Prognostic Impact of Stromal Profiles Educated by Gastric Cancer.

BACKGROUND: Cancer-associated fibroblasts exhibit diversity and have several subtypes. The underlying relationship between the diversity of cancer-associated fibroblasts and their effect on gastric cancer progression remains unclear. In this study, mesenchymal stem cells were differentiated into cancer-associated fibroblasts with gastric cancer cell lines; clinical specimens were used to further investigate the impact of cancer-associated fibroblast diversity on cancer progression. METHODS: Nine gastric cancer cell lines (NUGC3, NUGC4, MKN7, MKN45, MKN74, FU97, OCUM1, NCI-N87, and KATOIII) were used to induce mesenchymal stem cell differentiation into cancer-associated fibroblasts. The cancer-associated fibroblasts were classified based on ACTA2 and PDPN expression. Cell function analysis was used to examine the impact of cancer-associated fibroblast subtypes on cancer cell phenotype. Tissue samples from 97gastric patients who underwent gastrectomy were used to examine the clinical significance of each subtype classified according to cancer-associated fibroblast expression. RESULTS: Co-culture of mesenchymal stem cells with nine gastric cancer cell lines revealed different subtypes of ACTA2 and PDPN expression in differentiated cancer-associated fibroblasts. Cancer-associated fibroblast subtypes with high ACTA2 plus PDPN expression levels significantly increased gastric cancer cell migration, invasion, and proliferation. The cancer-associated fibroblast subtype with ACTA2 plus PDPN expression was an independent prognostic factor along with lymph node metastasis for patients who had gastric cancer and were undergoing surgery. CONCLUSIONS: Cancer-associated fibroblasts are educated by gastric cancer cells during the development of cancer-associated fibroblast diversity. Differentiated cancer-associated fibroblasts with distinct expression patterns could affect gastric cancer progression and enable prognostic stratification for gastric cancer.

Design, Synthesis, and Evaluation of Trivalent PROTACs Having a Functionalization Site with Controlled Orientation.

Trivalent PROTACs having a functionalization site with controlled orientation were designed, synthesized, and evaluated. Based on the X-ray structure of BRD protein degrader MZ1 (1) in complex with human VHL and BRD4BD2, we expected that the 1,2-disubstituted ethyl group near the JQ-1 moiety in MZ1 (1) could be replaced by a planar benzene tether as a platform for further functionalization. To test this hypothesis, we first designed six divalent MZ1 derivatives, 2a-c and 3a-c, by combining three variations of substitution patterns on the benzene ring (1,2-, 1,3-, and 1,4-substitution) and two variations in the number of ethylene glycol units (2 or 1). We then tested the synthesized compounds for the BRD4 degradation activity of each. As expected, we found that 1,2D-EG2-MZ1 (2a), an MZ1 derivative with 1,2-disubstituted benzene possessing two ethylene glycol units, had an activity profile similar to that of MZ1 (1). Based on the structure of 2a, we then synthesized and evaluated four isomeric trivalent MZ1 derivatives, 15a-15d, having a tert-butyl ester unit on the benzene ring as a handle for further functionalization. Among the four isomers, 1,2,5T-EG2-MZ1 (15c) retained a level of BRD4 depletion activity similar to that of 2a without inducing a measurable Hook effect, and its BRD4 depletion kinetics was the same as that of MZ1 (1). Other isomers were also shown to retain BRD4 depletion activity. Thus, the trivalent PROTACs we synthesized here may serve as efficient platforms for further applications.

Aboveground biomass increments over 26 years (1993-2019) in an old-growth cool-temperate forest in northern Japan.

Assessing long-term changes in the biomass of old-growth forests with consideration of climate effects is essential for understanding forest ecosystem functions under a changing climate. Long-term biomass changes are the result of accumulated short-term changes, which can be affected by endogenous processes such as gap filling in small-scale canopy openings. Here, we used 26 years (1993-2019) of repeated tree census data in an old-growth, cool-temperate, mixed deciduous forest that contains three topographic units (riparian, denuded slope, and terrace) in northern Japan to document decadal changes in aboveground biomass (AGB) and their processes in relation to endogenous processes and climatic factors. AGB increased steadily over the 26 years in all topographic units, but different tree species contributed to the increase among the topographic units. AGB gain within each topographic unit exceeded AGB loss via tree mortality in most of the measurement periods despite substantial temporal variation in AGB loss. At the local scale, variations in AGB gain were partially explained by compensating growth of trees around canopy gaps. Climate affected the local-scale AGB gain: the gain was larger in the measurement periods with higher mean air temperature during the current summer but smaller in those with higher mean air temperature during the previous autumn, synchronously in all topographic units. The influences of decadal summer and autumn warming on AGB growth appeared to be counteracting, suggesting that the observed steady AGB increase in KRRF is not fully explained by the warming. Future studies should consider global and regional environmental factors such as elevated CO2 concentrations and nitrogen deposition, and include cool-temperate forests with a broader temperature range to improve our understanding on biomass accumulation in this type of forests under climate change.

Prediction of return of spontaneous circulation during cardiopulmonary resuscitation by pulse-wave cerebral tissue oxygen saturation: a retrospective observational study.

BACKGROUND: It is difficult to predict the return of spontaneous circulation (ROSC) during cardiopulmonary resuscitation (CPR). Cerebral tissue oxygen saturation during CPR, as measured by near-infrared spectroscopy (NIRS), is anticipated to predict ROSC. General markers of cerebral tissue oxygen saturation, such as the tissue oxygenation index (TOI), mainly reflect venous oxygenation, whereas pulse-wave cerebral tissue oxygen saturation (SnO2), which represents hemoglobin oxygenation in the pulse wave within the cerebral tissue, is an index of arterial and venous oxygenation. Thus, SnO2 may reflect arterial oxygenation to a greater degree than does TOI. Therefore, we conducted this study to verify our hypothesis that SnO2 measured during CPR can predict ROSC. METHODS: Cardiac arrest patients who presented at the Emergency Department of Yamagata University Hospital in Japan were included in this retrospective, observational study. SnO2 and TOI were simultaneously measured at the patient's forehead using an NIRS tissue oxygenation monitor (NIRO 200-NX; Hamamatsu Photonics, Japan). We recorded the initial, mean, and maximum values during CPR. We plotted receiver operating characteristic curves and calculated the area under the curve (AUC) to predict ROSC. RESULTS: Forty-two patients were included. SnO2 was significantly greater in the ROSC group than in the non-ROSC group in terms of the initial (37.5% vs 24.2%, p = 0.015), mean (44.6% vs 10.8%, p < 0.001), and maximum (79.7% vs 58.4%, p < 0.001) values. Although the initial TOI was not significantly different between the two groups, the mean (45.1% vs 36.8%, p = 0.018) and maximum (71.0% vs 46.3%, p = 0.001) TOIs were greater in the ROSC group than in the non-ROSC group. The AUC was 0.822 for the mean SnO2 (95% confidence interval [CI]: 0.672-0.973; cut-off: 41.8%), 0.821 for the maximum SnO2 (95% CI: 0.682-0.960; cut-off: 70.8%), and 0.809 for the maximum TOI (95% CI: 0.667-0.951; cut-off: 49.3%). CONCLUSION: SnO2 values measured during CPR, including immediately after arrival at the emergency department, were higher in the ROSC group than in the non-ROSC group.

[Long-Term Prognosis of Patients with Biliary Tract Cancer Undergoing Pancreaticoduodenectomy].

We divided the patients with biliary tract cancer who underwent pancreaticoduodenectomy(PD)at our hospital into the 5-year recurrence-free and recurrence groups and investigated the prognostic factors. Additionally, we investigated the efficacy of adjuvant chemotherapy in patients with and without lymph node (LN) metastasis. There was no significant difference between the two groups for patient characteristics and perioperative factors. However, patients with LN metastasis tended to have a higher recurrence rate. For patients without LN metastasis, the median overall survival(OS)was not significantly different between the patients who received and did not receive adjuvant chemotherapy. For patients with LN metastasis, although it was not significantly different(p=0.234), the OS of patients who received adjuvant therapy was more than 3 times than that of patients who did not(58.6 months and 18.4 months, respectively). For patients with biliary tract cancer who underwent PD, positive LN metastasis may be a poor prognostic factor, and adjuvant therapy may possibly improve prognosis.

A Local Oscillator Phase Compensation Technique for Ultra-Wideband Stepped-Frequency Continuous Wave Radar Based on a Low-Cost Software-Defined Radio.

The paper discusses a way to configure a stepped-frequency continuous wave (SFCW) radar using a low-cost software-defined radio (SDR). The most of high-end SDRs offer multiple transmitter (TX) and receiver (RX) channels, one of which can be used as the reference channel for compensating the initial phases of TX and RX local oscillator (LO) signals. It is same as how commercial vector network analyzers (VNAs) compensate for the LO initial phase. These SDRs can thus acquire phase-coherent in-phase and quadrature (I/Q) data without additional components and an SFCW radar can be easily configured. On the other hand, low-cost SDRs typically have only one transmitter and receiver. Therefore, the LO initial phase has to be compensated and the phases of the received I/Q signals have to be retrieved, preferably without employing an additional receiver and components to retain the system low-cost and simple. The present paper illustrates that the difference between the phases of TX and RX LO signals varies when the LO frequency is changed because of the timing of the commencement of the mixing. The paper then proposes a technique to compensate for the LO initial phases using the internal RF loopback of the transceiver chip and to reconstruct a pulse, which requires two streaming: one for the device under test (DUT) channel and the other for the internal RF loopback channel. The effect of the LO initial phase and the proposed method for the compensation are demonstrated by experiments at a single frequency and sweeping frequency, respectively. The results show that the proposed method can compensate for the LO initial phases and ultra-wideband (UWB) pulses can be reconstructed correctly from the data sampled by a low-cost SDR.

Thermodynamic Analogy for Electrons Interacting with a Magnetic Nozzle.

The polytropic index of free electrons expanding in a magnetic nozzle of varying strength is experimentally investigated under a nearly zero electric field, allowing all the electrons to escape to the axial boundary and never return to the source. The measurements clearly demonstrate a continuous change in the polytropic index from adiabatic 5/3 for a strong magnetic field to isothermal unity for a weak magnetic field, showing that the polytropic index depends on the magnetic field strength. It is shown that the cross-field diffusion and the resultant plasma loss out of the magnetic nozzle effectively reduce the polytropic index. The azimuthal current induced in the plasma is diamagnetic, does work on the magnetic nozzle, and contributes to the reduction of the electron internal energy during the expansion.

In vitro and in vivo characterization of anti-malarial acylphenoxazine derivatives prepared from basic blue 3.

BACKGROUND: Basic blue 3 is a promising anti-malarial lead compound based on the π-delocalized lipophilic cation hypothesis. Its derivatives with nitrogen atoms bonded to carbon atoms at the 3- and 7-positions on the phenoxazine ring were previously shown to exert potent antiprotozoal activity against Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei rhodesiense, and Leishmania donovani parasites in vitro. However, compounds with nitrogen modification at the 10-position on the phenoxazine ring were not evaluated. METHODS: Six acylphenoxazine derivatives (ITT-001 to 006) with nitrogen modification at the 10-position on the phenoxazine ring, which were synthesized from basic blue 3, were characterized and evaluated for anti-malarial activity in vitro with an automated haematology analyzer (XN-30) and light microscopy. Intensity of self-fluorescence was measured using a fluorometer. Localization of basic blue 3 was observed by fluorescence microscopy. Cytotoxicity was evaluated using human cell lines, HEK293T and HepG2 cells. Finally, anti-malarial activity was evaluated in a rodent malaria model. RESULTS: All the six derivatives showed anti-malarial efficacy even against chloroquine-, pyrimethamine-, and artemisinin-resistant field isolates similar to the sensitive strains and isolates in vitro. The efficacy of basic blue 3 was the strongest, followed by that of ITT-001 to 004 and 006, while that of ITT-005 was the weakest. Basic blue 3 showed strong self-fluorescence, whereas ITT derivatives had five- to tenfold lower intensity than that of basic blue 3, which was shown by fluorescence microscopy to be selectively accumulated in the plasmodial cytoplasm. In contrast, ITT-003, 004, and 006 exhibited the lowest cytotoxicity in HEK293T and HepG2 cells in vitro and the highest selectivity between anti-malarial activity and cytotoxicity. The in vivo anti-malarial assay indicated that oral administration of ITT-004 was the most effective against the rodent malaria parasite, Plasmodium berghei NK65 strain. CONCLUSIONS: The six ITT derivatives were effective against chloroquine- and pyrimethamine-resistant strains and artemisinin-resistant field isolates as well as the sensitive ones. Among them, ITT-004, which had high anti-malarial activity and low cytotoxicity in vitro and in vivo, is a promising anti-malarial lead compound.

[Efficacy of Surgery and Adjuvant Chemotherapy for Distal Cholangiocarcinoma].

INTRODUCTION: Surgery alone shows an insufficient result for distal cholangiocarcinoma, and postoperative adjuvant chemotherapy is commonly used. However, no definite opinion has yet been accepted. SUBJECTS AND METHODS: A group of 46 patients who underwent surgery for distal bile duct cancer and who received adjuvant chemotherapy including gemcitabine (GEM)(Group A)and surgery alone group(Group S)were compared for disease-free survival(DFS)and overall survival (OS). RESULTS: Although the median DFS was 718 days in Group A and 367 days in Group S(p=0.306)and the median OS was 1,171 days in Group A and 859 days in Group S(p=0.07), no significant difference was observed; however, the prognosis improved. CONCLUSION: Postoperative adjuvant chemotherapy may improve prognosis.

[Pathologic Complete Response of Advanced Gastric Cancer after Chemotherapy with S-1 and Oxaliplatin and Conversion Surgery-A Case Report].

A man in his 70s was admitted to our hospital for the treatment of gastric cancer type 3 located in the antrum of the stomach. Computed tomography revealed tumor invasion of the liver and metastatic lymph node invasion of the pancreatic head and splenic artery. The patient was diagnosed with unresectable T4bN3M0, Stage ⅢC advanced gastric cancer. As radical excision was impossible, the patient underwent chemotherapy with S-1 and oxaliplatin(SOX). After 13 courses of SOX, imaging showed reduction in the size of the primary tumor and disappearance or marked reduction in the size of the metastatic lymph nodes. Therefore, conversion surgery was attempted after 14 courses of SOX. Distal gastrectomy with D2 lymphadenectomy including station 14v was performed. Pathological examination demonstrated no viable tumor cells in the resected stomach specimen or dissected lymph nodes, confirming that a pathologic complete response(pCR)had been achieved.

Adiabatic Expansion of Electron Gas in a Magnetic Nozzle.

A specially constructed experiment shows the near perfect adiabatic expansion of an ideal electron gas resulting in a polytropic index greater than 1.4, approaching the adiabatic value of 5/3, when removing electric fields from the system, while the polytropic index close to unity is observed when the electrons are trapped by the electric fields. The measurements were made on collisionless electrons in an argon plasma expanding in a magnetic nozzle. The collision lengths of all electron collision processes are greater than the scale length of the expansion, meaning the system cannot be in thermodynamic equilibrium, yet thermodynamic concepts can be used, with caution, in explaining the results. In particular, a Lorentz force, created by inhomogeneities in the radial plasma density, does work on the expanding magnetic field, reducing the internal energy of the electron gas that behaves as an adiabatically expanding ideal gas.

Studies on Instructive Construction of exo-Olefin Terminated Five- and Six-Membered Nitrogen Heterocycles: SmI2-Mediated Intramolecular Cyclization of Haloalkynals.

Stereoselective construction of exo-olefin terminated pyrrolidine and piperidine frameworks was developed by employing SmI2-mediated intramolecular radical cyclization of haloalkynaks. The radical cyclization affording 2,3-disubstituted pyrrolidines and piperidines proceeded in a highly stereoselective manner. However, decreasing stereoselectivety was observed in the preparation of 2,4-disubstituted pyrrolidine and 3,4-disubstituted piperidine derivatives in the cyclization.

Laboratory Observation of a Plasma-Flow-State Transition from Diverging to Stretching a Magnetic Nozzle.

An axial magnetic field induced by a plasma flow in a divergent magnetic nozzle is measured when injecting the plasma flow from a radio frequency (rf) plasma source located upstream of the nozzle. The source is operated with a pulsed rf power of 5 kW, and the high density plasma flow is sustained only for the initial ∼100 µsec of the discharge. The measurement shows a decrease in the axial magnetic field near the source exit, whereas an increase in the field is detected at the downstream side of the magnetic nozzle. These results demonstrate a spatial transition of the plasma-flow state from diverging to stretching the magnetic nozzle, where the importance of both the Alfvén and ion Mach numbers is shown.

Standing Helicon Wave Induced by a Rapidly Bent Magnetic Field in Plasmas.

An electron energy probability function and a rf magnetic field are measured in a rf hydrogen helicon source, where axial and transverse static magnetic fields are applied to the source by solenoids and to the diffusion chamber by filter magnets, respectively. It is demonstrated that the helicon wave is reflected by the rapidly bent magnetic field and the resultant standing wave heats the electrons between the source and the magnetic filter, while the electron cooling effect by the magnetic filter is maintained. It is interpreted that the standing wave is generated by the presence of a spatially localized change of a refractive index.

Axial momentum lost to a lateral wall of a helicon plasma source.

Momentum exerted to a lateral wall of a helicon plasma source is individually measured for argon, krypton, and xenon gases. A significant loss of the axial plasma momentum to the lateral wall, which has been assumed to be negligible, is experimentally identified when an axially asymmetric density profile is formed in the source. This indicates that the radially lost ions deliver not only the radial momentum but also the axial momentum to the lateral wall. The formation of the axial asymmetry causing the momentum loss is interpreted with competition between the magnetic field and neutral depletion effects.

Oxomollugin, an oxidized substance in mollugin, inhibited LPS-induced NF-κB activation via the suppressive effects on essential activation factors of TLR4 signaling.

Oxomollugin is a degraded product of mollugin and was found to be an active compound that inhibits LPS-induced NF-κB activation. In this study, we investigated the inhibitory activity of oxomollugin, focusing on TLR4 signaling pathway, resulting in NF-κB activation. Oxomollugin inhibited the LPS-induced association of essential factors for initial activation of TLR4 signaling, MyD88, IRAK4 and TRAF6. Furthermore, oxomollugin showed suppressive effects on LPS-induced modification of IRAK1, IRAK2 and TRAF6, LPS-induced association of TRAF6-TAK1/TAB2, and followed by IKKα/ß phosphorylation, which critical in signal transduction leading to LPS-induced NF-κB activation. The consistent results suggested that oxomollugin inhibits LPS-induced NF-κB activation via the suppression against signal transduction in TLR4 signaling pathway.The activities of oxomollugin reported in this study provides a deeper understanding on biological activity of mollugin derivatives as anti-inflammatory compounds.

Investigating Cytoglobin Expression in Colon Cancer: Clinicopathological Insights from Immunohistochemical Analysis.

BACKGROUND/AIM: Cytoglobin (Cygb), a protein involved in cellular oxygen metabolism and protection, has garnered attention owing to its potential role in the initiation and progression of cancer, particularly colon cancer (CC). This study investigated the expression and significance of Cygb in CC. PATIENTS AND METHODS: This study included 145 patients who underwent R0 surgery for CC (clinical stage II/III) at our institution between January 2007 and December 2014. Immunohistochemical analysis was performed to evaluate the Cygb expression patterns in CC tissues. Additionally, the correlation between Cygb expression levels and the clinicopathological characteristics of patients with CC was investigated. RESULTS: Colon cancer tissues were categorized into high-expression (95 cases) and low-expression (50 cases) groups. Cygb was highly expressed in well-differentiated cases, whereas its expression decreased in poorly differentiated cases. No significant differences in other clinicopathological factors were observed between the two groups. Cygb expression had no significant effect on recurrence-free survival or overall survival. CONCLUSION: This study contributes to the growing understanding of Cygb expression and its significance in CC. The expression of Cygb in CC was found to be unrelated to the recurrence rate and prognosis, but showed a correlation with differentiation status.

Approaching the theoretical limit of diamagnetic-induced momentum in a rapidly diverging magnetic nozzle.

Cross-field diffusion and plasma expansion in a rapidly diverging magnetic nozzle are controlled while maintaining constant plasma production in a contiguously attached radio frequency plasma source. It is demonstrated that the measured electron-diamagnetic-induced axial momentum increases with increasing magnetic field strength to approach the theoretical limit derived using an ideal nozzle approximation. The measured axial momentum exerted onto the axial and radial plasma source boundaries validate the prediction from a maximum electron pressure model on the back wall and from a zero net axial momentum model on the radial wall.