Radiation therapy induces an abscopal effect and upregulates programmed death-ligand 1 expression in a patient with non-small cell lung cancer

Radiation therapy (RT) activates the antigen presentation of dendritic cells and priming of cancer-specific cytotoxic CD8+ T cells, occasionally resulting in a systemic immune response to the tumor outside of the treatment field. The phenomenon of tumor regression at the site distant from irradiated fields is known as the abscopal effect. Several case reports have indicated a potential role of RT in overcoming primary and acquired resistance against immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) and melanoma patients. We herein report an NSCLC patient who developed acquired resistance to an RT-induced abscopal effect and subsequently experienced reactivation of the systemic antitumor immune response by pembrolizumab, an antiprogrammed death 1 antibody. In this case, RT not only induced an abscopal effect but also upregulated the programmed death-ligand 1 expression outside of the irradiated field when the patient developed resistance to the abscopal effect. This case can facilitate our understanding of the mechanism underlying the RT-induced systemic immune response against cancer cells and adaptive resistance mechanism of cancer cells from immune surveillance. These findings highlight the promising results of current clinical trials combining RT and immune checkpoint inhibitors. Ongoing clinical trials will further establish evidence supporting combination therapy with RT and immune checkpoint inhibitors

Antitumor studies. Part 1: Design, synthesis, antitumor activity, and AutoDock study of 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides as a new class of antitumor agents

Novel 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides were prepared as a new class of antitumor agents and showed significant antitumor activities against NCI-H 460, HCT 116, A 431, CCRF-HSB-2, and KB cell lines. In vivo investigation, 2-deoxo-10-methyl-2-phenyl-5-deazaflavin exhibited the effective antitumor activity against A 431 human adenocarcinoma cells transplanted subcutaneously into nude mouse. Furthermore, AutoDock study has been done by binding of the flavin analogs into PTK pp60(c-src), where a good correlation between their IC50 and AutoDock binding free energy was exhibited. In particular, 2-deoxo-2-phenylflavin-5-oxides exhibited the highest potential binding affinity within the binding pocket of PTK

Effect of human airway trypsin-like protease on intracellular free Ca2+ concentration in human bronchial epithelial cells

It has been shown that human airway trypsin-like protease (HAT) is localized in human bronchial epithelial cells (HBEC), and trypsin activates protease-activated receptor-2(PAR-2). Activation of PAR-2 activates G-protein followed by an increase of intracellular free Ca2+, [Ca2+]in. This study was undertaken to clarify whether HAT can activate PAR-2in HBEC or not. RT-PCR showed that HAT mRNA is expressed in HBEC, and PAR-2 mRNA is the most strongly expressed of the known PARs in HBEC. Both PAR-2 agonist peptide (PAR-2 AP) and HAT increased [Ca2+]in in HBEC in a biphasic fashion a prompt, sharp increase (peak I) and a sustained low plateau (peak II). PAR-2 AP over 100-200 μM and HAT over 200-300 mU/ml (0.08-0.12 μM) induced both peak I and II, and PAR-2 AP below100 μM and HAT below 200 mU/ml induced only peak II. Both PAR-2 AP-induced and　HAT-induced peak I were induced by Ca2+ mobilization from intracellular stores, because　they appeared even in Ca2+-free medium. Both PAR-2 AP-induced and HAT-induced peak II were induced by an influx of extracellular Ca2+, because they were abolished in Ca2+-free medium. The Ca2+ response to HAT was desensitized by exposure of HBEC to PAR-2 AP. These results indicate that HBEC have a functional PAR-2, and HAT regulates cellular functions of HBEC via activation of PAR-2

PHOSPHATEMIC INDEX EVALUATES PHOSPHORUS LOAD

Objective: Dietary phosphorus (P) restriction is crucial to treat hyperphosphatemia and reduce cardiovascular disease risk and mortality in patients with chronic kidney disease (CKD) and the wider population. Various methods for dietary P restriction exist, but the bioavailability of P in food should also be considered when making appropriate food choices to maintain patients’ quality of life. Here, we propose the ‘‘Phosphatemic Index’’ (PI) as a novel tool for evaluating dietary P load based on P bioavailability; we also evaluated the effect of continuous intake of different PI foods in mixed meals on serum intact fibroblast growth factor 23 concentration. Design and Methods: A 2-stage crossover study was conducted: Study 1: 20 healthy participants consumed 10 different foods containing 200 mg of P, and the PI was calculated from the area under the curve of a time versus serum P concentration curve; Study 2: 10 healthy participants consumed 4 different test meals (low, medium, or high PI meals or a control) over a 5-day period. Results: Study 1 showed milk and dairy products had high PI values, pork and ham had medium PI values, and soy and tofu had low PI values. In Study 2, ingestion of high PI test meals showed higher fasting serum intact fibroblast growth factor 23 levels and lower serum 1,25-dihydroxyvitamin D levels compared with ingestion of low PI test meals. Conclusion: These findings suggest that the PI can usefully evaluate the dietary P load of various foods and may help to make appropriate food choices for dietary P restriction in CKD patients

Analysis of DOC and Ram for NSCLC

Background: Current clinical trials demonstrated that combination regimens comprising chemotherapy and immunotherapy lead to better patient outcomes compared to chemotherapy alone as the first line of treatment for non-small cell lung cancer (NSCLC). In addition, the combination therapy of docetaxel (Doc) and ramucirumab (Ram) was considered one of the standard treatments for advanced or relapsed NSCLC patients. However, little is known about the therapeutic responders of this combination therapy among previously treated NSCLC patients. In the present study, we aimed to identify predictive factors for therapeutic response, including programmed death-ligand 1 (PD-L1) expression in tumors, for Doc treatment in combination with Ram. Methods: We retrospectively analyzed a total of 135 advanced or relapsed NSCLC patients who were refractory to platinum-based chemotherapy at eleven institutions in Japan between July 2016 and November 2018. Results: Our observations showed that PD-L1 expression in tumors is not associated with the efficacy of combined therapy of Doc and Ram in previously treated NSCLC patients. Analysis of the patient clinical profiles indicated that prior treatment with immune checkpoint inhibitors (ICIs) is a reliable predictor for the good progression-free survival (PFS) to this combination therapy (P=0.041). Conclusions: Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients

Rotational level structure of sodium isotopes inside the "island of inversion"

The neutron-rich nuclei 33,34,35Na were studied via in-beam γ-ray spectroscopy following nucleon removal reactions from a 36Mg secondary beam at ~220 MeV/u. Excited states of 34,35Na are reported for the first time. A third transition was observed for 33Na in addition to the known 7/2+ 1 → 5/2+ 1 → 3/2+ g.s. cascade and is suggested to be the 9/2+ 1 → 7/2+ 1 transition. Similarly, a 7/2+ 1 → 5/2+ 1 → 3/2+ g.s. cascade is proposed for the decay pattern observed for 35Na. The transition energy ratios are close to expectation values for K = 3/2 rotational bands in the strong coupling limit. Comparisons to large-scale shell model calculations in the sd-p f model space support the spin-parity assignments. © The Author(s) 2014.published_or_final_versio

Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population

<p>Abstract</p> <p>Background</p> <p>A reliable and inexpensive noninvasive marker of hepatic fibrosis is required in patients with nonalcoholic fatty liver disease (NAFLD). FIB4 index (based on age, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels, and platelet counts) is expected to be useful for evaluating hepatic fibrosis. We validated the performance of FIB4 index in a Japanese cohort with NAFLD.</p> <p>Methods</p> <p>The areas under the receiver operating characteristic curves (AUROC) for FIB4 and six other markers were compared, based on data from 576 biopsy-proven NAFLD patients. Advanced fibrosis was defined as stage 3-4 fibrosis. FIB4 index was assessed as: age (yr) × AST (IU/L)/(platelet count (10⁹/L) × √ALT (IU/L))</p> <p>Results</p> <p>Advanced fibrosis was found in 64 (11%) patients. The AUROC for FIB4 index was superior to those for the other scoring systems for differentiating between advanced and mild fibrosis. Only 6 of 308 patients with a FIB4 index below the proposed low cut-off point (< 1.45) were under-staged, giving a high negative predictive value of 98%. Twenty-eight of 59 patients with a FIB4 index above the high cut-off point (> 3.25) were over-staged, giving a low positive predictive value of 53%. Using these cutoffs, 91% of the 395 patients with FIB-4 values outside 1.45-3.25 would be correctly classified. Implementation of the FIB4 index in the Japanese population would avoid 58% of liver biopsies.</p> <p>Conclusion</p> <p>The FIB4 index was superior to other tested noninvasive markers of fibrosis in Japanese patients with NAFLD, with a high negative predictive value for excluding advanced fibrosis. The small number of cases of advanced fibrosis in this cohort meant that this study had limited power for validating the high cut-off point.</p