We report a method for detecting ligand-protein interactions occurring within cells using short peptide reactive tags appended to ligands and proteins, along with a split NanoLuc luciferase. This ...method can be applied to estimate the binding affinities of ligand-protein interactions and to detect the interactions of proteins with unstable synthetic ligands inside the cells.
Intracellular interactions of synthetic ligands with proteins were detected by interaction-dependent native chemical ligation and enzyme reconstitution (IDNCL-ER) using two reactive peptide tags and a split luciferase.
Gastrointestinal stromal tumors (GISTs) are the most frequent malignant mesenchymal tumors in the gastrointestinal tract. The clinical incidence of GISTs is estimated 10/million/year; however, the ...true incidence is complicated by frequent findings of tiny GISTs, of which the natural history is unknown. The initial work-up with endoscopy and endoscopic ultrasonography plays important roles in the differential diagnosis of GISTs. Surgery is the only modality for the permanent cure of localized GISTs. In terms of safety and prognostic outcomes, laparoscopy is similar to laparotomy for GIST treatment, including tumors larger than 5 cm. GIST progression is driven by mutations in KIT or PDGFRA or by other rare gene alterations, all of which are mutually exclusive. Tyrosine kinase inhibitors (TKIs) are the standard therapy for metastatic/recurrent GISTs. Molecular alterations are the most reliable biomarkers for TKIs and for other drugs, such as NTRK inhibitors. The pathological and genetic diagnosis prior to treatment has been challenging; however, a newly developed endoscopic device may be useful for diagnosis. In the era of precision medicine, cancer genome profiling by targeted gene panel analysis may enable potential targeted therapy even for GISTs without KIT or PDGFRA mutations.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The association between the tumor microenvironment (TME) and treatment response or survival has been a recent focus in several types of cancer. However, most study materials are resected specimens ...that were completely modified by prior chemotherapy; therefore, the unmodified host immune condition has not yet been clarified. The aim of the present study was to evaluate the relationship between TME assessed in pre–therapeutic biopsy samples and chemoresistance in esophageal cancer (EC). A total of 86 endoscopic biopsy samples from EC patients who received neoadjuvant chemotherapy (NAC) prior to surgery were evaluated for the number of intratumoral CD4+ lymphocytes (with/without Foxp3 expression), CD8+ lymphocytes (with/without PD‐1 expression), monocytes (CD14+) and macrophages (CD86+, CD163+ and CD206+) by multiplex immunohistochemistry (IHC). The number of tumor‐infiltrating CD206+ macrophages I significantly correlated with cT, cM, cStage and neutrophil/lymphocyte ratio (NLR), whereas the number of lymphocytes (including expression of Foxp3 and PD‐1) was not associated with clinico‐pathological features. The high infiltration of CD163+ or CD206+ macrophages was significantly associated with poor pathological response to NAC (P = 0.0057 and 0.0196, respectively). Expression of arginase‐1 in CD163+ macrophages tended to be higher in non–responders (29.4% vs 18.2%, P = 0.17). In addition, patients with high infiltration of M2 macrophages exhibited unfavorable overall survival compared to those without high infiltration of M2 macrophages (5‐year overall survival 57.2% vs 71.0%, P = 0.0498). Thus, a comprehensive analysis of TME using multiplex IHC revealed that M2 macrophage infiltration would be useful in predicting the response to NAC and long‐term survival in EC patients.
The present study confirmed that pre–therapeutic M2 macrophage infiltration would be a useful biomarker in predicting the response to NAC and unfavorable survival among a variety of immune cells in EC patients. Our results support the possibility of using immunotherapy, targeting M2 macrophages, alongside conventional neoadjuvant chemotherapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Pulmonary pneumatocele that forms immediately after pulmonary resection is extremely rare. This report describes a case of pneumatocele that formed rapidly in the left lower lobe immediately after ...left upper lobectomy in a patient with lung cancer and emphysema. Massive and persistent air leakage through a chest tube was noted immediately after chest closure. Therefore, the chest was reopened, and the cyst wall was incised. The air leakage point was cauterized and covered with a polyglycolic acid sheet and fibrin glue. Herein, we report a rare case of newly developed pneumatocele immediately after lobectomy.
OBJECTIVE:The aim of this study was to evaluate primary tumor (PT) and lymph node (LN) responses to neoadjuvant chemotherapy (NACT) for predicting long-term survival in patients with metastatic ...esophageal cancer (EC).
BACKGROUND:In evaluating NACT responses in patients with EC, imaging modalities typically target the PT in the esophagus, which is unmeasurable. Targeting measurable organs, like positive LNs, might provide more accurate assessments.
METHODS:We enrolled 251 patients with EC and clinically positive LNs that underwent curative resections, after triplet NACT. The percent reduction of PT area was measured with bidimensional computed tomography. The LN response was defined as the percent reduction of the sum of the short diameters in all positive LNs.
RESULTS:NACT reduced PTs and LNs by (median, range) 58.0% (38.1–94.9) and 34.5% (46.2–68.2), respectively. Based on the receiver-operating characteristic analyses for predicting a histological response and a 10% stepwise cutoff analyses of recurrence-free survival (RFS), responder/nonresponder cutoff values were ≥60% for PT area reductions and ≥30% for LN size reductions. 39.6% of patients showed discordant PT and LN responses. Compared with PT-responders, LN-responders had significantly less advanced pN (P < 0.0001) and pM (P = 0.015) in addition to less advanced pT (P < 0.0001) and better histological responses (P < 0.0001), and closer correlations to lymphatic, distant metastases and dissemination. A multivariate analysis of RFS identified 2 independent prognostic factorsthe LN response hazard ratio (HR) = 2.51, 95% confidence interval (CI) = 1.63–3.95, P < 0.0001 and the pN (HR = 2.72, 95% CI = 1.44–5.64, P = 0.0016), but not the PT response.
CONCLUSIONS:The LN response to NACT predicted long-term survival more precisely than the PT response in patients with metastatic EC.
A split intein-based method has been developed to detect peptide: N -glycanase (PNGase) activity in live cells. PNGase cleaves the linkage between N,N ′-diacetylchitobiose and the Asn side-chain of ...N-intein peptides and the products react rapidly with C-intein by protein trans-splicing to generate an active luciferase.
A high maximum frequency of oscillation (f max ) of 910 GHz was achieved at InAlAs/InGaAs highelectron mobility transistors (HEMTs) with a relatively long gate length (L G ) of 75 nm by adopting an ...asymmetric gate recess and a double-side-doped structure. The f max improved significantly by extending the drain-side gate recess length (L RD ) to 250 nm; meanwhile, the source-side gate-recess length (L RS ) was kept to 70 nm. The improvement in fmax was due to a decrease in the drain output conductance (g d ) and drain-to-gate capacitance (CGD) after the extension of L RD . gd was further suppressedby applying a double-side-doped structure to the InP-based HEMTs. A reduction in g d resulted in a drastic improvement in f max even though L G was a longer value.
The mechanism of liquefaction and the factors that cause liquefaction behavior have previously been examined and evaluated, both analytically and experimentally; construction including liquefaction ...countermeasures is being implemented, based on these findings. This study presents a theoretical visualization of the mechanism of liquefaction generation and evaluates the behavior of particles in the ground. Specifically, an MPSM-DEM coupled CAE system (CAES) is employed to view the events beneath the ground, modeled three-dimensionally when an external acceleration is applied to simulate seismic waves and reveals the behavior below the surface. The numerical simulation of the liquefaction phenomenon, as represented by an MPSM-DEM coupled CAES system, clearly showed the mechanism of liquefaction generation and contributed to the design and accountability of more economical and sustainable liquefaction countermeasures, regardless of the field of specialization.
Background
Microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) are candidate predictors for the response to immune checkpoint inhibitors, and may predict chemotherapy sensitivity. ...We investigated the simultaneous expression of mutL homolog 1 (MLH1), a mismatch repair gene, and PD-L1 in gastric cancers.
Methods
We examined MLH1 and PD-L1 expression in surgical specimens from 285 gastric cancer patients treated with or without preoperative chemotherapy, and assessed the relation between expression results and both histological response and recurrence-free survival (RFS).
Results
Of 285 patients, 28 (9.8%) and 70 (24.6%) exhibited negative MLH1 and high PD-L1 expression, respectively. Most MLH1-negative tumors (85.7%) showed high MSI, and these tumors exhibited high PD-L1 expression more frequently than MLH1-positive tumors (57.1% vs. 21.0%,
P
< 0.001). MLH1-negative patients were significantly less likely to respond to preoperative chemotherapy than MLH1-positive patients (16.7% vs. 61.2%,
P
= 0.005), whereas there was no significant difference between high- and low-PD-L1 expression patients (55.9% vs. 56.6%,
P
= 0.95). RFS in patients without preoperative chemotherapy was significantly longer in the MLH1-negative group than in the MLH1-positive group (HR 0.30; 95% CI 0.09–0.95;
P
= 0.030), whereas in patients with preoperative chemotherapy there was no significant difference in RFS between the two groups (HR 0.70; 95% CI 0.30–1.63;
P
= 0.41). PD-L1 expression was not associated with RFS in patients with or without chemotherapy.
Conclusions
Loss of MLH1 was associated with chemoresistance and did not prolong survival following neoadjuvant chemotherapy. The strong association between MLH1 and MSI status suggests that immune checkpoint inhibitors may be preferable to conventional chemotherapy for MLH1-negative gastric cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
OBJECTIVES:To investigate the residual pattern of esophageal cancer in the esophageal wall after neoadjuvant chemotherapy (NAC) and its clinical significance.
BACKGROUND:NAC is a standard treatment ...for locally advanced esophageal cancer; however, residual tumor patterns in resected specimens after NAC and their clinico-pathological characteristics remain unknown.
METHODS:One hundred twenty consecutive patients with cT3 or deeper esophageal cancer underwent curative esophagectomy after NAC and achieved grade 2 histological responses between 2000 and 2016. Hematoxylin-eosin staining of residual tumor sections revealed 4 remnant categoriesType 1shallow, Type 2central, Type 3deep, and Type 4diffuse. We examined associations between these Types and clinico-pathological factors, including prognosis.
RESULTS:Forty-five (38%) specimens had no residual tumor cells in the mucosal layer. The adventitia layer displayed the lowest residual tumor cell frequency (18%) among all layers. Types 1, 2, 3, and 4 residual tumor patterns were found in 49 (41%), 33 (28%), 9 (8%), and 29 (24%) patients, respectively. Type 4 showed the maximum standard uptake value after NAC; Types 3 and 4 had higher ratios of venous invasion than Type 1 or 2. Patients with Type 3 or 4 more frequently developed pleural dissemination or distant metastasis than patients with Type 1 or 2. Survival was similar among the 4 Types.
CONCLUSIONS:After NAC for locally advanced esophageal cancer, the shallow residual tumor pattern was most common, but approximately 40% of specimens showed no tumor cells in the mucosal layer. Deep and diffuse remnant patterns were associated with high risks of pleural dissemination and distant metastasis.
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