CD206+ M2-like macrophages protect against intervertebral disc degeneration partially by targeting R-spondin-2.

OBJECTIVE: This study aimed to explore the specific function of M2 macrophages in intervertebral disc degeneration (IDD). METHODS: Intervertebral disc (IVD) samples from normal (n = 4) and IDD (n = 6) patients were collected, and the expression of M2-polarized macrophage marker, CD206, was investigated using immunohistochemical staining. Nucleus pulposus cells (NPCs) in a TNF-α environment were obtained, and a mouse caudal IVD puncture model was established. Mice with Rheb deletions, specifically in the myeloid lineage, were generated and subjected to surgery-induced IDD. IDD-induced damage and cell apoptosis were measured using histological scoring, X-ray imaging, immunohistochemical staining, and TdT-mediated dUTP nick end labeling (TUNEL) assay. Finally, mice and NPCs were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in IDD. RESULTS: Accumulation of CD206 in human and mouse IDD tissues was detected. Rheb deletion in the myeloid lineage (RheBcKO) increased the number of CD206+ M2-like macrophages (mean difference 18.6% [15.7-21.6%], P < 0.001), decreased cell apoptosis (mean difference -15.6% [-8.9 to 22.2%], P = 0.001) and attenuated the IDD process in the mouse IDD model. NPCs treated with Rspo2 displayed increased extracellular matrix catabolism and apoptosis; co-culture with a conditioned medium derived from RheBcKO mice inhibited these changes. Anti-Rspo2 treatment in the mouse caudal IVD puncture model exerted protective effects against IDD. CONCLUSIONS: Promoting CD206+ M2-like macrophages could reduce Rspo2 secretion, thereby alleviating experimental IDD. Rheb deletion may help M2-polarized macrophages accumulate and attenuate experimental IDD partially by inhibiting Rspo2 production. Hence, M2-polarized macrophages and Rspo2 may serve as therapeutic targets for IDD.

Influence of macrophage polarization in herniated nucleus pulposus tissue on clinical efficacy after lumbar discectomy.

Background: Low back pain or sciatic pain because of lumbar intervertebral disc herniation (LDH) is caused by mechanical compression and/or an inflammatory component on the nerve root. However, it is difficult to define to what extent each component contributes to the pain. This study attempted to explore the effects of macrophage polarization on clinical symptoms in patients experiencing LDH after surgery, and investigated the association between macrophage cell percentages and clinical efficacy. Methods: This study retrospectively harvested nucleus pulposus (NP) tissue samples from 117 patients. Clinical symptoms and efficacy using the visual analog scale (VAS) and Oswestry Disability Index (ODI) were evaluated at different time points preoperatively and postoperatively. CD68, CCR7, CD163, and CD206 were selected as macrophage phenotypic markers. Results: Seventy-six samples showed positive expression of macrophage markers in NP samples of patients with LDH, whereas 41 patients displayed negative results. No significant differences were detected between the two groups, involvement of several demographic data, and preoperative clinical findings. With respect to the macrophage-positive group, no significant correlation was detected between the positive rate of the four markers and the VAS score or ODI after surgery. However, patients with NP samples positive for CD68 and CCR7 expression showed significantly lower VAS scores 1 week after surgery compared with those in the negative group. Moreover, the improvement in VAS score showed a strong positive correlation with CD68- and CCR7-positive cell percentages. Conclusions: Our results indicated that pro-inflammatory M1 macrophages may be associated with the reduction of chronic pain after surgery. Therefore, these findings contribute to better personalized pharmacological interventions for patients with LDH, considering the heterogeneity of pain.

Efficacy of concurrent radiotherapy in patients with locally advanced rectal cancer and synchronous metastasis receiving systemic therapy.

Background: Neoadjuvant chemoradiotherapy followed by total mesorectal excision is the standard treatment for patients with nonmetastatic locally advanced rectal cancer (LARC). However, for patients with LARC and synchronous metastasis, the optimal treatment strategy and sequence remain inconclusive. In the present study, we evaluated the efficacy and safety of concurrent radiotherapy in patients with de novo metastatic rectal cancer who received chemotherapy and targeted therapy. Methods: We retrospectively reviewed the data of 63 patients with LARC and synchronous metastasis who received intensive therapy at the study hospital between April 2015 and November 2018. The included patients were divided into two groups: RT-CT, those who received systemic chemotherapy with targeted therapy and concurrent radiotherapy (for primary rectal cancer), and CT, those who received only systemic chemotherapy with targeted therapy. Results: Treatment response was better in the RT-CT group than in the CT group. The rate of primary tumor resection (PTR) was higher in the RT-CT group than in the CT group (71.4% and 42.9%, respectively; P = .0286). The RT-CT group exhibited considerably longer local recurrence-free survival (P = .0453) and progression-free survival (PFS; from 13.3 to 22.5 months) than did the CT group (P = .0091); however, the groups did not differ in terms of overall survival (OS; P = .49). Adverse events were almost similar between the groups, except frequent diarrhea, the prevalence of which was higher in the RT-CT group than in the CT group (59.5% and 23.8%, respectively; P = .0075). Conclusions: In the era of biologics, radiotherapy may increase the resectability of primary rectal tumors, reducing the risk of locoregional failure and prolonging PFS. Concurrent pelvic radiotherapy may not substantially improve OS, which is indicated by metastasis. Hence, the resection of the distant metastases may be essential for improving long-term OS. To further determine the efficacy of concurrent radiotherapy, additional prospective, randomized studies must combine preoperative pelvic radiotherapy with PTR and metastectomy to treat patients with stage IV LARC.

Local Consolidative Therapy May Have Prominent Clinical Efficacy in Patients with EGFR-Mutant Advanced Lung Adenocarcinoma Treated with First-Line Afatinib.

Afatinib is an irreversible tyrosine kinase inhibitor (TKI) targeting the epidermal growth factor receptor (EGFR), which is utilized for the treatment of patients with advanced lung cancer that harbors EGFR mutations. No studies have evaluated the clinical efficacy of LCT in patients treated with first-line afatinib. In this study, we retrospectively enrolled patients with advanced lung adenocarcinomas harboring susceptible EGFR mutations who were diagnosed and treated with first-line afatinib in three hospitals. A total of 254 patients were enrolled, including 30 (12%) patients who received LCT (15 patients received definitive radiotherapy for the primary lung mass and 15 patients received curative surgery). Patients who received LCT had a significantly longer PFS than those who did not (median PFS: 32.8 vs. 14.5 months, p = 0.0008). Patients who received LCT had significantly longer OS than those who did not (median OS: 67.1 vs. 34.5 months, p = 0.0011). Multivariable analysis showed LCT was an independent prognostic factor for improved PFS (adjusted hazard ratio [aHR] [95% confidence interval (CI)]: 0.44 [0.26-0.73], p = 0.0016) and OS (aHR [95% CI]: 0.26 [0.12-0.54], p = 0.0004). The analyses using propensity score-weighting showed consistent results. We conclude that LCT may improve clinical outcomes, in terms of PFS and OS, in patients with advanced EGFR-mutant lung adenocarcinomas who are treated with first-line afatinib.

Investigation of macrophage polarization in herniated nucleus pulposus of patients with lumbar intervertebral disc herniation.

Macrophage infiltration and polarization during lumbar intervertebral disc herniation (LDH) have attracted increased attention but their role remains unclear. To explore macrophage polarization in herniated nucleus pulposus (NP) tissue of patients with LDH and investigate the association between cell frequency and different clinical characteristics or symptoms, we conducted a retrospective study by analyzing NP tissue samples from 79 patients. Clinical features and symptoms, using the visual analog scale (VAS) and Oswestry disability index (ODI), were collected. The macrophage markers CD68, CCR7, CD163, and CD206; pro-inflammatory cytokine TNF-α; and anti-inflammatory factor IL-4 were analyzed by immunohistochemistry. The frequency of polarized macrophages and positivity rate of pro- and anti-inflammatory cytokines showed significant differences in some of clinical characteristics. Specifically, higher CCR7+ and TNF-α + proportions were identified in the high-intensity zone (HIZ) and the type of extrusion and sequestration NP tissue than in non-HIZ and protrude NP tissue. Higher CD206+ and IL-4+ proportion were detected in Modic changes. However, no differences in gender, age, smoking status, Pfirrmann grade, analgesic use, leg pain duration, and segments were found between groups. CD68+ , CCR7+ , and CD206+ cell proportions, and TNF-α and IL-4 showed positive associations with VAS scores preoperation. Associations between ODI and the macrophages markers were weak/insignificant. Our results indicated that macrophage polarization or macrophage-like cells contribute to LDH pathological features. Macrophage populations displaying significant associations with VAS score reflected continuous M1/M2 transition contributing to pain during LDH. These findings may contribute to enhanced/personalized pharmacological interventions for patients with LDH considering pain heterogeneity.

Macrophage polarization regulates intervertebral disc degeneration by modulating cell proliferation, inflammation mediator secretion, and extracellular matrix metabolism.

Macrophage infiltration and polarization have been increasingly observed in intervertebral disc (IVD) degeneration (IDD). However, their biological roles in IDD are still unrevealed. We harvested conditioned media (CM) derived from a spectrum of macrophages induced from THP-1 cells, and examined how they affect nucleus pulposus cells (NPCs) in vitro, by studying cell proliferation, extracellular matrix (ECM) synthesis, and pro-inflammation expression; and in vivo by injection CM in a rat IDD model. Then, high-throughput sequencing was used to detect differentially expressed genes (DEGs). Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) networks were used to further analysis. Higher CCR7+ (M1 marker) and CD206+ (M2 marker) cell counts were found in the degenerated human IVD tissues as compared with the control. Furthermore, the cell co-culture model showed M1CM attenuated NPC proliferation, downregulated the expression of ECM anabolic genes encoding aggrecan and collagen IIα1, upregulated the expression of ECM catabolic genes encoding MMP-13, and inflammation-related genes encoding IL-1ß, IL-6, and IL-12, while M2CM showed contrasting trends. In IDD model, higher histological scores and lower disc height index were found following M1CM treatment, while M2CM exhibited opposite results. M1CM injection decreased ECM anabolic and increased ECM catabolic, as well as the upregulation of inflammation-related genes after 8 weeks treatment, while M2CM slowed down these trends. Finally, a total of 637 upregulated and 655 downregulated genes were detected in M1CM treated NPCs, and 975 upregulated genes and 930 downregulated genes in the M2CM groups. The top 30 GO terms were shown and the most significant KEGG pathway was cell cycle in both groups. Based on the PPI analysis, the five most significant hub genes were PLK1, KIF20A, RRM2, CDC20, and UBE2C in the M1CM groups and RRM2, CCNB1, CDC20, PLK1, and UBE2C in the M2CM groups. In conclusion, macrophage polarization exhibited diverse roles in IDD progression, with M1CM exacerbating cell proliferation suppression and IVD degeneration, while M2CM attenuated IDD development. These findings may facilitate the further elucidation of the role of macrophage polarization in IDD, and provide novel insights into the therapeutic potential of macrophages.

Role of non-coding RNAs in radiosensitivity of colorectal cancer: A narrative review.

Colorectal cancer (CRC) is a global public health concern because of its high prevalence and mortality. Although radiotherapy is a key method for treating CRC, radioresistance is an obstacle to radiotherapy use. The molecular mechanisms underlying the radioresistance of CRC remain unclear. Increasing evidence has revealed the multiple regulatory functions of non-coding RNAs (ncRNAs) in numerous malignancies, including CRC. Several ncRNAs have been reported to be involved in the determination of radiosensitivity of CRC cells, and some have excellent potential to be prognostic biomarkers or therapeutic targets in CRC treatment. The present review discusses the biological functions and underlying mechanisms of ncRNAs (primarily lncRNA, miRNA, and circRNA) in the regulation of the radiosensitivity of CRC. We also evaluate studies that examined ncRNAs as biomarkers of response to radiation and as therapeutic targets for enhancing radiosensitivity.

HIF-1α Expression Increases Preoperative Concurrent Chemoradiotherapy Resistance in Hyperglycemic Rectal Cancer.

Purpose: Preoperative concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced rectal cancer patients. However, the poor therapeutic efficacy of CCRT was found in rectal cancer patients with hyperglycemia. This study investigated how hyperglycemia affects radiochemotherapy resistance in rectal cancer. Methods and Materials: We analyzed the correlation between prognosis indexes with hypoxia-inducible factor-1 alpha (HIF-1α) in rectal cancer patients with preoperative CCRT. In vitro, we investigated the effect of different concentrated glucose of environments on the radiation tolerance of rectal cancers. Further, we analyzed the combined HIF-1α inhibitor with radiation therapy in hyperglycemic rectal cancers. Results: The prognosis indexes of euglycemic or hyperglycemic rectal cancer patients after receiving CCRT treatment were investigated. The hyperglycemic rectal cancer patients (n = 13, glycosylated hemoglobin, HbA1c > 6.5%) had poorer prognosis indexes. In addition, a positive correlation was observed between HIF-1α expression and HbA1c levels (p = 0.046). Therefore, it is very important to clarify the relationship between HIF-1α and poor response in patients with hyperglycemia receiving pre-operative CCRT. Under a high glucose environment, rectal cancer cells express higher levels of glucose transport 1 (GLUT1), O-GlcNAc transferase (OGT), and HIF-1α, suggesting that the high glucose environment might stimulate HIF-1α expression through the GLUT1-OGT-HIF-1α pathway promoting tolerance to Fluorouracil (5-FU) and radiation. In the hyperglycemic rectal cancer animal model, rectal cancer cells confirmed that radiation exposure reduces apoptosis by overexpressing HIF-1α. Combining HIF-1α inhibitors was able to reverse radioresistance in a high glucose environment. Lower HIF-1α levels increased DNA damage in tumors leading to apoptosis. Conclusions: The findings here show that hyperglycemia induces the expression of GLUT1, OGT, and HIF-1α to cause CCRT tolerance in rectal cancer and suggest that combining HIF-1α inhibitors could reverse radioresistance in a high glucose environment. HIF-1α inhibitors may be useful for development as CCRT sensitizers in patients with hyperglycemic rectal cancer.

Colonization of nasal cavities by Staphylococcus epidermidis mitigates SARS-CoV-2 nucleocapsid phosphoprotein-induced interleukin (IL)-6 in the lung.

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can trigger excessive interleukin (IL)-6 signalling, leading to a myriad of biological effects including a cytokine storm that contributes to multiple organ failure in severe coronavirus disease 2019 (COVID-19). Using a mouse model, we demonstrated that nasal inoculation of nucleocapsid phosphoprotein (NPP) of SARS-CoV-2 increased IL-6 content in bronchoalveolar lavage fluid (BALF). Nasal administration of liquid coco-caprylate/caprate (LCC) onto Staphylococcus epidermidis (S. epidermidis)-colonized mice significantly attenuated NPP-induced IL-6. Furthermore, S. epidermidis-mediated LCC fermentation to generate electricity and butyric acid that promoted bacterial colonization and activated free fatty acid receptor 2 (Ffar2) respectively. Inhibition of Ffar2 impeded the effect of S. epidermidis plus LCC on the reduction of NPP-induced IL-6. Collectively, these results suggest that nasal S. epidermidis is part of the first line of defence in ameliorating a cytokine storm induced by airway infection of SARS-CoV-2.

M2 macrophage-conditioned medium inhibits intervertebral disc degeneration in a tumor necrosis factor-α-rich environment.

Inflammation is the primary pathological phenomenon associated with disc degeneration; the inflammatory cytokine tumor necrosis factor (TNF-α) plays a crucial role in this pathology. The anti-inflammatory and regenerative effects of M2 macrophages on nucleus pulposus cells (NPCs) in intervertebral disc degeneration (IDD) progression remain unknown. Here, M2 conditioned medium (M2CM) was harvested and purified from human acute monocytic leukaemia cell line (THP-1) cells and mouse peritoneal macrophages, respectively; it was used for culturing human NPCs and a mouse intervertebral disc (IVD) organ culture model. NPCs and IVD organ models were divided into three groups: group 1 treated with 10% fetal bovine serum (control); group 2 treated with 10 ng/ml TNF-α; and group 3 treated with 10 ng/ml TNF-α and M2CM (coculture group). After 2-14 days, cell proliferation, extracellular matrix synthesis, apoptosis, and NPC senescence were assessed. Cell proliferation was reduced in TNF-α-treated NPCs and inhibited in the M2CM co-culture treatment. Moreover, TNF-α treatment enhanced apoptosis, senescence, and expression of inflammatory factor-related genes, including interleukin-6, MMP-13, ADAMTS-4, and ADAMTS-5, whereas M2CM coculture significantly reversed these effects. In addition, co-culture with M2CM promoted aggrecan and collagen II synthesis, but reduced collagen Iα1 levels in TNF-α treatment groups. Using our established three-dimensional murine IVD organ culture model, we show that M2CM suppressed the inhibitory effect of TNF-α-rich environment. Therefore, co-culture with M2CM promotes cell proliferation and extracellular matrix synthesis and inhibits inflammation, apoptosis, and NPC senescence. This study highlights the therapeutic potential of M2CM for IDD.

Critical reappraisal of neoadjuvant concurrent chemoradiotherapy for treatment of locally advanced colon cancer.

BACKGROUND: Locally advanced colon cancer (LACC) is associated with surgical challenges during R0 resection, increased postoperative complications, and unfavorable treatment outcomes. Neoadjuvant concurrent chemoradiotherapy followed by surgical resection is an effective treatment strategy that can increase the complete surgical resection rate and improve the patient survival rate. This study investigated the efficacy and toxicity of concurrent chemoradiotherapy in patients with LACC as well as the prognosis and long-term clinical outcomes of these patients. MATERIALS: From January 2012 to July 2020, we retrospectively reviewed the real-world data of 75 patients with LACC who received neoadjuvant concurrent chemoradiotherapy. The chemotherapy regimen consisted of folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX). The following data were obtained from medical records: patients' characteristics, pathologic results, toxicity, and long-term oncologic outcome. RESULTS: Of the 75 patients, 13 (17.3%) had pathologic complete responses. Hematologic adverse effects were the most common (grade 1 anemia: 80.0% and leukopenia: 82.7%). Conversely, grade 2 or 3 adverse effects were relatively uncommon (<10%). Pathologic N downstaging, ypT0, and pathologic complete responses were significant prognostic factors for patient survival. Multivariate analysis revealed that pathologic N downstaging was an independent predictor of patients' overall survival (P = 0.019). The estimated 5-year overall and disease-free survival rates were 68.6% and 50.6%, and the medians of overall and disease-free survival periods were 72.3 and 58.7 months, respectively. Moreover, patients with pathologic complete responses had improved overall survival (P = 0.039) and an improved local recurrence control rate (P = 0.042) but an unfavorable distant metastasis control rate (P = 0.666) in the long-term follow-up. CONCLUSION: The long-term oncologic outcome of patients with LACC following concurrent chemoradiotherapy is acceptable, and the adverse effects seem to be tolerable. Pathologic N downstaging was an independent prognostic factor for patients' overall survival. However, a large prospective, randomized control study is required to confirm the current results.

miRNA-148a Enhances the Treatment Response of Patients with Rectal Cancer to Chemoradiation and Promotes Apoptosis by Directly Targeting c-Met.

Patients with locally advanced rectal cancer (LARC) who achieve a pathological complete response (pCR) to neoadjuvant chemoradiotherapy (NACRT) have an excellent prognosis, but only approximately 30% of patients achieve pCR. Therefore, identifying predictors of pCR is imperative. We employed a microRNA (miRNA) microarray to compare the miRNA profiles of patients with LARC who achieved pCR (pCR group, n = 5) with those who did not (non-pCR group, n = 5). The validation set confirmed that miRNA-148a was overexpressed in the pCR group (n = 11) compared with the non-pCR group (n = 40). Cell proliferation and clonogenic assays revealed that miRNA-148a overexpression radio-sensitized cancer cells and inhibited cellular proliferation, before and after irradiation (p < 0.01). Apoptosis assays demonstrated that miRNA-148a enhanced apoptosis before and after irradiation. Reporter assays revealed that c-Met was the direct target gene of miRNA-148a. An in vivo study indicated that miRNA-148a enhanced the irradiation-induced suppression of xenograft tumor growth (p < 0.01). miRNA-148a may be a biomarker of pCR following NACRT and can promote apoptosis and inhibit proliferation in CRC cells by directly targeting c-Met in vitro and enhancing tumor response to irradiation in vivo.

Pretreatment Neutrophil-to-Lymphocyte Ratio Associated with Tumor Recurrence and Survival in Patients Achieving a Pathological Complete Response Following Neoadjuvant Chemoradiotherapy for Rectal Cancer.

The clinical influence of the neutrophil-to-lymphocyte ratio (NLR) in predicting outcomes in patients with locally advanced rectal cancer (LARC) who achieve a pathological complete response (pCR) to neoadjuvant chemoradiotherapy (NACRT) has seldom been investigated. We retrospectively recruited 102 patients with LARC who achieved a pCR to NACRT and the association of NLR status with survival and tumor recurrence in the patients was analyzed. Thirteen patients (12.7%) developed tumor recurrence. A high NLR (≥3.2) was significantly associated with tumor recurrence (p = 0.039). The 5-year OS rates in patients with a low NLR and patients with a high NLR were 95.1% and 77.7%, respectively (p = 0.014); the 5-year DFS rates in patients with low NLR and patients with a high NLR were 90.6% and 71.3%, respectively (p = 0.031). The Cox proportional hazards model indicated that an NLR of ≥3.2 was an independent poor prognostic factor for DFS (hazard ratio [HR] = 3.12, 95% confidence interval [CI] = 1.06-9.46, p = 0.048) and OS (HR = 6.96, 95% CI = 1.53-35.51, p = 0.013). A pretreatment high NLR (≥3.2) was a promising predictor of reduced OS and DFS in patients with LARC who achieved a pCR to NACRT.

Gut probiotic Lactobacillus rhamnosus attenuates PDE4B-mediated interleukin-6 induced by SARS-CoV-2 membrane glycoprotein.

Membrane glycoprotein is the most abundant protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but its role in coronavirus disease 2019 (COVID-19) has not been fully characterized. Mice intranasally inoculated with membrane glycoprotein substantially increased the interleukin (IL)-6, a hallmark of the cytokine storm, in bronchoalveolar lavage fluid (BALF), compared to mice inoculated with green fluorescent protein (GFP). The high level of IL-6 induced by membrane glycoprotein was significantly diminished in phosphodiesterase 4 (PDE4B) knockout mice, demonstrating the essential role of PDE4B in IL-6 signaling. Mycelium fermentation of Lactobacillus rhamnosus (L. rhamnosus) EH8 strain yielded butyric acid, which can down-regulate the PDE4B expression and IL-6 secretion in macrophages. Feeding mice with mycelia increased the relative abundance of commensal L. rhamnosus. Two-week supplementation of mice with L. rhamnosus plus mycelia considerably decreased membrane glycoprotein-induced PDE4B expression and IL-6 secretion. The probiotic activity of L. rhamnosus plus mycelia against membrane glycoprotein was abolished in mice treated with GLPG-0974, an antagonist of free fatty acid receptor 2 (Ffar2). Activation of Ffar2 in the gut-lung axis for down-regulation of the PDE4B-IL-6 signalling may provide targets for development of modalities including probiotics for treatment of the cytokine storm in COVID-19.

Sclerosing polycystic adenosis of the submandibular gland: Two case reports.

BACKGROUND: Sclerosing polycystic adenosis (SPA) is a rare disease of salivary glands, similar to fibrocystic disease of the breast. It occurs over a wide age range and exhibits a slight female preference. Most SPA cases have occurred in the parotid gland. The exact nature of SPA is unclear, but its tumor nature has recently been proposed. Although SPA has a good prognosis after adequate surgery, atypical lesions might occur, ranging from mild dysplasia to carcinoma in situ in some cases. To the best of our knowledge, only five cases of SPA in the submandibular gland have been reported to date. Here, we present two new cases of SPA involving the submandibular gland. CASE SUMMARY: A 50-year-old woman and a 52-year-old woman were referred to Tongji Hospital in Wuhan, China, with complaints of moderate pain, recurrent swelling, and a mass in the submandibular area. After admission, the two cases of the submandibular mass were examined physically. The boundary of the submandibular tumor was clear, and the range of motion was good. After preoperative examinations, surgery was performed on a selective basis. Postoperative histopathological examination revealed a well-defined mass with acinar structures, ducts, or cystic dilated glands of various sizes scattered in a large number of proliferative sclerosing stroma. There were flat and cuboidal cells, and eosinophils in the duct epithelium. There was also a eosinophilic substance in the lumen of dilated cysts. No atypical epithelial hyperplasia, invasive growth, or carcinoma in situ was found. Based on the above findings, the mass was diagnosed as SPA. Both patients have remained asymptomatic and no recurrence or distant metastasis had occurred by the 7-mo and 5-year follow-up, respectively. CONCLUSION: SPA is a rare disease of the salivary gland. Even though it has a good prognosis after adequate surgery, atypical lesions may occur from mild dysplasia to carcinoma in situ. However, no recurrence, distant metastasis, or mortality has been reported for submandibular gland SPA. Clinicians and pathologists should be familiar with the characteristics of SPA in the submandibular gland to avoid misdiagnosis and overtreatment.

Probiotic Activity of Staphylococcus epidermidis Induces Collagen Type I Production through FFaR2/p-ERK Signaling.

Collagen type I is a key structural component of dermis tissue and is produced by fibroblasts and the extracellular matrix. The skin aging process, which is caused by intrinsic or extrinsic factors, such as natural aging or free radical exposure, greatly reduces collagen expression, thereby leading to obstructed skin elasticity. We investigated the effective fermentation of Cetearyl isononanoate (CIN), a polyethylene glycol (PEG) analog, as a carbon source with the skin probiotic bacterium Staphylococcus epidermidis (S.epidermidis) or butyrate, as their fermentation metabolites could noticeably restore collagen expression through phosphorylated extracellular signal regulated kinase (p-ERK) activation in mouse fibroblast cells and skin. Both the in vitro and in vivo knockdown of short-chain fatty acid (SCFA) or free fatty acid receptor 2 (FFaR2) considerably blocked the probiotic effect of S. epidermidis on p-ERK-induced collagen type I induction. These results demonstrate that butyric acid (BA) in the metabolites of fermenting skin probiotic bacteria mediates FFaR2 to induce the synthesis of collagen through p-ERK activation. We hereby imply that metabolites from the probiotic S. epidermidis fermentation of CIN as a potential carbon source could restore impaired collagen in the dermal extracellular matrix (ECM), providing integrity and elasticity to skin.

Outcomes of neoadjuvant chemoradiotherapy followed by radical resection for T4 colorectal cancer.

BACKGROUND: Patients with clinical T4 colorectal cancer (CRC) have a poor prognosis because of compromised surgical margins. Neoadjuvant therapy may be effective in downstaging tumors, thereby rendering possible radical resection with clear margins. AIM: To evaluate tumor downsizing and resection with clear margins in T4 CRC patients undergoing neoadjuvant concurrent chemoradiotherapy followed by surgery. METHODS: This study retrospectively included 86 eligible patients with clinical T4 CRC who underwent neoadjuvant concurrent chemoradiotherapy followed by radical resection. Neoadjuvant therapy consisted of radiation therapy at a dose of 45-50.4 Gy and chemotherapy agents, either FOLFOX or capecitabine. A circumferential resection margin (CRM) of < 1 mm was considered to be a positive margin. We defined pathological complete response (pCR) as the absence of any malignant cells in a specimen, including the primary tumor and lymph nodes. A multivariate logistic regression model was used to identify independent predictive factors for pCR. RESULTS: For 86 patients who underwent neoadjuvant chemoradiotherapy and surgery, the rate of pCR was 14%, and the R0 resection rate was 91.9%. Of the 61 patients with rectal cancer, 7 (11.5%) achieved pCR and 5 (8.2%) had positive CRMs. Of the 25 patients with colon cancer, 5 (20%) achieved pCR and 2 (8%) had positive CRMs. We observed that the FOLFOX regimen was an independent predictor of pCR (P = 0.046). After a median follow-up of 47 mo, the estimated 5-year overall survival (OS) and disease-free survival (DFS) rates were 70.8% and 61.4%, respectively. Multivariate analysis revealed that a tumor with a negative resection margin was associated with improved DFS (P = 0.014) and OS (P = 0.001). Patients who achieved pCR exhibited longer DFS (P = 0.042) and OS (P = 0.003) than those who did not. CONCLUSION: Neoadjuvant concurrent chemoradiotherapy engenders favorable pCR and R0 resection rates among patients with T4 CRC. The R0 resection rate and pCR are independent prognostic factors for patients with T4 CRC.

Production of electricity and reduction of high-fat diet-induced IL-6 by glucose fermentation of Leuconostoc mesenteroides.

Electrogenic bacteria can mediate electron transfer to conserve energy and promote growth. To examine bacterial electrogenicity, an L. mesenteroides EH-1 strain was cultured in rich media in the presence and absence of 2% glucose. After 12 h incubation, glucose triggered fermentation of L. mesenteroides EH-1 to produce >10 mmol/l acetate and elicit electricity measured by voltage changes. The electricity production was mediated by glucose fermentation since pre-treatment of L. mesenteroides EH-1 with furfural, a fermentation inhibitor, completely diminished the voltage increases. The deficiency of furfural pre-treated L. mesenteroides EH-1 in electricity production can be restored by the external addition of acetate into the bacterial culture, suggesting the function of acetate as an electron donor. Oral administration of HFD-fed mice with L. mesenteroides EH-1 in the presence or absence of glucose significantly attenuated the high level of pro-inflammatory IL-6 cytokine in blood. Bacterial electricity can be elicited by fermentation. Supplementation of fermenting and electrogenic L. mesenteroides EH-1 may provide a novel approach for the reduction of pro-inflammatory IL-6 cytokine that increased in chronic inflammation, autoimmune diseases, cancers, and infections.

ERCC overexpression associated with a poor response of cT4b colorectal cancer with FOLFOX-based neoadjuvant concurrent chemoradiation.

Colorectal cancer (CRC) of the clinical tumor stage T4b (cT4b) refers to advanced tumors with direct invasion of adjacent structures and the tumors are considered unresectable. Despite advancements in aggressive surgery and combination chemotherapy, the prognosis of cT4b CRC remains poor. Optimizing the therapeutic sequence administered to patients with cT4b CRC to improve clinical outcomes is crucial. In the present study, patients with unresectable cT4b and nodal stage N1-2 CRC were investigated at a single institution. A total of 20 consecutive patients were treated with pre-operative concurrent chemoradiation by using 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) since February 2015 and were regularly followed up until March 2020. Due to their poor response to concurrent chemoradiation (CCRT) with FOLFOX, the chemotherapy regimen was changed to irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as the second-line neoadjuvant treatment. Genetic alterations, such as microsatellite instability (MSI), were documented, and the expression levels of excision repair cross-complementing group 1 (ERCC1) and ERCC2 were examined. Of the 20 patients, the tumors of 14 patients (70%) became resectable after FOLFIRI administration. The median duration between the last date of radiotherapy and surgery was 32.7 weeks (range, 10.1-59.3 weeks). Of note, 4 of the 14 patients with resectable tumors (28.6%) achieved a pathologic complete response. The median overall survival and progression-free survival were 27.5 months (range, 12-39 months) and 27.5 months (range, 8-39 months), respectively. The cancerous specimens of all of the patients (100%) exhibited ERCC2 overexpression and 18 specimens (90%) had ERCC1 overexpression. Only one tumor (5%) exhibited high MSI. The present study indicated that ERCC overexpression associated with the poor response of FOLFOX-based CCRT and FOLFIRI after FOLFOX-based CCRT failure may have a potential role in conversion to resectable tumors by neoadjuvant treatment in cT4b CRC. However, a further prospective study with more patients is required to improve the precision of the conclusions.

Machine learning for predicting pathological complete response in patients with locally advanced rectal cancer after neoadjuvant chemoradiotherapy.

For patients with locally advanced rectal cancer (LARC), achieving a pathological complete response (pCR) after neoadjuvant chemoradiotherapy (CRT) provides them with the optimal prognosis. However, no reliable prediction model is presently available. We evaluated the performance of an artificial neural network (ANN) model in pCR prediction in patients with LARC. Predictive accuracy was compared between the ANN, k-nearest neighbor (KNN), support vector machine (SVM), naïve Bayes classifier (NBC), and multiple logistic regression (MLR) models. Data from two hundred seventy patients with LARC were used to compare the efficacy of the forecasting models. We trained the model with an estimation data set and evaluated model performance with a validation data set. The ANN model significantly outperformed the KNN, SVM, NBC, and MLR models in pCR prediction. Our results revealed that the post-CRT carcinoembryonic antigen is the most influential pCR predictor, followed by intervals between CRT and surgery, chemotherapy regimens, clinical nodal stage, and clinical tumor stage. The ANN model was a more accurate pCR predictor than other conventional prediction models. The predictors of pCR can be used to identify which patients with LARC can benefit from watch-and-wait approaches.