Unique immunohistochemical profiles of MUC5AC, MUC6, P53, and Ki67 in gastric atypical hyperplasia and dysplasia.

OBJECTIVES: Differentiating gastric atypical hyperplasia (AH) from dysplasia, including low-grade dysplasia (LGD) and high-grade dysplasia (HGD), poses significant challenges in small biopsies and specimens with technical artifacts. This study aims to establish objective diagnostic criteria for these conditions through combined morphologic and immunohistochemical (IHC) analyses. METHODS: Between January 2018 and September 2020, a total of 123 gastric mucosa biopsy specimens were collected at Anyang Tumor Hospital. According to the WHO Classification of Digestive System Tumors (5th edition), specimens were categorized into three groups: AH (n=48), LGD (n=30), and HGD (n=45). Morphologic characteristics were assessed, and IHC staining for MUC5AC, MUC6, MUC2, CD10, P53, and Ki67 was performed, followed by statistical analysis. RESULTS: Histologically, AH was predominantly marked by a pronounced inflammatory background (60.42%), intestinal metaplasia (64.58%), indistinct boundaries (83.33%), and a distinct maturation gradient (97.72%). AH nuclei were typically circular (97.92%), with a high nucleus-to-cytoplasm ratio (64.58%), prominent nucleoli (47.92%), and preserved polarity (89.58%). In contrast, LGD and HGD typically exhibited well-defined boundaries with an absent maturation gradient. LGD nuclei were rod-shaped (96.67%), with a low nucleus-to-cytoplasm ratio (96.67%) and preserved polarity (100%), whereas HGD demonstrated a loss of cellular polarity (77.78%). IHC findings revealed a consistent maturation gradient in AH, with polarized MUC5AC and MUC6 expression, significantly reduced in LGD (86.67%), and absent in HGD. P53 expression in HGD showed a predominant 'mutation-type pattern' (66.67%), contrasting with 'wild-type pattern' expression in AH and LGD (100%, 93.33%). Ki67 expression patterns varied from a 'pit neck pattern' in AH (95.83%) to a 'polarity pattern' in LGD (76.67%) and a 'diffuse pattern' in HGD (57.78%). The expression patterns of MUC5AC, MUC6, CD10, P53, and Ki67 varied significantly across the three groups (P<0.001). CONCLUSIONS: The integration of histomorphological features and expression profiles of MUC5AC, MUC6, P53, and Ki67 is instrumental in diagnosing gastric atypical hyperplasia and dysplasia.

Clinicopathological characteristics of well-differentiated gastric cancer missed by endoscopy.

The objective was to explore the clinicopathological features of moderately well-differentiated gastric cancer missed by endoscopy. The clinicopathological data of 88 patients who were diagnosed as moderately well-differentiated gastric cancer by biopsy and pathology from January 2019 to December 2020 in Anyang Tumor Hospital were analyzed retrospectively. The clinicopathological features and immunophenotypic characteristics of these gastric cancers were analyzed together with the literature review. Seventy males and 18 females were included in this study. There were 59 cases of gastritis, 14 cases of ulcer and 15 cases of polyp under endoscope. Based on mucous phenotype, there were 27 gastric cases, 18 intestinal cases, 39 gastrointestinal cases and 4 untyping cases. 54 cases expressed mutant p53 and 34 cases had wild type p53. None of the indicators could yield reliablediagnosis, which requires comprehensive morphological and immunohistochemical analysis by the pathologist. Meanwhile, the clinician should give the patient a systematic treatment plan incuding endoscopy, magnifying endoscopy, NBI, linear endoscopic ultrasound and other examinations. Regardless of the diagnostic criteria, once the pathology suggests a tumor lesion, local resection should be performed first. Additional surgery can be performed if there is submucosal invasion.

Bilateral transcranial direct-current stimulation promotes migration of subventricular zone-derived neuroblasts toward ischemic brain.

Ischemic insult stimulates proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) after stroke. However, only a fraction of NSC-derived neuroblasts from SVZ migrate toward poststroke brain region. We have previously reported that direct-current stimulation guides NSC migration toward the cathode in vitro. Accordingly, we set up a new method of transcranial direct-current stimulation (tDCS), in which the cathodal electrode is placed on the ischemic hemisphere and anodal electrode on the contralateral hemisphere of rats subjected to ischemia-reperfusion injury. We show that the application of this bilateral tDCS (BtDCS) promotes the migration of NSC-derived neuroblasts from SVZ toward the cathode direction into poststroke striatum. Reversing the position of the electrodes blocks the effect of BtDCS on the migration of neuroblasts from SVZ. BtDCS protects against neuronal death and improves the functional recovery of stroke animals. Thus, the migration of NSC-derived neuroblasts from SVZ toward poststroke brain region contributes to the effect of BtDCS against ischemia-induced neuronal death, supporting a potential development of noninvasive BtDCS as an endogenous neurogenesis-based stroke therapy.

A tumor immune microenvironment-related integrated signature can predict the pathological response and prognosis of esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy: A multicenter study in China.

BACKGROUND: Currently, there are insufficient indicators for the reliable assessment of treatment response following neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal squamous cell carcinoma (ESCC). Considering the essential role of protein-coding and non-coding RNAs in gene regulation and cellular processes, we systematically explored the molecular features and clinical significance of mRNA and lncRNA in 249 pretreatment biopsies from four hospitals in three districts with a high incidence of ESCC patients in China. METHODS: During the discovery phrase, 13 differentially expressed genes were identified and validated between samples with a complete pathological response (pCR) and those with an incomplete pathological response (

Warthin-like mucoepidermoid carcinoma of the parotid gland: a clinicopathological analysis of two cases.

Mucoepidermoid carcinoma (MEC) is the most common malignant tumour of the salivary gland, primarily involving the parotid gland. Here, the cases of two patients, aged 47 and 67 years, respectively, who underwent surgery for pathologically confirmed Warthin-like MEC of the parotid gland between January 2019 and December 2019 in Anyang Tumour Hospital, are described. In each case, the tumour consisted of epithelial and lymphoid cell components, covered with two or more layers of epithelium, with visible scattered mucous cells, and lymphoid stroma with a large number of lymphocytes and germinal centres formed. Most importantly, the tumours lacked the well-organized, bilayered oncocytic epithelial structure that is characteristic of Warthin's tumour. Mastermind like transcriptional coactivator 2 (MAML2) gene rearrangements were identified in the tumour cells using break-apart fluorescence in situ hybridization (FISH) probes, confirming the diagnosis of Warthin-like MEC. Post-operatively, patients have remained disease free for 31 and 27 months, respectively. Warthin-like MEC of the parotid gland is rare and is often misdiagnosed as metaplastic Warthin's tumour. Diagnosis depends mainly on the unique clinicopathologic features together with FISH analyses.

Thyroid papillary carcinoma with the 'snowstorm appearance': a clinicopathological analysis of three cases.

This current case report presents the detailed clinicopathological analysis of three patients with papillary thyroid carcinoma, each of which presented with the 'snowstorm appearance' on ultrasonography. Ultrasonography of this tumour typically shows a diffusely enlarged thyroid with hypoechoic and heterogeneous internal echoes, and diffusely scattered microcalcifications, which form the 'snowstorm appearance'. Microscopically, case 1 had a large number of psammoma bodies, infiltration of lymphocytes, formation of lymphatic follicles and extensive squamous metaplasia, leading to the diagnosis of a diffuse sclerosing variant of papillary thyroid carcinoma (DSVPTC). Case 2 was diagnosed with follicular papillary thyroid carcinoma. Their tumour had numerous calcifications in the stroma and follicles. Case 3 was diagnosed with a multifocal papillary thyroid carcinoma in the background of Hashimoto's thyroiditis. Their tumour showed calcification in the stroma and follicles, together with cervical lymph node metastasis. DSVPTC is a rare variant of thyroid papillary carcinoma. It has the 'snowstorm appearance' on ultrasound, but this can also be found in follicular papillary carcinoma and multifocal thyroid papillary carcinoma. Papillary thyroid carcinoma with the 'snowstorm appearance' has a large number of peripheral lymph nodes metastases, thus requiring radical surgery and postoperative adjuvant therapy.

The methylation of SDC2 and TFPI2 defined three methylator phenotypes of colorectal cancer.

BACKGROUND: Methylated SDC2 and TFPI2 are widely used for colorectal cancer (CRC) detection. However, they often miss some CRCs, which directly diminishes the sensitivity. Further investigations of the underlying mechanisms leading to the missed samples will facilitate developing more eligible methylation markers. METHODS: CRC samples from TCGA and GEO datasets were divided into three groups, High-methylation/ High-methylation (HH), High-methylation/Low-methylation (HL), and Low-methylation/Low-methylation (LL) according to the methylation status of SDC2 and TFPI2 promoters. Variations in age, tumor location and microsatellite instable were then assessed between the three groups and verified in our custom cohort. RESULTS: Samples of HL group preferred to derive from left-sided CRCs (P < 0.05). HH samples showed the highest microsatellite instability and mutation load (mean nonsynonymous mutations for HH/HL/LL: 10.55/3.91/7.02, P = 0.0055). Almost all mutations of BRAF, one of the five typical CpG island methylator phenotype (CIMP) related genes, were observed in HH group (HH/HL/LL: 51/0/1, P = 0.018). Besides, older patients were frequently found in HH group. Expression analysis identified 37, 84, and 22 group-specific differentially expressed genes (DEGs) for HH, HL, and LL, respectively. Functional enrichment analysis revealed that HH-specific DEGs were mainly related to transcription regulation, while LL-specific DEGs were enriched in the biological processes of extracellular matrix interaction and cell migration. CONCLUSIONS: The current study revealed that the performance of methylation-based markers might be affected by tumor location, patient age, mutation load and MSI, and these respective sides should be considered when developing new methylation markers for CRC detection.

Methylation of SDC2/TFPI2 and Its Diagnostic Value in Colorectal Tumorous Lesions.

Background: SDC2 methylation is a feasible biomarker for colorectal cancer detection. Its specificity for colorectal cancer is higher than 90%, but the sensitivity is normally lower than 90%. This study aims to improve the sensitivity of SDC2 detection through finding a high positive target from the false-negative samples of SDC2 detection based on analysis of the bowel subsite difference in methylation. Methods: Hypermethylated TFPI2 was identified in SDC2 hypomethylated colorectal cancer samples retrieved from TCGA database with the methylation level lower than 0.2. The methylation-specific PCR assay was developed and then evaluated using tissue samples (184 cancer and 54 healthy control samples) and stool samples (289 cancer, 190 adenoma, and 217 healthy control samples). Results: TFPI2 was hypermethylated in most SDC2 hypomethylated colorectal cancer samples. When the SDC2/TFPI2-combined PCR assay was performed in stool specimens, the AUC value of cancer vs. control was 0.98, with the specificity of 96.40% and sensitivity of 96.60%, and the AUC value of adenoma vs. control was 0.87, with the specificity of 95.70% and the sensitivity of 80.00%. The improvement in sensitivity was the most momentous in the left colon. As the detection index, the Ct value was better in improving the sensitivity of detection than the methylation level based on the 2-ΔΔCt value. Conclusion: TFPI2 can improve the sensitivity of SDC2 methylation-specific detection of colorectal tumorous lesions while maintaining high specificity, in particular reducing the missed detection of left colon cancer and adenoma.

Author Correction: Near-real-time monitoring of global CO2 emissions reveals the effects of the COVID-19 pandemic.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20254-5.

Primary squamous cell carcinoma of the breast: report of two cases with HER2 overexpression.

OBJECTIVE: To investigate the clinicopathologic features and immunophenotype of primary squamous cell carcinoma of the breast (PSCCB) with HER2 overexpression. Methods Two cases of PSCCB with HER2 overexpression were retrospectively reviewed, and the pathological features, immunophenotype and prognosis were discussed. Results The tumor showed malignant squamous cells arranged in sheets, groups and nests, forming keratin-pearl and intercellular bridges. Immunohistochemical (IHC) analysis showed that the tumor cells were positive for 34ßE12, p63, CK5/6, E-cadherin and P120, while negative for ER and PR. Furthermore, HER2 overexpression showed strong continuous expression in cell membrane with a score of 3+ by IHC, or amplification by FISH. Conclusions PSCCB is a rare tumor in breast cancer and HER2 overexpression is rather unusual in PSCCB. The diagnosis mainly depends on the clinicopathologic features together with the immunophenotype. HER2 positive indicates poor prognosis. However, targeted therapy for HER2 may be a new hope for patients.

Near-real-time monitoring of global CO2 emissions reveals the effects of the COVID-19 pandemic.

The COVID-19 pandemic is impacting human activities, and in turn energy use and carbon dioxide (CO2) emissions. Here we present daily estimates of country-level CO2 emissions for different sectors based on near-real-time activity data. The key result is an abrupt 8.8% decrease in global CO2 emissions (-1551 Mt CO2) in the first half of 2020 compared to the same period in 2019. The magnitude of this decrease is larger than during previous economic downturns or World War II. The timing of emissions decreases corresponds to lockdown measures in each country. By July 1st, the pandemic's effects on global emissions diminished as lockdown restrictions relaxed and some economic activities restarted, especially in China and several European countries, but substantial differences persist between countries, with continuing emission declines in the U.S. where coronavirus cases are still increasing substantially.

A three-lncRNA signature of pretreatment biopsies predicts pathological response and outcome in esophageal squamous cell carcinoma with neoadjuvant chemoradiotherapy.

BACKGROUND: Current strategies are insufficient to predict pathologically complete response (pCR) for esophageal squamous cell carcinomas (ESCCs) before treatment. Here, we aim to develop a novel long noncoding RNA (lncRNA) signature for pCR and outcome prediction of ESCCs through a multicenter analysis for a Chinese population. METHODS: Differentially expressed lncRNAs (DELs) between pCRs and less than pCR (

An individualized immune signature of pretreatment biopsies predicts pathological complete response to neoadjuvant chemoradiotherapy and outcomes in patients with esophageal squamous cell carcinoma.

No clinically available biomarkers can predict pathological complete response (pCR) for esophageal squamous cell carcinomas (ESCCs) with neoadjuvant chemoradiotherapy (nCRT). Considering that antitumor immunity status is an important determinant for nCRT, we performed an integrative analysis of immune-related gene profiles from pretreatment biopsies and constructed the first individualized immune signature for pCR and outcome prediction of ESCCs through a multicenter analysis. During the discovery phase, 14 differentially expressed immune-related genes (DEIGs) with greater than a twofold change between pCRs and less than pCRs (

Arginine is neuroprotective through suppressing HIF-1α/LDHA-mediated inflammatory response after cerebral ischemia/reperfusion injury.

Neuroinflammation is a secondary response following ischemia stroke. Arginine is a non-essential amino acid that has been shown to inhibit acute inflammatory reaction. In this study we show that arginine treatment decreases neuronal death after rat cerebral ischemia/reperfusion (I/R) injury and improves functional recovery of stroke animals. We also show that arginine suppresses inflammatory response in the ischemic brain tissue and in the cultured microglia after OGD insult. We further provide evidence that the levels of HIF-1α and LDHA are increased after rat I/R injury and that arginine treatment prevents the elevation of HIF-1α and LDHA after I/R injury. Arginine inhibits inflammatory response through suppression of HIF-1α and LDHA in the rat ischemic brain tissue and in the cultured microglia following OGD insult, and protects against ischemic neuron death after rat I/R injury by attenuating HIF-1α/LDHA-mediated inflammatory response. Together, these results indicate a possibility that arginine-induced neuroprotective effect may be through the suppression of HIF-1α/LDHA-mediated inflammatory response in microglia after cerebral ischemia injury.

l-lysine confers neuroprotection by suppressing inflammatory response via microRNA-575/PTEN signaling after mouse intracerebral hemorrhage injury.

l-lysine is a basic amino acid that has been shown to exert neuroprotective effect. However, the underlying mechanism remains to be elucidated. In this study, we investigate how l-lysine exerts its neuroprotective effect in hemin-insulted mouse cortical neurons in vitro and the mouse model of intracerebral hemorrhage (ICH) in vivo. We demonstrate that l-lysine treatment promotes M2 microglial polarization and reduces inflammatory response both in vitro and in vivo, suggesting that l-lysine may play a neuroprotective role in ICH injury. Indeed, we show that l-lysine treatment reduces cortical neuronal death after hemin insult in vitro and decrease the number of degenerating neurons after ICH in vivo. l-lysine also improves the functional recovery of ICH animals in neurobehavioral tests. Consistent with the role of PTEN in regulating inflammatory response, we find that PTEN inhibition promotes M2 microglial polarization and suppresses pro-inflammatory response in mouse ICH injury, which contribute to the neuroprotective effect of l-lysine. Moreover, our results reveal that microRNA-575 directly suppressed PTEN to promote M2 microglial polarization and mediate the neuroprotective effect of l-lysine in ICH injury. Together, our results suggest that l-lysine confers neuroprotection after ICH injury through enhancing M2 microglial polarization and reducing inflammatory response, which is mediated by microRNA-575 upregulation and subsequent PTEN downregulation.

Invasive stratified mucin-producing carcinoma: a clinicopathological analysis of three cases.

Objective: To investigate the clinicopathologic features and immunophenotype of invasive-stratified mucin-producing carcinoma (ISMC). Methods: We retrospectively analyzed three patients who underwent surgery for pathologically confirmed ISMC from January 2017 to December 2017 in Anyang Tumor Hospital. The pathological features, immunophenotype, and prognosis were discussed. Results: Clinical symptoms and imaging were atypical. Microscopically, the arrangement of tumor cells is close to that of squamous cell carcinoma, showing flake or nested growth. Morphologically, tumor cells were reminiscent of adenocarcinoma. The tumor cells showed abundant intracytoplasmic mucus which routinely created spacing between adjacent nuclei. The nuclei was round or oval with irregular karyotypes, thick nuclear membrane, staining empty light, rough chromatin, visible small nucleoli. Mucous vacuoles or pink-stained foam were visible in the cytoplasm. Mitotic features and apoptotic bodies were seen in the invasive component of all three cases, whereas all but one of these showed a neutrophil-dominant inflammatory cells infiltration. A large number of histocytes were found in the stroma of two cases. Special staining of mucus confirmed the presence of mucus in cytoplasm. Immunohistochemical results showed that tumor cells were strongly and diffusely positive for p16 and CK7 and had high Ki-67 expression. Conclusions: ISMC is a rare tumor in female genital tract and is often misdiagnosed as squamous cell carcinoma and other cervical cancers. The diagnosis mainly depends on the unique clinicopathologic features together with the immunophenotype. Treatment and prognosis, like other cervical cancer, are mainly based on clinical stages.

DJ-1 Suppresses Cytoplasmic TDP-43 Aggregation in Oxidative Stress-Induced Cell Injury.

DJ-1 (also called PARK7) is a multifunctional redox-sensitive protein that is protective against oxidative stress-induced cell death. TAR DNA-binding protein 43 (TDP-43) is a major protein component of pathological inclusions in amyotrophic lateral sclerosis and frontotemporal dementia. Reducing aberrant aggregation of TDP-43 is a potential approach to prevent cell death. To investigate whether DJ-1 might inhibit TDP-43 aggregation to exert a protective effect in oxidative stress-induced injury, we tested the protein level and subcellular localization of TDP-43 and DJ-1 in SH-SY5Y cells transfected with wild-type DJ-1, DJ-1 mutant (L166P) cDNA, or DJ-1 siRNA. We show that oxidative stress induced by paraquat leads to the formation of cytosolic TDP-43 aggregation in SH-SY5Y cells. DJ-1 overexpression decreases paraquat-induced cytoplasmic accumulation of TDP-43 in SH-SY5Y cells and protects against paraquat-induced cell death. Transfection of DJ-1 L166P mutant or DJ-1 siRNA leads to increased cytosolic aggregation of TDP-43 in paraquat-treated SH-SY5Y cells and promotes cell death. These data suggest that DJ-1 may protect against oxidative stress-induced cell death through the suppression of cytoplasmic TDP-43 aggregation.

ERK 1/2 Activation Mediates the Neuroprotective Effect of BpV(pic) in Focal Cerebral Ischemia-Reperfusion Injury.

Bisperoxovanadium (pyridine-2-carboxyl) [bpV(pic)] is a commercially available PTEN inhibitor. Previous studies from us and others have shown that bpV(pic) confers neuroprotection in cerebral ischemia injury. We set up to determine whether ERK 1/2 activation plays a role in bpV(pic)-induced neuroprotective effect in cerebral ischemia injury. We found that the phosphorylation levels of Akt (p-AKT) and ERK1/2 (p-ERK 1/2) were down-regulated after cerebral ischemia-reperfusion injury. The injection of bpV(pic) after injury not only increased the level of p-AKT but also the level of p-ERK 1/2. While the inhibition of PTEN mediated the up-regulatation of p-AKT and p-ERK 1/2 by bpV(pic). Interestingly, the ERK 1/2 activation induced by bpV(pic) was also independent of the inhibition of PTEN. Our results indicate that bpV(pic) protects against OGD-induced neuronal death and promotes the functional recovery of stroke animals through PTEN inhibition and ERK 1/2 activation, respectively. This study suggests that the effect of bpV(pic) on ERK 1/2 signaling should be considered while using bpV(pic) as a PTEN inhibitor.

Glioblastoma recurrence correlates with NLGN3 levels.

Glioblastoma (GBM) is the most aggressive glioma in the brain. Recurrence of GBM is almost inevitable within a short term after tumor resection. In a retrospective study of 386 cases of GBM collected between 2013 and 2016, we found that recurrence of GBM mainly occurs in the deep brain regions, including the basal ganglia, thalamus, and corpus callosum. But the mechanism underlying this phenomenon is not clear. Previous studies suggest that neuroligin-3 (NLGN3) is necessary for GBM growth. Our results show that the levels of NLGN3 in the cortex are higher than those in the deep regions in a normal human brain, and similar patterns are also found in a normal mouse brain. In contrast, NLGN3 levels in the deep brain regions of GBM patients are high. We also show that an increase in NLGN3 concentration promotes the growth of U251 cells and U87-MG cells. Respective use of the cortex neuron culture medium (C-NCM) and basal ganglia neuron culture medium (BG-NCM) with DMEM to cultivate U251, U87-MG and GBM cells isolated from patients, we found that these cells grew faster after treatment with C-NCM and BG-NCM in which the cells treated with C-NCM grew faster than the ones treated with BG-NCM group. Inhibition of NLGN3 release by ADAM10i prevents NCM-induced cell growth. Together, this study suggests that increased levels of NLGN3 in the deep brain region under the GBM pathological circumstances may contribute to GBM recurrence in the basal ganglia, thalamus, and corpus callosum.

Endometrial stromal sarcoma: a clinicopathological analysis of 14 cases.

OBJECTIVE: To investigate the clinicopathologic features and immunophenotype of endometrial stromal sarcoma (ESS) and extra uterine endometrial stromal sarcoma (EESS). METHODS: 14 cases of ESS (8 cases of ESS and 6 cases of EESS) were retrospectively reviewed, and the pathological features, immunophenotype and prognosis were discussed. RESULTS: In 14 cases of ESS, 12 cases (8 cases of ESS and 4 cases of EESS) were diagnosed as low grade endometrial stromal sarcoma (LGESS) and 2 cases of EESS were diagnosed as high grade endometrial stromal sarcoma (HGESS). Microscopically, the tumor cells in LGESS cases were composed of densely arranged endometrial stromal cells with a similar proliferative phase. They were surrounded by spiral arterioles and mitosis was rare. The tumor cells in HGESS cases displayed marked cellular atypia, increased mitosis, infiltration, and necrosis. However, small blood vessels which were common in LGESS were rarely observed in HGESS. Immunohistochemical results showed that most tumor cells were positive for CD10, vimentin, PR, and ER. CONCLUSIONS: ESS is a rare tumor in the female genital tract and is often misdiagnosed as other mesenchymal tumors before operation. The diagnosis mainly depends on the clinicopathologic features together with the immunophenotype. LGESS has better long term survival and lower incidence of disease recurrence than HGESS. Thus, LGESS has better prognosis than HGESS.