This paper examines the role of capital flows in the interwar German economy. We use a calibrated model of sudden stops as our analytical framework and derive four key findings. First, capital flows ...aggravated the boom–bust cycle of the Weimar economy. Second, these flows were strongly associated—during different periods—with reparations, conditions in the US capital market, and German domestic events. Third, capital flows before 1930 allowed Germany to pay reparations on credit and thus postponed the hour of reckoning when that debt had to be serviced using trade surpluses. Fourth, the German economic downturn in 1931 was due more to capital flows than to productivity shocks or reparations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are current standard of care for patients with EGFR mutation and metastatic non-small-cell lung carcinoma (NSCLC), ...but most patients using EGFR TKIs acquire resistance later. So, overcoming resistance of EGFR TKIs has become an important issue in the treatment of NSCLC. Previously, therapeutics targeting Bruton’s tyrosine kinase (BTK) have been successful in treating several hematologic malignancies. However, the role of BTK in NSCLC is still unknown. In this study, by examining surgical specimens from 80 NSCLC patients and their clinicopathologic parameters, we found significant correlation between high BTK expression and tumor differentiation, p-stage, lymph node metastatic status, maximum tumor size, and poor prognosis of patients. Using two NSCLC cell lines A540 and PC9, we demonstrated that BTK
pos
cells exhibited more stemness (OCT4, SOX2) and EMT (E-Cadherin, Slug) markers than BTK
neg
cells. Knockdown of BTK sensitized the NSCLC cells to Gefitinib. Meanwhile, the second-generation BTK inhibitor Acalabrutinib effectively suppressed SOX2, STAT3/JAK2/Akt axis and potentiated the anti-proliferative effect of Gefitinib and Osimertinib in NSCLC cells, including the T790M H1975 cells. Furthermore, Acalabrutinib and Osimertinib combination exhibited significant tumor growth inhibition of H1975-derived tumors in vivo. Our findings suggested that BTK mediates stemness and EMT properties, and inhibition of BTK potentiates the effect of Gefitinib and Osimertinib in NSCLC cells resistant to TKI. This implies a new approach to treat the NSCLC patients with resistance to previous TKI treatment.
The cancer stem cells (CSCs) have been shown to play key roles in the oral cancer initiation, distant metastasis, the development of chemoresistance and recurrence after treatment. Therefore, the ...inhibition of oral CSCs has been the target for therapeutic development.
In this study, we investigated the anti-CSCs potential of Ovatodiolide (Ova), a diterpenoid isolate of Anisomeles indica, in vitro and in vivo.
Oral CSCs were treated with Ova, and the expression of pluripotency factors Oct4, Sox-2, and Nanog were evaluated by western blot. Effect of Ova on self-renewal capacity and clonogenicity were assessed with the sphere formation and clonogenic assay in CSCs model derived from oral cancer cell. The effect of Ova was also investigated in a mouse xenograft model obtained by injecting nude mice with oral CSCs cells.
We demonstrated that Ova significantly and dose-dependently suppressed oral cancer cell viability and colony formation; Ova markedly inhibited the ALDH1 activities and reduced the CD44high/ALDHrich cell sub-population. Additionally, Ova suppressed orosphere formation by down-regulating CD133, Klf4, Oct4A, Nanog and JARID1B expression. Furthermore, Ova-mediated anti-cancer effects were associated with the dose-dependent reduction in the expression levels of STAT3, p-STAT3, pJAK2, pAKT and pERK1/2 protein. Moreover, Ova synergistically enhanced the anticancer effect of cisplatin against the SAS, FaDu, HSC-3 and TW2.6 orospheres. Ova significantly attenuated the tumor-initiating potential of orosphere in mouse xegnograft model.
These results demonstrate that Ova effectively suppressed oral tumorigenesis and stemness properties via JAK2/STAT3 signaling. Ova may be considered for future clinical usage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The clinical efficacy of spectral entropy monitoring in improving postoperative recovery remains unclear. This trial aimed to investigate the impact of M-Entropy (GE Healthcare, Helsinki, Finland) ...guidance on emergence from anesthesia and postoperative delirium in thoracic surgery. Adult patients undergoing video-assisted thoracoscopic surgery for lung resection at a medical center were randomly allocated into the M-Entropy guidance group (n = 39) and the control group (n = 37). In the M-Entropy guidance group, sevoflurane anesthesia was titrated to maintain response and state entropy values between 40 and 60 intraoperatively. In the control group, the dosing of sevoflurane was adjusted based on clinical judgment and vital signs. The primary outcome was time to spontaneous eye opening. M-Entropy guidance significantly reduced the time proportion of deep anesthesia (entropy value <40) during surgery, mean difference: −21.5% (95% confidence interval (CI): −32.7 to −10.3) for response entropy and −24.2% (−36.3 to −12.2) for state entropy. M-Entropy guidance significantly shortened time to spontaneous eye opening compared to clinical signs, mean difference: −154 s (95% CI: −259 to −49). In addition, patients of the M-Entropy group had a lower rate of emergence agitation (absolute risk reduction: 0.166, 95% CI: 0.005−0.328) and delirium (0.245, 0.093−0.396) at the postanesthesia care unit. M-Entropy-guided anesthesia hastened awakening and potentially prevented emergence agitation and delirium after thoracic surgery. These results may provide an implication for facilitating postoperative recovery and reducing the complications associated with delayed emergence and delirium.
Metastatic and/or recurrent breast carcinomas are leading causes of cancer-related death worldwide. Breast cancer stem cells (BCSCs) have been implicated in cancer metastases and progression, thus, ...the need for the discovery and development of effective BCSCs-specific therapies against metastatic and triple negative breast cancer (TNBC). The expression of SCUBE2, originally identified in vascular endothelia, then in several non-endothelial cell types, is downregulated in invasive breast carcinomas. However, the role of SCUBE2 in BCSCs remains unknown. This present study investigated the probable involvements of SCUBE2 in BCSCs and TNBC metastasis.
The mRNA expression of SCUBE2, stemness and EMT markers in MDA-MB-231 and Hs578T tumorspheres or adherent cells were evaluated by qRT-PCR and microarray analyses. Using gene overexpression, in vitro migration and invasion assays, as well as in vivo bioluminescence imaging, we evaluated the role of SCUBE2 in MDA-MB-231 or Hs578T BCSCs. Western blot and cytotoxicity assays helped identify and validate SCUBE2 molecular target(s) and inhibitor(s).
Concurrently increased SCUBE2 expression and cell motility were observed in TNBC tumorspheres compared to the parental adherent cells. SCUBE2 overexpression augmented BCSCs motility in vitro, and enhanced TNBC metastasis in vivo. While SCUBE2 overexpression activated Notch signaling its downregulation suppressed Notch signal effectors NICD, Jagged 1, HEY1, and HES1.
We demonstrate that SCUBE2 expression is upregulated in BCSCs, promote EMT and enhance TNBC metastasis by activating Notch signaling. This reveals a potential druggable molecular target and an effective therapeutic strategy against metastatic and aggressive TNBC.
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•SCUBE2 overexpression enhances the cancer stem cell-like and metastatic phenotypes.•SCUBE2 modulation of the Notch signaling pathway.•SCUBE2 high/ALDH+ TNBC cells exhibit enhanced tumorigenicity in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Resistance to TGF-β is frequently observed in ovarian cancer, and disrupted TGF-β/SMAD4 signaling results in the aberrant expression of downstream target genes in the disease. Our previous study ...showed that ADAM19, a SMAD4 target gene, is downregulated through epigenetic mechanisms in ovarian cancer with aberrant TGF-β/SMAD4 signaling. In this study, we investigated the mechanism of downregulation of FBXO32, another SMAD4 target gene, and the clinical significance of the loss of FBXO32 expression in ovarian cancer. Expression of FBXO32 was observed in the normal ovarian surface epithelium, but not in ovarian cancer cell lines. FBXO32 methylation was observed in ovarian cancer cell lines displaying constitutive TGF-β/SMAD4 signaling, and epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines regardless of FBXO32 methylation status, suggesting that epigenetic regulation of this gene in ovarian cancer may be a common event. In advanced-stage ovarian tumors, a significant (29.3%; P<0.05) methylation frequency of FBXO32 was observed and the association between FBXO32 methylation and shorter progression-free survival was significant, as determined by both Kaplan–Meier analysis (P<0.05) and multivariate Cox regression analysis (hazard ratio: 1.003, P<0.05). Reexpression of FBXO32 markedly reduced proliferation of a platinum-resistant ovarian cancer cell line both in vitro and in vivo, due to increased apoptosis of the cells, and resensitized ovarian cancer cells to cisplatin. In conclusion, the novel tumor suppressor FBXO32 is epigenetically silenced in ovarian cancer cell lines with disrupted TGF-β/SMAD4 signaling, and FBXO32 methylation status predicts survival in patients with ovarian cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lung cancer is one of the most lethal malignancies worldwide, but useful biomarkers of lung cancer are still insufficient. The aim of this study is to identify some membrane-bound protein(s) ...associated with migration and invasion in human non-small cell lung cancer (NSCLC) cells.
We classified four NSCLC cell lines into high and low migration/invasion groups by Transwell and Matrigel assays. Using two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), we identified 10 membrane-associated proteins being significantly overexpressed in the high migration/invasion group. The expression of the target protein in the four NSCLC cell lines was then confirmed by reverse transcription polymerase chain reaction (RT-PCR), western blot and immunostaining. RNA interference technique was applied to observe the influence of the target protein on migration and invasion. Gelatin zymography was also performed to evaluate the activities of matrix metalloproteinase (MMP)-2 and MMP-9. Expression condition of the target protein on surgical specimens was further examined by immunohistochemical staining and the clinicopathologic data were analyzed.
We identified a mitochondria-bound protein cytochrome c oxidase subunit Va (COX Va) because of its abundant presence found exclusively in tumorous areas. We also demonstrated that migration and invasion of NSCLC cells decreased substantially after knocking down COX Va by siRNA. Meanwhile, we found a positive correlation between COX Va expression, Bcl-2 expression and activities of MMP-2 and MMP-9 in NSCLC cells. Immunohistochemical staining of surgically resected lung adenocarcinomas in 250 consecutive patients revealed that strong COX Va expression was found in 54.8% (137/250) of patients and correlated positively with the status of lymph node metastasis (P = 0.032). Furthermore, strong COX Va expression was associated with the presence of distant metastasis (P = 0.033).
Our current study showed that COX Va may play a role in migration and invasion of NSCLC cells and can be used as a biomarker to predict aggressiveness of NSCLC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Esophageal squamous cell carcinoma (ESCC) is a lethal malignancy, but only limited molecular markers can predict its prognosis. Recently, a DNA double-strand break repair protein Nijmegen ...breakage syndrome 1 (NBS1) was reported to induce Snail expression and predict poor prognosis in head and neck cancers. However, the clinicopathologic roles of NBS1 and Snail in ESCC remain unclear.
Methods
From January 1995 to September 1999, tissue samples from 153 patients with ESCC who underwent esophagectomies at our institutions were collected and made into tissue core arrays for study. Expression of NBS1 and Snail was examined by immunohistochemical staining. The clinicopathologic data were analyzed, and some additional studies were performed to explore the relationship between NBS1 and Snail.
Results
NBS1 overexpression was observed in 28.1% (43/153) of ESCC, whereas Snail overexpression was observed in 26.1% (40/153) of ESCC. Overexpression of NBS1 correlated inversely with nodal status (
P
= 0.009) and was associated with better overall survival (
P
= 0.002). On the other hand, overexpression of Snail correlated positively with lymphovascular invasion (
P
= 0.034) and was associated with worse overall survival (
P
= 0.036). Meanwhile, NBS1 overexpression correlated inversely with Snail overexpression marginally (
P
= 0.084). Using the Cox regression analysis, T status (
P
= 0.006), M status (
P
= 0.008), and NBS1 overexpression (
P
= 0.007) were the independent factors of overall survival.
Conclusions
Our results showed that NBS1 overexpression was an independent factor of better survival and Snail overexpression predicted a worse survival in ESCC. Combination of NBS1 plus Snail expression status could be used as a predictor of prognosis in ESCC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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