Although the role of insulin-like growth factor-I receptor (IGF-IR) in promoting colorectal liver metastasis is known, the mechanism by which IGF-IR is upregulated in colorectal cancer (CRC) is not ...defined. In this study, we obtained evidence that mutant KRAS transcriptionally activates IGF-IR gene expression through Y-box-binding protein (YB)-1 upregulation via a novel MEK-Sp1-DNMT1-miR-137 pathway in CRC cells. The mechanistic link between the tumor suppressive miR-137 and the translational regulation of YB-1 is intriguing because epigenetic silencing of miR-137 represents an early event in colorectal carcinogenesis due to promoter hypermethylation. This proposed signaling axis was further verified by the immunohistochemical evaluations of liver metastases from a cohort of 46 KRAS mutant CRC patients, which showed a significant correlation in the expression levels among Sp1, miR-137, YB-1, and IGF-1R. Moreover, suppression of the expression of YB-1 and IGF-IR via genetic knockdown or the pharmacological inhibition of MEK hampers KRAS-driven colorectal liver metastasis in our animal model studies. From a translational perspective, the identification of this KRAS-driven pathway might provide a mechanistic rationale for the use of a MEK inhibitor as an adjuvant, in combination with standard of care, to prevent the recurrence of colorectal liver metastasis in KRAS mutant CRC patients after receiving liver resection, which warrants further investigation.
Analyzing EGFR mutations and detecting ALK gene fusion are indispensable when planning to treat pulmonary adenocarcinoma. Malignant pleural effusion (MPE) is a devastating complication of lung cancer ...and sometimes the only source for mutation analysis. The percentage of tumor cells in the pleural effusion may be low; therefore, mutant enrichment is required for a successful analysis. The EGFR mutation status in MPE was determined using three methods: (1) PCR sequencing of genomic DNA (direct sequencing), (2) mutant-enriched PCR sequencing of genomic DNA using peptide nucleic acid (PNA-sequencing), and (3) PCR sequencing of cDNA after reverse transcription for cellular RNA (RNA-sequencing). RT-PCR was also used to test cases for ALK gene fusion. PNA-sequencing and RNA-sequencing had similar analytical sensitivities (< 1%), which indicates similar enrichment capabilities. The clinical sensitivity in 133 cases when detecting the common EGFR exon 19 and exon 21 mutations was 56.4% (75/133) for direct sequencing, 63.2% (84/133) for PNA-sequencing, and 65.4% (87/133) for RNA-sequencing. RT-PCR and sequencing showed 5 cases (3.8%) with ALK gene fusion. All had wild-type EGFR. For EGFR analysis of MPE, RNA-sequencing is at least as sensitive as PNA-sequencing but not limited to specific mutations. Detecting ALK fusion can be incorporated in the same RNA workflow. Therefore, RNA is a better source for comprehensive molecular diagnoses in MPE.
The short isoform of human TIAM2 has been shown to promote proliferation and invasion in various cancer cells. However, the roles of TIAM2S in immune cells in relation to tumor development have not ...been investigated. To characterize the effects of TIAM2S, we generated TIAM2S-overexpressing mouse lines and found that aged TIAM2S-transgenic (TIAM2S-TG) developed significantly higher occurrence of lymphocytic infiltration and tumorigenesis in various organs, including colon. In addition, TIAM2S-TG is more sensitized to AOM-induced colon tumor development, suggesting a priming effect toward tumorigenesis. In the light of our recent findings that TIAM2S functions as a novel regulator of cellular serotonin level, we found that serotonin, in addition to Cox2, is a unique inflammation marker presented in the colonic lesion sites in the aged TG animals. Furthermore, our results demonstrated that ectopic TIAM2S altered immunity via the expansion of T lymphocytes; this was especially pronounced in CD8+ T cells in combination with CXCL13/BCA-1 pro-inflammatory chemokine in the serum of TIAM2S-TG mice. Consequently, T lymphocytes and B cells were recruited to the lesion sites and stimulated IL-23/IL17A expression to form the tertiary lymphoid organs. Collectively, our research suggests that TIAM2S provokes a pro-inflammatory immune microenvironment permissive to colorectal tumorigenesis through the serotonin-induced immunomodulatory effects.
The growing demand for bioelectronics has generated widespread interest in implantable energy storage. These implantable bioelectronic devices, powered by a complementary battery/capacitor system, ...have faced difficulty in miniaturization without compromising their functionality. This paper reports on the development of a promising high‐rate cathode material for implantable power sources based on Li‐exchanged Na1.5VOPO4F0.5 anchored on reduced graphene oxide (LNVOPF‐rGO). LNVOPF is unique in that it offers dual charge storage mechanisms, which enable it to exhibit mixed battery/capacitor electrochemical behavior. In this work, electrochemical Li‐ion exchange of the LNVOPF structure is characterized by operando X‐ray diffraction. Through designed nanostructuring, the charge storage kinetics of LNVOPF are improved, as reflected in the stored capacity of 107 mAh g−1 at 20C. A practical full cell device composed of LNVOPF and T‐Nb2O5, which serves as a pseudocapacitive anode, is fabricated to demonstrate not only high energy/power density storage (100 Wh kg−1 at 4000 W kg−1) but also reliable pulse capability and biocompatibility, a desirable combination for applications in biostimulating devices. This work underscores the potential of miniaturizing biomedical devices by replacing a conventional battery/capacitor couple with a single power source.
An implantable power source based on Li‐exchanged Na1.5VOPO4F0.5 anchored on reduced graphene oxide and Nb2O5 is developed to demonstrate not only high energy/power density storage (100 Wh kg−1 at 4000 W kg−1) but also reliable pulse capability and biocompatibility, a desirable combination for applications in biostimulating devices.
Abstract
Circulating cell-free DNA (cfDNA) analysis is an important tool for cancer monitoring. The patient-specific mutations identified in colorectal cancer (CRC) tissues are usually used to design ...the cfDNA analysis. Despite high specificity in predicting relapse, the sensitivity in most studies is around 40–50%. To improve this weakness, we designed a cfDNA panel according to the CRC genomic landscape and recurrent-specific mutations. The pathological variants in cfDNA samples from 60 CRC patients were studied by a next-generation sequencing (NGS) method incorporating the dual molecular barcode. Interestingly, patients in the disease positive group had a significantly higher cfDNA concentration than those in the disease negative group. Based on receiver operating characteristic analysis, the cfDNA concentration of 7 ng/mL was selected into the analytical workflow. The sensitivity in determining the disease status was 72.4%, which represented a considerable improvement on prior studies, and the specificity remained high at 80.6%. Compared to standard imaging and laboratory studies, earlier detection of residual disease and clinical benefits were shown on two cases by this cfDNA assay. We conclude this integrative framework of cfDNA analytical pipeline with a satisfactory sensitivity and specificity could be used in postoperative CRC surveillance.
Amiodarone is a commonly used antiarrhythmic agent but exhibits potential pulmonary toxicity. In this case series, we describe the clinical, radiographic, and histologic manifestations of three ...patients who developed interstitial lung disease (ILD) following amiodarone treatment for variable lengths of time with different dosages. The presentations on computed tomographic images and in pulmonary pathology differed among the three patients. All three had immediate discontinuation of amiodarone and received treatment with systemic corticosteroids. One patient eventually died from ventilator‐associated pneumonia after an initial improvement. The other two patients recovered well but later experienced ILD recurrence following brief re‐exposure to amiodarone. Through this case series, we aim to demonstrate the variable features of amiodarone‐related ILD, and highlight the importance of timely amiodarone cessation and avoiding re‐exposure to prevent the progression and recurrence of ILD.
Amiodarone‐related interstitial lung disease may exhibit variable clinical, radiographic, and histologic presentations. Prompt discontinuation and avoiding re‐exposure of the agent is important to prevent the progression and recurrence of the interstitial lung disease.
Systemic lupus erythematosus (SLE) is an autoimmune disease with various clinical presentations. Mucin deposition is a characteristic finding in skin lesions, but it is rare in other organs. We ...present a case with erythematous patches from the terminal ileum to the anus in an SLE patient. Diffuse colitis was diagnosed clinically. However, in addition to inflammatory cell infiltration, there was abundant mucinous material deposition in the submucosa. The mucinous material was positive for Alcian blue staining (pH 2.5) and was sensitive to hyaluronidase digestion. These findings are similar to those of cutaneous mucinosis in SLE patients. This is thought to be the first case of gastrointestinal tract mucinosis in SLE reported in the literature.
Colorectal adenomas can show focal squamous differentiation or squamoid morules. We describe histologic findings of squamoid morules in the pseudoinvasive foci of colorectal polyps mimicking invasive ...carcinoma. Five colonic polyps with squamoid morules in the pseudoinvasive foci were collected. Histologic review and immunostains for cytokeratin 5/6, p63, synaptophysin, and chromogranin were performed on cases with squamoid morules. Forty-seven consecutive colorectal polyps with pseudoinvasion, none of which showed squamoid morules by histology review, and their clinicopathologic features were compared with the cases containing squamoid morules. Cases with squamoid morules more frequently occurred in younger patients (P=.047) and were located in right colon (P=.027) than those without squamoid morules. Diagnosis of the polyps included tubular/tubulovillous adenoma with low-grade (with squamoid morules, n=3; versus without squamoid morules, n=29) or high-grade dysplasia (n=2 versus n=15) and sessile serrated adenoma (none versus n=3). Squamoid morules formed nodules protruding into the lumen of glandular structures or partially replaced adenomatous glands without forming a discrete nodule. They also presented as solid nests showing a well-formed morular structure around the bottom of adenomatous glands or myxoinflammatory stroma. Importantly, squamoid morules often formed a pseudocribriform or solid nest sitting in the stroma of pseudoinvasive foci. All cases (n=4) showed cytokeratin 5/6 positivity and p63 negativity in squamoid morules. Three and 1 of 4 cases showed focal positivity for synaptophysin and chromogranin, respectively, in squamoid morules. Squamoid morules in colonic adenomatous polyps can mimic invasive carcinoma when present in the pseudoinvasive foci. Pathologists should be aware of their presence.
•Squamoid morules can be seen in colonic adenomas.•Morules may present as pseudocribriform or solid nests.•Morules in pseudoinvasive foci of colonic adenoma can mimic invasive carcinoma.•Pathologists should be aware of their presence to avoid overdiagnosis of carcinoma.
Telisotuzumab vedotin is a
MET
-targeting antibody–drug conjugate that has demonstrated a good treatment response in patients with
EGFR
wild-type MET-overexpressing non-squamous non-small cell lung ...cancer. However, patients have been reported to acquire resistance to this drug, and the subsequent therapy has not been standardized. Here, we present a case of a 56-year-old woman diagnosed with
KIF5B-MET
fusion-positive non-small cell lung cancer who had a durable response to capmatinib after acquired resistance to telisotuzumab vedotin.
Tracheopathia osteochondroplastica (TO) is a rare and benign condition. It typically manifests as multiple osteocartilaginous nodules in the submucosa of the central airway. TO‐related clinical ...symptoms and physical signs are nonspecific. The bronchoscopic examination is helpful in establishing the diagnosis. Treatment for TO is mostly conservative and symptom‐oriented. The prognosis of TO is generally good, although cases of associated airway stenosis have been reported. In this case report, we describe the clinical, imaging, and histological features, and videoed bronchoscopic findings, of a middle‐aged male patient with incidentally diagnosed TO.
Tracheopathia osteochondroplastica (TO) is a rare and benign condition of the central airway, but with a daunting appearance. In this case report, we describe the clinical, imaging, and histological features, and videoed bronchoscopic findings, of a middle‐aged male patient with incidentally diagnosed TO.
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