Acousto-Electrical Computed Tomography (MAE-CT) for Image Quality Improvement.

Magneto-acousto-electrical computed tomography (MAE-CT) is a recently developed rotational magneto-acousto-electrical tomography (MAET) method, which can map the conductivity parameter of tissues with high spatial resolution. Since the imaging mode of MAE-CT is similar to that of CT, the reconstruction algorithms for CT are possible to be adopted for MAE-CT. Previous studies have demonstrated that the filtered back-projection (FBP) algorithm, which is one of the most common CT reconstruction algorithms, can be used for MAE-CT reconstruction. However, FBP has some inherent shortcomings of being sensitive to noise and non-uniform distribution of views. In this study, we introduced iterative reconstruction (IR) method in MAE-CT reconstruction and compared its performance with that of the FBP. The numerical simulation, the phantom, and in vitro experiments were performed, and several IR algorithms (ART, SART, SIRT) were used for reconstruction. The results show that the images reconstructed by the FBP and IR are similar when the data is noise-free in the simulation. As the noise level increases, the images reconstructed by SART and SIRT are more robust to the noise than FBP. In the phantom experiment, noise and some stripe artifacts caused by the FBP are removed by SART and SIRT algorithms. In conclusion, the IR method used in CT is applicable in MAE-CT, and it performs better than FBP, which indicates that the state-of-the-art achievements in the CT algorithm can also be adopted for the MAE-CT reconstruction in the future.

Altered in vivo early neurogenesis traits in patients with depression: Evidence from neuron-derived extracellular vesicles and electroconvulsive therapy.

BACKGROUND: The neurogenesis hypothesis is a promising candidate etiologic hypothesis for depression, and it is associated with electroconvulsive therapy (ECT). However, human in vivo molecular-level evidence is lacking. OBJECTIVE: We used neuron-derived extracellular vesicles (NDEVs) as a "window to the neurons" to explore the in vivo neurogenesis status associated with ECT in patients with treatment-resistant depression (TRD). METHODS: In this study, we enrolled 40 patients with TRD and 35 healthy controls (HCs). We isolated NDEVs from the plasma of each participant to test the levels of doublecortin (DCX), a marker of neurogenesis, and cluster of differentiation (CD) 81, a marker of EVs. We also assessed the plasma levels of brain-derived neurotrophic factor (BDNF), a protein that is known to be associated with ECT and neuroplastic processes. RESULTS: Our findings indicated that both the levels of DCX in NDEVs and BDNF in plasma were significantly lower in TRD patients compared to HCs at baseline, but increased following ECTs. Conversely, levels of CD81 in NDEVs were found higher in TRD patients at baseline, but did not change after the ECT treatments. Exploratory analyses revealed that lower levels of BDNF in plasma and DCX in NDEVs, along with higher CD81 levels in NDEVs, were associated with more severe depressive symptoms and reduced cognitive function at baseline. Furthermore, higher baseline CD81 concentrations in NDEVs were correlated with greater decreases in depression symptoms. CONCLUSIONS: We first present human in vivo evidence of early neurogenesis using DCX through NDEVs: decreased in TRD patients, increased after ECTs.

Tissue factor targeting peptide enhances nanoparticle binding and delivery of a synthetic specialized pro-resolving lipid mediator to injured arteries.

Background: Specialized pro-resolving lipid mediators (SPM) such as resolvin D1 (RvD1) attenuate inflammation and exhibit vasculo-protective properties. Methods: We investigated poly-lactic-co-glycolic acid (PLGA)-based nanoparticles (NP), containing a peptide targeted to tissue factor (TF) for delivery of 17R-RvD1 and a synthetic analog 17-R/S-benzo-RvD1 (benzo-RvD1) using in vitro and in vivo models of acute vascular injury. NPs were characterized in vitro by size, drug loading, drug release, TF binding, and vascular smooth muscle cell migration assays. NPs were also characterized in a rat model of carotid angioplasty. Results: PLGA NPs based on a 75/25 lactic to glycolic acid ratio demonstrated optimal loading (507.3 pg 17R-RvD1/mg NP; P = ns) and release of RvD1 (153.1 pg 17R-RvD1/mg NP; P < .05). NPs incorporating the targeting peptide adhered to immobilized TF with greater avidity than NPs with scrambled peptide (50 nM: 41.6 ± 0.52 vs 32.66 ± 0.34; 100 nM: 35.67 ± 0.95 vs 23.5 ± 0.39; P < .05). NPs loaded with 17R-RvD1 resulted in a trend toward blunted vascular smooth muscle cell migration in a scratch assay. In a rat model of carotid angioplasty, 16-fold more NPs were present after treatment with TF-targeted NPs compared with scrambled NPs (P < .01), with a corresponding trend toward higher tissue levels of 17R-RvD1 (P = .06). Benzo-RvD1 was also detectable in arteries treated with targeted NP delivery and accumulated at 10 times higher levels than NP loaded with 17R-RvD1. There was a trend toward decreased CD45 immunostaining in vessels treated with NP containing benzo-RvD1 (0.76 ± 0.38 cells/mm2 vs 122.1 ± 22.26 cells/mm2; P = .06). There were no significant differences in early arterial inflammatory and cytokine gene expression by reverse transcription-polymerase chain reaction. Conclusions: TF-targeting peptides enhanced NP-mediated delivery of SPM to injured artery. TF-targeted delivery of SPMs may be a promising therapeutic approach to attenuate the vascular injury response.

Visualization of photothermal therapy by semiconducting polymer dots mediated photoacoustic detection in NIR II.

Visualization of photothermal therapy mediated by photothermal transduction agents (PTAs) is important to promote individual treatment of patients with low side effects. Photoacoustic detection has emerged as a promising noninvasive method for the visualization of PTAs distribution but still has limitations in temperature measurement, including poor measurement accuracy and low tissue penetration depth. In this study, we developed biocompatible semiconducting polymer dots (SPD) for in situ coupling of photothermal and photoacoustic detection in the near-infrared II window. SPD has dual photostability under pulsed laser and continuous-wave laser irradiation with a photothermal conversion efficiency of 42.77%. Meanwhile, a strong correlation between the photoacoustic signal and the actual temperature of SPD can be observed. The standard deviation of SPD-mediated photoacoustic thermometry can reach 0.13 °C when the penetration depth of gelatin phantom is 9.49 mm. Preliminary experimental results in vivo show that SPD-mediated photoacoustic signal has a high signal-to-noise ratio, as well as good performance in temperature response and tumor enrichment. Such a study not only offers a new nanomaterial for the visualization of photothermal therapy but will also promote the theranostic platform for clinical applications.

Handheld interventional ultrasound/photoacoustic puncture needle navigation based on deep learning segmentation.

Interventional ultrasound (US) has challenges in accurate localization of the puncture needle due to intrinsic acoustic interferences, which lead to blurred, indistinct, and even invisible needles in handheld linear array transducer-based US navigation, especially the incorrect needle tip positioning. Photoacoustic (PA) imaging can provide complementary image contrast, without additional data acquisition. Herein, we proposed an internal illumination to solely light up the needle tip in PA imaging. Then deep-learning-based feature segmentation alleviates acoustic interferences, enhancing the needle shaft-tip visibility. Further, needle shaft-tip compensation aligned the needle shaft in US image and the needle tip in the PA image. The experiments on phantom, ex vivo chicken breast, preclinical radiofrequency ablation and in vivo biopsy of sentinel lymph nodes were piloted. The target registration error can reach the submillimeter level, achieving precise puncture needle tracking ability with in-plane US/PA navigation.

N6-methyladenosine modification of PLOD2 causes spermatocyte damage in rats with varicocele.

BACKGROUND: In recent years, N6-methyladenosine (m6A) methylation modification of mRNA has been studied extensively. It has been reported that m6A determines mRNA fate and participates in many cellular functions and reactions, including oxidative stress. The PLOD2 gene encodes a protein that plays a key role in tissue remodeling and fibrotic processes. METHODS: The m6A methylation and expression levels of PLOD2 were determined by m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq) and MeRIP-quantitative polymerase chain reaction (qPCR) in the testes of varicocele rats compared with control. To determine whether IGF2BP2 had a targeted effect on the PLOD2 mRNA, RNA immunoprecipitation-qPCR (RIP-qPCR) and luciferase assays were performed. CRISPR/dCas13b-ALKBH5 could downregulate m6A methylation level of PLOD2, which plays an important role in PLOD2-mediated cell proliferation and apoptosis in GC-2 cells. RESULTS: PLOD2 was frequently exhibited with high m6A methylation and expression level in the testes of varicocele rats compared with control. In addition, we found that IGF2BP2 binds to the m6A-modified 3' untranslated region (3'-UTR) of PLOD2 mRNA, thereby positively regulating its mRNA stability. Targeted specific demethylation of PLOD2 m6A by CRISPR/dCas13b-ALKBH5 system can significantly decrease the m6A and expression level of PLOD2. Furthermore, demethylation of PLOD2 mRNA dramatically promote GC-2 cell proliferation and inhibit cell apoptosis under oxidative stress. CONCLUSION: As a result, we found that varicocele-induced oxidative stress promoted PLOD2 expression level via m6A methylation modification. In addition, targeting m6A demethylation of PLOD2 by CRISPR/dCas13b-ALKBH5 system can regulate GC-2 cell proliferation and apoptosis under oxidative stress. Taken together, our study has acquired a better understanding of the mechanisms underlying male infertility associated with oxidative stress, as well as a novel therapeutic target for male infertility.

Human in vivo evidence of reduced astrocyte activation and neuroinflammation in patients with treatment-resistant depression following electroconvulsive therapy.

AIM: The current study aimed to investigate the neuroinflammatory hypothesis of depression and the potential anti-inflammatory effect of electroconvulsive therapy (ECT) in vivo, utilizing astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma. METHODS: A total of 40 patients with treatment-resistant depression (TRD) and 35 matched healthy controls were recruited at baseline, and 34 patients with TRD completed the post-ECT visits. Blood samples were collected at baseline and post-ECT. Plasma ADEVs were isolated and confirmed, and the concentrations of two astrocyte markers (glial fibrillary acidic protein [GFAP] and S100ß), an extracellular vesicle marker cluster of differentiation 81 (CD81), and nine inflammatory markers in ADEVs were measured as main analyses. In addition, correlation analysis was conducted between clinical features and ADEV protein levels as exploratory analysis. RESULTS: At baseline, the TRD group exhibited significantly higher levels of two astrocyte markers GFAP and S100ß, as well as CD81 compared with the healthy controls. Inflammatory markers interferon γ (IFN-γ), interleukin (IL) 1ß, IL-4, IL-6, tumor necrosis factor α, IL-10, and IL-17A were also significantly higher in the TRD group. After ECT, there was a significant reduction in the levels of GFAP, S100ß, and CD81, along with a significant decrease in the levels of IFN-γ and IL-4. Furthermore, higher levels of GFAP, S100ß, CD81, and inflammatory cytokines were associated with more severe depressive symptoms and poorer cognitive function. CONCLUSION: This study provides direct insight supporting the astrocyte activation and neuroinflammatory hypothesis of depression using ADEVs. ECT may exert an anti-inflammatory effect through inhibition of such activation of astrocytes.

Can water dating trace the transport history of HCHs in the ocean?

Long-range atmospheric and oceanic transport play a crucial role in the accumulation of persistent organic pollutants (POPs), including hexachlorocyclohexanes (HCHs), in the Arctic Ocean. Herein, transient tracers, specifically chlorofluorocarbon-12 and sulfur hexafluoride, were used to determine the ventilation time of HCHs. Results revealed that dissolved HCHs can penetrate to a depth of ~500 m in the western Arctic Ocean, corresponding to water masses with a mean age of 45 ± 14 years. The average long-range transport time for α-HCH from initial atmospheric release to entering the western Arctic Ocean was estimated to be >30 ± 5 years, indicating continued moderate to high ecological risks from HCHs in the Arctic. This study demonstrates that transient tracers serve as effective water dating tools to elucidate the transport history of stable POPs in the ocean, contributing to a better understanding of their environmental characteristics and fate.

Young Adults with Major Depression Show Altered Microbiome.

There is growing basic and clinical evidence that major depressive disorder (MDD) is associated with gut microbiome alterations, but clinical studies have tended not to adjust for confounding factors. And few studies on the gut microbiome focused on young adults with MDD. Here we performed a pilot study to compare the gut microbiome of young adults with MDD with healthy controls. Shotgun metagenomic sequencing was performed on stool samples obtained from 40 young adults with MDD and 42 healthy controls. After controlling for confounding factors including sex, age, BMI, alcohol or cigarette consumption, bowel movement quality, exercise or defecation frequency, we compared microbiome diversity between groups, identified differentially abundant taxa, and further compared functional differences through gut-brain and gut-metabolic module analysis. There were no significant differences in overall gut microbiome structure and function in young adults with MDD compared with controls. Abundance of Sutterellaceae and species belonging to Clostridium, Eubacterium, and Ruminococcus were significantly different between groups. The cysteine degradation I pathway was increased in MDD. After controlling for most confounding factors, this pilot study provides new evidence on the specific, often subtle gut dysbiosis affecting young adults with depression.

KRT17 Promotes T-lymphocyte Infiltration Through the YTHDF2-CXCL10 Axis in Colorectal Cancer.

Poor infiltration of T lymphocytes has been regarded as a crucial mechanism of tumor immune escape. Here, we demonstrate a protective role of KRT17 in colorectal cancer, where KRT17 reversed the tumor immunosuppressive microenvironment by increasing T-lymphocyte infiltration. High-throughput RNA sequencing suggested that KRT17 was significantly upregulated in deficient mismatch repair (dMMR) tumors compared with proficient mismatch repair (pMMR) tumors. In a colorectal cancer cohort of 446 cases, KRT17 expression positively correlated with better clinical outcomes. Krt17 overexpression decreased xenograft tumor growth in immune-competent mice. T-cell depletion in a murine model showed that the presence of T lymphocytes was necessary for Krt17-mediated disruption of tumorigenesis. Mass spectrometry and coimmunoprecipitation assays suggested KRT17 caused YTHDF2 degradation through the ubiquitin-proteasome system. Through high-throughput RNA immunoprecipitation sequencing, we found that CXCL10 was the target gene of the N6-methyladenosine (m6A) "reader" YTHDF2. KRT17 synergized with anti-PD-1 for better tumor control in an immunotherapy-resistant murine model. In a cohort of patients with colorectal cancer receiving pembrolizumab, high KRT17 expression was found within the tumors of responders. Collectively, we elucidated a critical role of KRT17 in colorectal cancer to prevent immune escape. These findings present new insights into potential therapeutic strategies and effective markers of immunotherapy reactivity against pMMR tumors.

The Deepest Extent of Acellular Mucin Pools in Resected Locally Advanced Rectal Cancer With Pathological Complete Response After Preoperative Chemoradiotherapy: A Hidden Killer?

For patients with locally advanced rectal cancer (LARC) with pathological complete response (pCR), the clinical significance of the distribution extent of acellular mucin pools (AMP) distribution remains unclear, so this study was conducted to address key unanswered questions. We performed a retrospective analysis of 317 patients with LARC with pCR after preoperative chemoradiotherapy and total mesorectal resection from January 2011 to June 2020. Based on AMP existence and the deepest tissue layer of distribution, patients were assigned new stages. The patient information was recorded, and the main outcome measures included 5-year disease-free survival (DFS) and 5-year overall survival (OS). A total of 83/317 (26.2%) patients exhibited AMP, and disease recurrence occurred in 46/317 (14.5%) patients. Over the 5-year median follow-up period, the patients with AMP showed 5-year DFS rates (75.9% vs. 88.9%, P =0.004) and 5-year OS rates (85.5% vs. 95.7%, P =0.002) statistically lower than those of patients without AMP. Disease recurrence was seen in 15/54 (27.8%) patients with AMP within the subserosa and/or the serosa, or adipose tissue. Univariate and multivariate analysis showed that the existence of AMP within the subserosa and/or the serosa, or adipose tissue was an independent risk factor for DFS [hazard ratio (HR): 2.344; 95% confidence interval (CI): 1.256-4.376; P =0.007] and OS [HR: 3.374; 95% CI: 1.438-7.917; P =0.005]. The new stages based on the deepest extent of AMP were related to worse DFS ( P =0.004) and OS ( P =0.003) rates among patients with pCR. In conclusion, the presence of AMP might reduce the prognosis of LARC patients with pCR after chemoradiotherapy, especially in patients with AMP in deeper tissue layers. Therefore, the influence of the deepest AMP extent might be worth considering in staging. Moreover, the revised staging of patients with pCR according to the deepest extent of AMP, which is unrelated to the clinical T stage, might facilitate postoperative management.