Monitoring the transition to open access through its mode of implementation: A principal component analysis of two surveys.

Open access (OA) is transforming scholarly communication. Various modes of OA implementation have emerged, which reflect the complexity surrounding OA development. This study aimed to examine this development from the perspective of how OA is implemented. The sample comprised 2,368 randomly selected articles published in 2013 and 2,999 published in 2018 indexed in the Web of Science. We also conducted searches in Google and Google Scholar in 2015 for articles published in 2013 and in 2020 for articles published in 2018. Selected articles were categorized as either an "OA article," "electronic subscription journal article," or "not available online." OA articles were classified into 10 implementation modes: Gold, Hybrid, Delayed, Bronze, Subject Repositories, Institutional Repositories, Personal/Institutional Websites, Academic Social Networks (ASNs), Others, and Web Aggregator. Overall, 56.5% of all sampled articles in 2013 were available for free on at least one website in 2015, while 61.7% of all sampled articles in 2018 were freely available on at least one website in 2020. Concerning implementation mode, ASNs had the highest frequency (44.4% in 2015 and 56.0% in 2020), followed by Subject Repositories (35.0% in 2015 and 39.6% in 2020) and Gold (24.1% in 2015 and 37.4% in 2020). To obtain an overview of OA implementation, we conducted principal component analysis with OA implementation mode as the variable for both 2015 and 2020. The first principal component was the axis indicating the number of overlapping OA implementations for each article in 2015 and 2020, while the second principal component was the axis orthogonal to the first, which was difficult to interpret. We identified three groups of OA implementation in each plot of the principal component scores for articles in 2015 and 2020; however, the OA implementation of each group differed in 2015 and 2020. This diversity reflects the respective positions of various stakeholders regarding OA.

Inhibition of cell movement and proliferation by cell-cell contact-induced interaction of Necl-5 with nectin-3.

Immunoglobulin-like Necl-5/Tage4/poliovirus receptor (PVR)/CD155, originally identified as the PVR, has been shown to be up-regulated in cancer cells and to enhance growth factor-induced cell movement and proliferation. In addition, Necl-5 heterophilically trans-interacts with nectin-3, a cell-cell adhesion molecule known to form adherens junctions in cooperation with cadherin. We show here that Necl-5 was down-regulated from cell surface upon cell-cell contacts in NIH3T3 cells. This down-regulation of Necl-5 was initiated by its interaction with nectin-3 and was mainly mediated by clathrin-dependent endocytosis. Then, the down-regulation of Necl-5 induced in this way reduced movement and proliferation of NIH3T3 cells. These results indicate that the down-regulation of Necl-5 induced by its interaction with nectin-3 upon cell-cell contacts may be at least one mechanism underlying contact inhibition of cell movement and proliferation.

Interaction and localization of Necl-5 and PDGF receptor beta at the leading edges of moving NIH3T3 cells: Implications for directional cell movement.

It was previously shown that platelet-derived growth factor (PDGF) receptor physically and functionally interacts with integrin alpha(v)beta(3), effectively inducing cell movement. We previously showed that Necl-5, originally identified as a poliovirus receptor, interacts with integrin alpha(v)beta(3) and enhances its clustering and the formation of focal complexes at the leading edges of moving cells, resulting in an enhancement of cell movement. We showed here that Necl-5 additionally interacts with PDGF receptor in NIH3T3 cells and regulates the interaction between PDGF receptor and integrin alpha(v)beta(3), effectively inducing directional cell movement. PDGF receptor co-localized with Necl-5 and integrin alpha(v)beta(3) at peripheral ruffles over lamellipodia, which were formed at the leading edges of moving cells in response to PDGF, but not at the focal complexes under these ruffles, whereas Necl-5 and integrin alpha(v)beta(3) co-localized at these focal complexes. The clustering of these three molecules at peripheral ruffles required the activation of integrin alpha(v)beta(3) by vitronectin and the PDGF-induced activation of the small G protein Rac and subsequent re-organization of the actin cytoskeleton. These results indicate a key role of Necl-5 in directional cell movement by physically and functionally interacting with both integrin alpha(v)beta(3) and PDGF receptor.

Activation of Cdc42 by trans interactions of the cell adhesion molecules nectins through c-Src and Cdc42-GEF FRG.

Nectins, Ca2+ -independent immunoglobulin-like cell-cell adhesion molecules, initiate cell-cell adhesion by their trans interactions and recruit cadherins to cooperatively form adherens junctions (AJs). In addition, the trans interactions of nectins induce the activation of Cdc42 and Rac small G proteins, which increases the velocity of the formation of AJs. We examined here how nectins induce the activation of Cdc42 in MDCK epithelial cells and L fibroblasts. Nectins recruited and activated c-Src at the nectin-based cell-cell adhesion sites. FRG, a GDP/GTP exchange factor specific for Cdc42, was then recruited there, tyrosine phosphorylated by c-Src, and activated, causing an increase in the GTP-bound active form of Cdc42. Inhibition of the nectin-induced activation of c-Src suppressed the nectin-induced activation of FRG and Cdc42. Inhibition of the nectin-induced activation of FRG or depletion of FRG by RNA interference suppressed the nectin-induced activation of Cdc42. These results indicate that nectins induce the activation of Cdc42 through c-Src and FRG locally at the nectin-based cell-cell adhesion sites.

[A new method of short-term high volume (6 g of 5-FU in a week) intermittent hepatic arterial infusion using repeated transient catheter insertion].

We report a case of liver metastases, which had hepatectomy twice and a partial lung resection after sigmoidectomy with partial bladder resection for advanced sigmoid colon cancer. The patient could not be tolerated the systemic chemotherapy, and percutaneous implantation of a catheter also could not have done with subcutaneous reservoir for hepatic arterial infusion because of an anomaly of hepatic artery branched-out from super mesenteric artery. Therefore, we tried an intermittent hepatic arterial infusion using a transient insertion of catheter to control the liver metastases' growth. A total amount of 6 g of 5-FU was continuously injected in a week by one insertion of catheter at the hepatic artery taking one day rest at day 4. During the next 21 months, a total of 11 courses have been done. CEA and CA19-9 were changed from 15 ng/mL, 48 U/ mL to 18, 30, respectively. The patient was able to keep working except for the duration of this treatment. This procedure could be one of the hepatic arterial infusion options.

[A case report-advanced pancreas cancer with liver and lung metastases well controlled over one year by combination therapy with systemic chemotherapy, radiation and hepatic arterial infusion in an outpatient setting].

We report a case of advanced pancreatic cancer with liver and lung metastases that was well controlled over one year by combination therapy with systemic chemotherapy, radiation and hepatic arterial infusion in an outpatient setting. The patient was a 74-year-old woman. Chief complaints were back pain and anorexia. She was diagnosed with pancreas cancer with liver and lung metastases at the time of first visit. We started systemic chemotherapy with gemcitabine 1 g/body and 5-FU 1 g/body alternately every other week on an outpatient basis. At 1.5 months (M) after initiation of chemotherapy, we started radiation therapy to the main tumor at a total dose of 40 Gy. After radiation, chemotherapy was resumed. As a result, the size of the main tumor decreased but metastatic liver tumors got larger. Then we changed to combination therapy with systemic chemotherapy (gemcitabine and 5-FU) and hepatic arterial infusion (5-FU weekly). Liver metastases almost disappeared after 7.5 M. Despite all these treatments, however, the number of metastatic lung tumors increased. The patient was hospitalized for 15 M and died after 17 M. We focused on and succeeded in the prolongation of lifetime and maintenance of QOL by combination therapy with systemic chemotherapy, radiation and hepatic arterial infusion therapy.

[omega-3 Fatty acid-containing diet (Racol) reduces toxicity of chemoradiation therapy for patients with esophageal cancer].

Recently, it is reported that a omega-3 fatty acid-containing diet (Racol) enhances innate immunity and reduces mucosal damage in the small intestine during chemotherapy. The aim of this study is to examine the effects of a omega-3 fatty acid-containing diet (Racol) on the toxicity of chemoradiation therapy (CRT) for patients with esophageal cancers. Toxicity of CRT was evaluated in 10 patients who took Rakol at a maximum dose of 600 mL/day during CRT, compared with 10 patients who did not take Rakol. Regarding blood toxicity, the decrease of platelets did not differ between the former and the latter. However, the incidence of grade 2~4 neutropenia was lower in the former than in the latter (p=0.0043). With regard to gastrointestinal toxicity, the incidence of grade 2~4 diarrhea was also lower in the former than in the latter (p=0.0118). Moreover, the incidence of grade 2~4 stomatitis/pharyngitis tended to decrease in patients who took Rakol compared with those who did not (p=0.0812). The current results indicated that a omega-3 fatty acid-containing diet (Racol) may be beneficial to patients with esophageal cancers who receive CRT by reducing CRT toxicity.

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel-Mediated Intestinal Sodium Absorption and Blood Pressure Regulation.

BACKGROUND: Mineralocorticoid receptor (MR) has pathological roles in various cell types, including renal tubule cells, myocytes, and smooth muscle cells; however, the role of MR in intestinal epithelial cells (IECs) has not been sufficiently evaluated. The intestine is the sensing organ of ingested sodium; accordingly, intestinal MR is expected to have essential roles in blood pressure (BP) regulation. METHODS AND RESULTS: We generated IEC-specific MR knockout (IEC-MR-KO) mice. With a standard diet, fecal sodium excretion was 1.5-fold higher in IEC-MR-KO mice, with markedly decreased colonic expression of ß- and γ-epithelial sodium channel, than in control mice. Urinary sodium excretion in IEC-MR-KO mice decreased by 30%, maintaining sodium balance; however, a low-salt diet caused significant reductions in body weight and BP in IEC-MR-KO mice, and plasma aldosterone exhibited a compensatory increase. With a high-salt diet, intestinal sodium absorption markedly increased to similar levels in both genotypes, without an elevation in BP. Deoxycorticosterone/salt treatment elevated BP and increased intestinal sodium absorption in both genotypes. Notably, the increase in BP was significantly smaller in IEC-MR-KO mice than in control mice. The addition of the MR antagonist spironolactone to deoxycorticosterone/salt treatment eliminated the differences in BP and intestinal sodium absorption between genotypes. CONCLUSIONS: Intestinal MR regulates intestinal sodium absorption in the colon and contributes to BP regulation. These regulatory effects are associated with variation in epithelial sodium channel expression. These findings suggest that intestinal MR is a new target for studying the molecular mechanism of hypertension and cardiovascular diseases.

Evaluating the effect of the new incentive system for high-risk pressure ulcer patients on wound healing and cost-effectiveness: a cohort study.

OBJECTIVE: To evaluate the effectiveness and cost-effectiveness of new incentive system for pressure ulcer management, which focused on skilled nurse staffing in terms of rate of healing and medical costs. DESIGN, SETTING AND PARTICIPANTS: A prospective cohort study included two types of groups: 39 institutions, which introduced the new incentive system, and 20 non-introduced groups (control). Sixty-seven patients suffering from severe pressure ulcers in the introduced group and 38 patients in the non-introduced group were included. Wound healing and medical costs were monitored weekly for three weeks by their skilled nurses in charge. MAIN OUTCOME MEASURES: Healing status and related medical costs. RESULTS: The introduced group showed significantly higher rate of healing compared with the control group at each weekly assessment. Multiple regression analysis revealed that the introduction of the new incentive system was independently associated with the faster healing rate (beta=3.44, P<.001). The budget impact analysis demonstrated that introducing this system could reduce cost of treating severe pressure ulcers by 1.776 billion yen per year. CONCLUSIONS: The new incentive system for the management of pressure ulcers, which focused on staffing with skilled nurses can improve healing rate with reduced medical cost.

Metachronous double cancer of the gallbladder and pancreas associated with pancreaticobiliary maljunction.

A 50-year-old Japanese woman complained of abdominal and back pain. Ten years previously she had undergone cholecystectomy, choledochectomy, and Roux-en-Y choledochojejunostomy for gallbladder cancer associated with pancreaticobiliary maljunction without bile duct dilatation. On the present admission, ultrasonography (US) and computed tomography (CT) demonstrated a large mass, 60 mm in size, in the pancreatic tail. Endoscopic retrograde cholangiopancreatography (ERCP) showed obstruction of the main pancreatic duct in the tail of the pancreas and revealed that the pancreatic duct was joined to the bile duct 25 mm above the papilla of Vater. The patient underwent distal pancreatectomy, splenectomy, left adrenalectomy, and partial gastrectomy. Histological examination revealed moderately differentiated ductal adenocarcinoma that had invaded to the proper muscle of the stomach. Double cancer of the gallbladder and pancreas in a patient with pancreaticobiliary maljunction is rare. Although the etiology of cancer of the pancreas associated with pancreaticobiliary maljunction is unclear, we should pay close attention to the pancreas as well as the biliary tract during the long-term follow-up of patients with pancreaticobiliary maljunction after they have undergone a choledochojejunostomy.

Involvement of up-regulated Necl-5/Tage4/PVR/CD155 in the loss of contact inhibition in transformed NIH3T3 cells.

Normal cells show contact inhibition of cell movement and proliferation, but this is lost following transformation. We found that Necl-5, originally identified as a poliovirus receptor and up-regulated in many cancer cells, enhances growth factor-induced cell movement and proliferation. We showed that when cells contact other cells, Necl-5 interacts in trans with nectin-3 and is removed by endocytosis from the cell surface, resulting in a reduction of cell movement and proliferation. We show here that up-regulation of the gene encoding Necl-5 by the oncogene V12-Ki-Ras causes enhanced cell movement and proliferation. Upon cell-cell contact, de novo synthesis of Necl-5 exceeds the rate of Necl-5 endocytosis, eventually resulting in a net increase in the amount of Necl-5 at the cell surface. In addition, expression of the gene encoding nectin-3 is markedly reduced in transformed cells. Thus, up-regulation of Necl-5 following transformation contributes to the loss of contact inhibition in transformed cells.

Necl-5/poliovirus receptor interacts in cis with integrin alphaVbeta3 and regulates its clustering and focal complex formation.

Integrin alphavbeta3, which forms focal complexes at leading edges in moving cells, is up-regulated in cancer cells and so is implicated in their invasiveness. Necl-5, originally identified as a poliovirus receptor and also up-regulated in cancer cells, colocalizes with integrin alphavbeta3 at leading edges in moving cells and enhances growth factor-induced cell movement. Here, we show that Necl-5 interacts directly, in cis, with integrin alphavbeta3, and enhances integrin alphavbeta3 clustering and focal complex formation at leading edges in NIH3T3 cells. The extracellular region of Necl-5, but not the cytoplasmic region, is necessary for its interaction with integrin alphavbeta3; however, both regions are necessary for its action. An interaction between integrin alphavbeta3 and vitronectin and PDGF-induced activation of Rac are also necessary for integrin alphavbeta3 clustering. The interaction between Necl-5 and integrin alphavbeta3 enhances PDGF-induced Rac activation, facilitating integrin alphavbeta3 clustering presumably in a feedback amplification manner. Thus, Necl-5 has a critical role in integrin alphavbeta3 clustering and focal complex formation.

Vav2 as a Rac-GDP/GTP exchange factor responsible for the nectin-induced, c-Src- and Cdc42-mediated activation of Rac.

Nectins are Ca2+-independent immunoglobulin-like cell-cell adhesion molecules that form homo- and hetero-trans-dimers (trans-interactions). Nectins first form cell-cell contact and then recruit cadherins to the nectin-based cell-cell contact sites to form adherens junctions cooperatively with cadherins. In addition, the trans-interactions of nectins induce the activation of Cdc42 and Rac small G proteins, which enhances the formation of adherens junctions by forming filopodia and lamellipodia, respectively. The trans-interactions of nectins first recruit and activate c-Src at the nectin-based cell-cell contact sites. c-Src then phosphorylates and activates FRG, a Cdc42-GDP/GTP exchange factor (GEF) for Cdc42. The activation of both c-Src and Cdc42 by FRG is necessary for the activation of Rac, but the Rac-GEF responsible for this activation of Rac remains unknown. We showed here that the nectin-induced activation of Rac was inhibited by a dominant negative mutant of Vav2, a Rac-GEF. Nectins recruited and tyrosine-phosphorylated Vav2 through c-Src at the nectin-based cell-cell contact sites, whereas Cdc42 was not necessary for the nectin-induced recruitment of Vav2 or the nectin-induced, c-Src-mediated tyrosine phosphorylation of Vav2. Cdc42 activated through c-Src then enhanced the GEF activity of tyrosine-phosphorylated Vav2 on Rac1. These results indicate that Vav2 is a GEF responsible for the nectin-induced, c-Src-, and Cdc42-mediated activation of Rac.

Enhancement of serum- and platelet-derived growth factor-induced cell proliferation by Necl-5/Tage4/poliovirus receptor/CD155 through the Ras-Raf-MEK-ERK signaling.

Necl-5/Tage4/poliovirus receptor/CD155 has been shown to be the poliovirus receptor and to be up-regulated in rodent and human carcinoma. We have found previously that mouse Necl-5 regulates cell motility. We show here that mouse Necl-5 is furthermore involved in the regulation of cell proliferation. Studies using a specific antibody against Necl-5 and a dominant negative mutant of Necl-5 revealed that Necl-5 enhanced the serum-induced proliferation of NIH3T3, Swiss3T3, and mouse embryonic fibroblast cells. Necl-5 enhanced the serum-induced activation of the Ras-Raf-MEK-ERK signaling, up-regulated cyclins D2 and E, and down-regulated p27(Kip1), eventually shortening the period of the G(0)/G(1) phase of the cell cycle in NIH3T3 cells. Necl-5 similarly enhanced the platelet-derived growth factor-induced activation of the Ras-Raf-MEK-ERK signaling and shortened the period of the G(0)/G(1) phase of the cell cycle in NIH3T3 cells. Necl-5 acted downstream of the platelet-derived growth factor receptor and upstream of Ras. Moreover, up-regulated Necl-5 was involved at least partly in the enhanced proliferation of transformed cells including NIH3T3 cells transformed by an oncogenic Ras or v-Src. These results indicate that Necl-5 plays roles not only in cell motility but also in cell proliferation.