Bacillus licheniformis Jrh14-10 enhances alkaline tolerance in Arabidopsis thaliana by regulating crosstalk between ethylene and polyamine pathways.

Plant growth-promoting rhizobacteria (PGPR) are known for their role in ameliorating plant stress, including alkaline stress, yet the mechanisms involved are not fully understood. This study investigates the impact of various inoculum doses of Bacillus licheniformis Jrh14-10 on Arabidopsis growth under alkaline stress and explores the underlying mechanisms of tolerance enhancement. We found that all tested doses improved the growth of NaHCO3-treated seedlings, with 109 cfu/mL being the most effective. Transcriptome analysis indicated downregulation of ethylene-related genes and an upregulation of polyamine biosynthesis genes following Jrh14-10 treatment under alkaline conditions. Further qRT-PCR analysis confirmed the suppression of ethylene biosynthesis and signaling genes, alongside the activation of polyamine biosynthesis genes in NaHCO3-stressed seedlings treated with Jrh14-10. Genetic analysis showed that ethylene signaling-deficient mutants (etr1-3 and ein3-1) exhibited greater tolerance to NaHCO3 than the wild type, and the growth-promoting effect of Jrh14-10 was significantly diminished in these mutants. Additionally, Jrh14-10 was found unable to produce 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase, indicating it does not reduce the ethylene precursor ACC in Arabidopsis. However, Jrh14-10 treatment increased the levels of polyamines (putrescine, spermidine, and spermine) in stressed seedlings, with spermidine particularly effective in reducing H2O2 levels and enhancing Fv/Fm under NaHCO3 stress. These findings reveal a novel mechanism of PGPR-induced alkaline tolerance, highlighting the crosstalk between ethylene and polyamine pathways, and suggest a strategic redirection of S-adenosylmethionine towards polyamine biosynthesis to combat alkaline stress.

Neoadjuvant PD-(L)1 blockade plus platinum-based chemotherapy for potentially resectable oncogene-positive non-small cell lung cancer.

BACKGROUND: Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non-small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC. METHODS: Patients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained. RESULTS: A total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, including EGFR, KRAS, ERBB2, ROS1, MET, RET, ALK, and FGFR3 alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group. CONCLUSION: Compared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice.

Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin- and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed non-polypoid lesions. Seven (88%) showed multifocal GI disease, including five with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single-system), with the remaining 14 (36%) exhibiting multi-system disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multi-system LCH more frequently presented with GI symptoms (92%, P<0.001), non-colorectal GI site involvement (50%, P=0.02), multifocal GI lesions (43%, P=0.005), non-polypoid lesions (71%, P<0.001), infiltrative histologic growth pattern (78%, P=0.04), and persistent disease (57%, P<0.001). Adult multi-system LCH patients appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrate that adults with single-system LCH involving the GI tract have an excellent prognosis, while multi-system LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, non-colorectal GI involvement, multifocal GI disease, non-polypoid lesions, and infiltrative growth pattern.

Histologic Features of Mycobacterial Spindle Cell Pseudotumors: A Multi-institutional Clinicopathologic Analysis of 14 Cases.

Mycobacterial spindle cell pseudotumors (MSPs) are a rare and diagnostically challenging manifestation of non-tuberculous mycobacterial (NTM) infections. Proper recognition of these pseudotumors is important because they are treatable and benign. In this study, we evaluated the morphologic patterns of MSPs to improve their pathologic identification. Clinical and morphologic features of 14 MSPs were analyzed. Histologic factors evaluated included the architectural growth pattern of spindled or epithelioid macrophages, granulomas and their location within the lesion, neutrophilic microabscesses, multinucleated giant cells, necrosis, and effacement of background tissue. The composition of inflammatory infiltrates, organism density by acid-fast staining, and stromal changes were also assessed. In addition, 8 of 14 cases underwent molecular microbiology identification by a clinical amplicon-sequencing assay for non-tuberculous mycobacteria. MSP sites included 2 bowel, 10 lymph nodes, 1 liver, and 1 extremity. Cases with available clinical history (n=10) all occurred in immunocompromised patients. All demonstrated effacement of normal structures with spindled cells arranged in a storiform or fascicular architectural pattern. In addition, all cases showed lymphocytic inflammation, with prominent concurrent neutrophilic inflammation in 50% (7/14) of cases. Other morphologic findings included foamy histiocytes (64%, 9/14), peripherally situated granulomas (21%, 3/14), and neutrophilic microabscesses (21%, 3/14). All tested cases were positive for NTM by PCR methods. Mycobacterium avium was the most commonly isolated pathogen (6/8). Mycobacterial spindle cell pseudotumors show predominantly spindled morphology that may be mistaken as a neoplasm. Surgical pathologists who evaluate lymph nodes, soft tissue, and gastrointestinal tissues should be aware of this spindled tumefactive phenomenon in the setting of immunocompromised patients. Recognition of key morphologic features of neutrophilic inflammation, peripheral granulomas, or foamy histiocytes within a spindled lesion can help guide the pathologist to a correct diagnosis of an inflammatory process secondary to infection rather than a spindle cell neoplasm. Accurate diagnosis to facilitate appropriate antimicrobial and/or surgical therapy requires a comprehensive evaluation combining clinical, histopathologic, and microbiological findings.

Artificial intelligence-aided steatosis assessment in donor livers according to the Banff consensus recommendations.

OBJECTIVES: Severe macrovesicular steatosis in donor livers is associated with primary graft dysfunction. The Banff Working Group on Liver Allograft Pathology has proposed recommendations for steatosis assessment of donor liver biopsy specimens with a consensus for defining "large droplet fat" (LDF) and a 3-step algorithmic approach. METHODS: We retrieved slides and initial pathology reports from potential liver donor biopsy specimens from 2010 to 2021. Following the Banff approach, we reevaluated LDF steatosis and employed a computer-assisted manual quantification protocol and artificial intelligence (AI) model for analysis. RESULTS: In a total of 113 slides from 88 donors, no to mild (<33%) macrovesicular steatosis was reported in 88.5% (100/113) of slides; 8.8% (10/113) was reported as at least moderate steatosis (≥33%) initially. Subsequent pathology evaluation, following the Banff recommendation, revealed that all slides had LDF below 33%, a finding confirmed through computer-assisted manual quantification and an AI model. Correlation coefficients between pathologist and computer-assisted manual quantification, between computer-assisted manual quantification and the AI model, and between the AI model and pathologist were 0.94, 0.88, and 0.81, respectively (P < .0001 for all). CONCLUSIONS: The 3-step approach proposed by the Banff Working Group on Liver Allograft Pathology may be followed when evaluating steatosis in donor livers. The AI model can provide a rapid and objective assessment of liver steatosis.

Histopathology and its clinical correlation of liver biopsy in patients with treated autoimmune hepatitis.

The diagnosis of autoimmune hepatitis (AIH) relies on well-established criteria encompassing histological, serological, and clinical features. Diagnosing AIH may become challenging when encountering patients who have undergone steroid therapy for other co-existing diseases. Thirty-nine liver biopsies from 25 patients with treated and untreated AIH were classified into three groups: 1) Newly diagnosed untreated biopsies (n = 16); 2) Newly diagnosed partially treated biopsies from patients already on steroid treatment for other co-existing diseases (n = 9); 3) Previously diagnosed biopsies from patients who had undergone complete treatment (n = 14). In the untreated AIH group, at least 50 % of the cases exhibited the following features: at least moderate portal inflammation (81 %), at least moderate lobular inflammation (56 %), ductular reaction (94 %), inflammation gradient from bile duct to interface (88 %), unequivocal interface hepatitis (100 %), emperipolesis (56 %), plasma cell cluster (88 %), apoptosis or necrosis (63 %), pericentral inflammation (63 %), and periportal fibrosis (88 %). Although all these diagnostically sensitive histologic features were present in significantly fewer cases after treatment (p < 0.05), the features of ductular reaction, inflammation gradient from bile duct to interface, pericentral inflammation, and periportal fibrosis were likely to persist after treatment, especially in partially treated cases; these features did not show a significant association with higher transaminase levels (P > 0.05) and were considered as indirect features of hepatocytic injury. Our data suggest categorizing AIH histological features into direct and indirect hepatocytic injuries. Direct hepatocytic injury features significantly correlate with transaminase levels and respond well to treatment, while indirect ones show weaker transaminase correlation and relative treatment resistance.

Esophageal squamous cell carcinoma with pagetoid spread: a clinicopathologic study.

Pagetoid spread in esophageal squamous epithelium associated with underlying esophageal adenocarcinoma (EAC) has been well studied. Case reports describing pagetoid spread of esophageal squamous cell carcinomas (ESCC) also exist in the literature. The latter, however, has not been systematically studied. In this study, we report seven cases of pagetoid spread associated with ESCC. The clinical, morphologic, and immunophenotypic profiles of pagetoid spread in the context of ESCC and EAC are compared. Cases of pagetoid spread of ESCC were identified through computerized search of pathology archives at five institutions. Additional cases were identified through manual review of surgical resection cases of treatment naive ESCC in Mass General Brigham (MGB) pathology archive. Clinical history was collected via chart review. Immunohistochemistry for CK7, CK20, CDX2, p53, p63, and p40 was performed on selected cases. A computerized search of pathology archives of five institutions revealed only two cases. A manual review of 76 resected untreated ESCC revealed five additional cases with unequivocal pagetoid spread of ESCC, indicating the condition was not uncommon but rarely reported. Patient age ranged from 54 to 78 years (median, 65). There were six women and one man. One case had in situ disease, five had pT1 (1 pT1a and 4 pT1b), and one had pT3 disease. One of the patients with pT1 tumor had a positive lymph node, while the remaining six patients were all N0. Four tumors were in the proximal to mid esophagus, and three in the distal esophagus. Patient survival ranged from 25 months to more than 288 months. The pagetoid tumor cells demonstrated enlarged, hyperchromatic nuclei with variable amounts of eosinophilic cytoplasm. The cytoplasm was often condensed to the perinuclear area, creating peripheral clearing. By immunohistochemistry, the pagetoid cells were positive for p40 (6/6) and p63 (7/7) and negative for CDX2 (7/7). The tumor cells showed mutant-type staining for p53 in five of seven cases. One of the patients had pagetoid tumor cells at the resection margin and subsequently had recurrent disease 2 years later. All other patients had negative resection margins and did not have local recurrence. Four cases of pagetoid spread in the context of EAC were used as a comparison group. Previously published studies were also analyzed. These tumors were all located in the distal esophagus or gastroesophageal junction. All cases were associated with underlying invasive EAC. Pagetoid spread associated with EAC often had cytoplasmic vacuoles or mucin. They were more frequently positive for CK7 than pagetoid ESCC (p = 0.01). Both ESCC and EAC may give rise to pagetoid spread of tumor cells within surface squamous epithelium. Pagetoid spread from ESCC and EAC have overlapping morphologic features. P40 and p63 immunostains can facilitate the distinction between ESCC and EAC. P53 immunostain can aid in confirmation of malignancy. Understanding their overlapping pathologic features will help pathologists avoid pitfalls and diagnose these lesions correctly on biopsy specimens.

Synthesis of flowerlike vanadium diselenide microspheres for efficient electromagnetic wave absorption.

The revelation of MoS2as an efficient electromagnetic wave (EMW) absorbing material has ratcheted up people's attention to other transition metal dichalcogenides (TMDs). To date, extensive studies have been conducted on the semiconducting VIB-Group TMDs while research into metallic VB-Group TMDs has been relatively rare. In this work, we successfully fabricated VB-Group VSe2microspheres through a facile one-step hydrothermal method and used them as EMW absorbers. The flowerlike VSe2microspheres based on VSe2nanosheets exhibited a minimum reflection loss of 46.58 dB with an effective absorption bandwidth of 4.86 GHz. The influence of material morphology, microstructure, and dielectric properties on the EMW absorption performance was systematically investigated. The hierarchically layered structure promoted dielectric loss and EMW absorption by means of multiple reflection, interfacial polarization and related relaxation, and enhanced attenuation ability. This work not only demonstrates that VSe2is potentially a high-efficiency single component EMW absorber, but also provides fresh insights into exploration on the EMW loss mechanisms of the metallic TMD-based absorbing materials.

Improving diagnostic yield of pancreatic serous cystadenoma with cyst fluid ancillary testing, adjunct immunohistochemistry, and additional fine-needle biopsy sampling.

BACKGROUND: Fine-needle aspiration (FNA) diagnosis of pancreatic serous cystadenoma (SCA) remains challenging. This retrospective study aimed to evaluate the roles of cyst fluid ancillary testing and combined fine-needle biopsy (FNB) in improving the diagnostic yield. METHODS: The authors retrospectively reviewed cytology cases that were histologically confirmed SCAs. Clinical features and FNA cyst fluid biochemical and molecular analysis results along FNB findings were reviewed. RESULTS: The study cohort included 31 cases from 13 male and 18 female patients with a mean age of 65. The original cytologic diagnoses were nondiagnostic (n = 6, 19%), negative for malignant cells/cyst contents (n = 7, 23%), atypical cells (n = 3, 10%), nonmucinous cyst (n = 11, 35%), and serous cystadenoma (n = 4, 13%). Cyst fluid carcinoembryonic antigen (CEA) analysis was performed in 17 cases, all of which showed a low CEA level (<192 ng/mL). All 14 cases with molecular testing showed a wild-type KRAS. Inhibin immunohistochemistry was retrospectively performed on the FNA cell blocks, inhibin was positive in six of seven cases tested. In 15 cases with concurrent FNA and FNB biopsies, the diagnosis of SCA was seen in only one FNA case (7%) but 13 FNB cases (87%). CONCLUSIONS: This study suggests that FNA diagnosis of SCA remains challenging even with ancillary testing including cyst fluid CEA level and KRAS mutation analysis. Adjunct inhibin immunostaining may help improve the cytologic diagnosis of selective SCA cases. FNB appears superior to FNA for a definite diagnosis of SCA.

Cholangiocarcinoma: Pathologic and Molecular Classification in the Era of Precision Medicine.

CONTEXT.­: Cholangiocarcinoma (CCA) is a heterogeneous cancer of the bile duct, and its diagnosis is often challenging. OBJECTIVE.­: To provide insights into state-of-the-art approaches for the diagnosis of CCA. DATA SOURCES.­: Literature review via PubMed search and authors' experiences. CONCLUSIONS.­: CCA can be categorized as intrahepatic or extrahepatic. Intrahepatic CCA is further classified into small-duct-type and large-duct-type, whereas extrahepatic CCA is classified into distal and perihilar according to site of origin within the extrahepatic biliary tree. Tumor growth patterns include mass forming, periductal infiltrating, and intraductal tumors. The clinical diagnosis of CCA is challenging and usually occurs at an advanced tumor stage. Pathologic diagnosis is made difficult by tumor inaccessibility and challenges in distinguishing CCA from metastatic adenocarcinoma to the liver. Immunohistochemical stains can assist in differentiating CCA from other malignancies, such as hepatocellular carcinoma, but no distinctive CCA-specific immunohistochemical profile has been identified. Recent advances in next-generation sequencing-based high-throughput assays have identified distinct genomic profiles of CCA subtypes, including genomic alterations that are susceptible to targeted therapies or immune checkpoint inhibitors. Detailed histopathologic and molecular evaluations of CCA by pathologists are critical for correct diagnosis, subclassification, therapeutic decision-making, and prognostication. The first step toward achieving these goals is to acquire a detailed understanding of the histologic and genetic subtypes of this heterogeneous tumor group. Here, we review state-of-the-art approaches that should be applied to establish a diagnosis of CCA, including clinical presentation, histopathology, staging, and the practical use of genetic testing methodologies.

Detection of Large-Droplet Macrovesicular Steatosis in Donor Livers Based on Segment-Anything Model.

Liver transplantation is an effective treatment for end-stage liver disease, acute liver failure, and primary hepatic malignancy. However, the limited availability of donor organs remains a challenge. Severe large-droplet fat (LDF) macrovesicular steatosis, characterized by cytoplasmic replacement with large fat vacuoles, can lead to liver transplant complications. Artificial intelligence models, such as segmentation and detection models, are being developed to detect LDF hepatocytes. The Segment-Anything Model, utilizing the DEtection TRansformer architecture, has the ability to segment objects without prior knowledge of size or shape. We investigated the Segment-Anything Model's potential to detect LDF hepatocytes in liver biopsies. Pathologist-annotated specimens were used to evaluate model performance. The model showed high sensitivity but compromised specificity due to similarities with other structures. Filtering algorithms were developed to improve specificity. Integration of the Segment-Anything Model with rule-based algorithms accurately detected LDF hepatocytes. Improved diagnosis and treatment of liver diseases can be achieved through advancements in artificial intelligence algorithms for liver histology analysis.

Colorectal Carcinoma With Sarcomatoid Components: Report of 15 Cases and Literature Review of an Exceedingly Rare Carcinoma Subtype.

Colorectal carcinoma with sarcomatoid components (which includes so-called carcinosarcomas and sarcomatoid carcinomas) is a rare subtype with 50 reported cases in the literature and overlapping criteria with undifferentiated carcinoma. We collected and described 15 cases from 10 men and 5 women, with a mean age of 66 years. Symptoms included abdominal pain and gastrointestinal bleeding. Most tumors presented in the rectosigmoid region, with a mean size of 8.2 cm. The sarcomatoid component, on average, represented 58% of the tumors and took many forms, including spindled (10 cases), anaplastic (9 cases), and rhabdoid (3 cases); one case showed osteoid matrix. Tumor budding was usually high, and tumor-infiltrating lymphocytes were usually low. The sarcomatoid component was keratin-positive in 10 cases. One case showed loss of mismatch repair protein expression, and 2 cases showed SMARCA4 loss (1 also with SMARCA2 loss). Molecular testing identified mutations in KRAS (n=1), NRAS (n=2), BRAF (n=2), APC (n=1), and TP53 (n=1) in a few cases. Tumors often presented at advanced stage, with 11 cases pT4, 9 cases with nodal metastases, and 7 cases with distant metastases. Follow-up was available for 10 cases (median: 2 months), with 2 alive without disease, 3 alive with disease, and 5 dead. Our findings roughly corresponded with those in previously reported cases. Colorectal carcinoma with sarcomatoid components is rare and aggressive, with a poor prognosis for many patients. We suggest that spindled cells, anaplasia, heterologous elements, and/or a component with definable sarcomatous lineage be used to distinguish colorectal carcinoma with sarcomatoid components from undifferentiated carcinoma.

Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition.

AGPAT2 (1-acyl-sn-glycerol-3-phosphate-acyltransferase-2) converts lysophosphatidic acid (LPA) into phosphatidic acid (PA), and mutations of the AGPAT2 gene cause the most common form of congenital generalized lipodystrophy which leads to steatohepatitis. The underlying mechanism by which AGPAT2 deficiency leads to lipodystrophy and steatohepatitis has not been elucidated. We addressed this question using an antisense oligonucleotide (ASO) to knockdown expression of Agpat2 in the liver and white adipose tissue (WAT) of adult male Sprague-Dawley rats. Agpat2 ASO treatment induced lipodystrophy and inflammation in WAT and the liver, which was associated with increased LPA content in both tissues, whereas PA content was unchanged. We found that a controlled-release mitochondrial protonophore (CRMP) prevented LPA accumulation and inflammation in WAT whereas an ASO against glycerol-3-phosphate acyltransferase, mitochondrial (Gpam) prevented LPA content and inflammation in the liver in Agpat2 ASO-treated rats. In addition, we show that overnutrition, due to high sucrose feeding, resulted in increased hepatic LPA content and increased activated macrophage content which were both abrogated with Gpam ASO treatment. Taken together, these data identify LPA as a key mediator of liver and WAT inflammation and lipodystrophy due to AGPAT2 deficiency as well as liver inflammation due to overnutrition and identify LPA as a potential therapeutic target to ameliorate these conditions.

Let-7 suppresses liver fibrosis by inhibiting hepatocyte apoptosis and TGF-ß production.

OBJECTIVE: FAS-mediated apoptosis of hepatocytes and aberrant TGF-ß signaling are major drivers of liver fibrosis. Decreased miRNA let-7 expression in the livers of patients and animals with fibrosis suggests a mechanistic link of let-7 to hepatic fibrogenesis. METHODS: Using transient transfection we tested the effects of let-7 overexpression and TET3 siRNA knockdown on FAS and TGF-ß1 expression and FAS-mediated apoptosis in human and mouse primary hepatocytes. We assessed the therapeutic activity of let-7 miRNA delivered via adeno-associated viral vectors in mouse models of carbon tetrachloride (CCl4)-induced and bile duct ligation (BDL)-induced liver fibrosis. RESULTS: Let-7 decreased TGF-ß1 production from hepatocytes through a negative feedback loop involving TET3. On the other hand, let-7 post-transcriptionally inhibits FAS expression, thereby suppressing hepatocyte apoptosis. Hepatic-specific delivery of let-7 miRNA mitigated liver fibrosis in both CCl4 and BDL mouse models. CONCLUSIONS: Let-7 is a crucial node in the signaling networks that govern liver fibrosis progression. Let-7 and/or its derivatives may be used as therapeutic agents for liver fibrosis.

Histology Shift in Esophageal Cancer Between Biopsies and Resections After Neoadjuvant Therapy: A Pilot Study.

Preoperative neoadjuvant therapy followed by resection is the mainstay treatment for locally advanced esophageal adenocarcinoma. We recently observed the histology shift from predominant esophageal adenocarcinoma in the biopsy to neuroendocrine neoplasm with or without adenocarcinoma in the post-treatment resection. The underlying mechanism of this finding is uncertain, and there is limited information in the literature. A total of 11 patients were identified: 10 patients received presurgical chemoradiation and 1 with chemotherapy. All biopsies were diagnosed with adenocarcinoma. When neuroendocrine immunomarkers were retrospectively performed on 5 biopsies, 2 showed focal positivity, although the classic neuroendocrine morphology was not readily appreciated. All resections contained neuroendocrine neoplasm, including 8 of well-differentiated type and 3 of neuroendocrine carcinomas. Two post-treatment esophagectomies consisted of neuroendocrine neoplasm only without residual adenocarcinoma. Upon follow-up, 8 patients died of the disease (median survival = 26 months), and 3 patients were alive after a median follow-up of 14 months. The overall median survival time was better than the reported esophageal neuroendocrine carcinoma (15 months). The 5-year observed survival rate was 11.3%, which was lower than the Surveillance, Epidemiology, and End Results 5-year survival rate of adenocarcinoma (21.8%). We reported a small series of esophageal adenocarcinoma that showed histology shift between biopsy and esophagectomy after neoadjuvant therapy. Our limited data suggest that prognosis of this group is different than the conventional adenocarcinoma. Awareness of this morphological change reminds pathologists to examine the biopsy specimens thoroughly, because recognition of neuroendocrine neoplasm, especially high-grade neuroendocrine component, might potentially affect pre- and post-surgical regimens.

Enhancement of sulfur metabolism and antioxidant machinery confers Bacillus sp. Jrh14-10-induced alkaline stress tolerance in plant.

Alkaline stress is a major environmental challenge that restricts plant growth and agricultural productivity worldwide. Plant growth-promoting rhizobacteria (PGPR) can be used to effectively enhance plant abiotic stress in an environment-friendly manner. However, PGPR that can enhance alkalinity tolerance are not well-studied and the mechanisms by which they exert beneficial effects remain elusive. In this study, we isolated Jrh14-10 from the rhizosphere soil of halophyte Halerpestes cymbalaria (Pursh) Green and found that it can produce indole-3-acetic acid (IAA) and siderophore. By 16S rRNA gene sequencing, it was classified as Bacillus licheniformis. Inoculation Arabidopsis seedlings with Jrh14-10 significantly increased the total fresh weight (by 148.1%), primary root elongation (by 1121.7%), and lateral root number (by 108.8%) under alkaline stress. RNA-Seq analysis showed that 3389 genes were up-regulated by inoculation under alkaline stress and they were associated with sulfur metabolism, photosynthetic system, and oxidative stress response. Significantly, the levels of Cys and GSH were increased by 144.3% and 48.7%, respectively, in the inoculation group compared to the control under alkaline stress. Furthermore, Jrh14-10 markedly enhanced the activities of antioxidant enzymes, resulting in lower levels of O2•-, H2O2, and MDA as well as higher levels of Fv/Fm in alkaline-treated seedlings. In summary, Jrh14-10 can improve alkaline stress resistance in seedlings which was accompanied by an increase in sulfur metabolism-mediated GSH synthesis and antioxidant enzyme activities. These results provide a mechanistic understanding of the interactions between a beneficial bacterial strain and plants under alkaline stress.

The Sympathetic Nervous System Promotes Hepatic Lymphangiogenesis, which Is Protective Against Liver Fibrosis.

Liver is the largest lymph-producing organ. In cirrhotic patients, lymph production significantly increases concomitant with lymphangiogenesis. The aim of this study was to determine the mechanism of lymphangiogenesis in liver and its implication in liver fibrosis. Liver biopsies from portal hypertensive patients with portal-sinusoidal vascular disease (n = 22) and liver cirrhosis (n = 5) were evaluated for lymphangiogenesis and compared with controls (n = 9 and n = 6, respectively). For mechanistic studies, rats with partial portal vein ligation (PPVL) and bile duct ligation (BDL) were used. A gene profile data set (GSE77627), including 14 histologically normal liver, 18 idiopathic noncirrhotic portal hypertension, and 22 cirrhotic patients, was analyzed. Lymphangiogenesis was significantly increased in livers from patients with portal-sinusoidal vascular disease, cirrhotic patients, as well as PPVL and BDL rats. Importantly, Schwann cells of sympathetic nerves highly expressed vascular endothelial growth factor-C in PPVL rats. Vascular endothelial growth factor-C neutralizing antibody or sympathetic denervation significantly decreased lymphangiogenesis in livers of PPVL and BDL rats, which resulted in progression of liver fibrosis. Liver specimens from cirrhotic patients showed a positive correlation between sympathetic nerve/Schwann cell-positive areas and lymphatic vessel numbers, which was supported by gene set analysis from patients with noncirrhotic portal hypertension and cirrhotic patients. Sympathetic nerves promote hepatic lymphangiogenesis in noncirrhotic and cirrhotic livers. Increased hepatic lymphangiogenesis can be protective against liver fibrosis.

Postinfantile Giant Cell Hepatitis in Native and Allograft Livers: A Multi-Institutional Clinicopathologic Study of 70 Cases.

Postinfantile giant cell hepatitis (PIGCH) is a rare hepatitis pattern in adults with variable etiologies and clinical outcomes. We conducted a multi-institutional retrospective study to define the clinicopathologic characteristics of patients with PIGCH. A total of 70 PIGCH cases were identified and reviewed for pathological features, including fibrosis, cholestasis, inflammation, steatosis, necrosis, and apoptosis, as well as the distribution of giant cells and the maximum number of giant cells per high-power field. Demographic and clinical data, including age, sex, laboratory results, etiologies, and follow-up results, were recorded. Among the 70 cases, 40% (28/70) were associated with autoimmune liver diseases, followed by 9 (13%) with unknown etiology, 8 (11%) with viral infection, 5 (7%) with medications, 5 with combined etiologies, and 4 (6%) with malignancies (mostly chronic lymphocytic leukemia). Notably, another 16% were de novo PIGCH in liver allografts, most of which occurred after a rejection event. During follow-up, 26 (37%) patients died of the disease and 44 (63%) were alive. Deceased patients were characterized by older age (mean age, 54.9 vs 45.5 years; P = .02), higher alkaline phosphatase level (mean value, 253.3U/L vs 166.3 U/L; P = .03), higher fibrosis stage (stage 3-4 vs stage 0-2, 57.7% vs 29.6%; P = .03), being more likely to have de novo PIGCH after transplantation (23.1% vs 11.4%; P = .04), and being less likely to have primary autoimmune liver disease etiology (26.9% vs 47.7%; P = .04). These results indicate that PIGCH is a rare pattern of liver injury associated with different etiologies and variable clinical outcomes. Autoimmune liver disease with PIGCH is associated with better survival, whereas de novo PIGCH in allografts is associated with poorer survival. Older age, higher alkaline phosphatase level, and advanced fibrosis are adverse prognostic factors.