Significance of signal recognition particle 9 nuclear translocation: Implications for pancreatic cancer prognosis and functionality.

Signal recognition particles (SRPs) are essential for regulating intracellular protein transport and secretion. Patients with tumors with high SRP9 expression tend to have a poorer overall survival. However, to the best of our knowledge, no reports have described the relationship between SRP9 localization and prognosis in pancreatic cancer. Thus, the present study aimed to investigate this relationship. Immunohistochemical staining for SRP9 using excised specimens from pancreatic cancer surgery cases without preoperative chemotherapy or radiotherapy showed that SRP9 was preferentially expressed in the nucleus of the cancerous regions in some cases, which was hardly detected in other cases, indicating that SRP9 was transported to the nucleus in the former cases. To compare the prognosis of patients with SRP9 nuclear translocation, patients were divided into two groups: Those with a nuclear translocation rate of >50% and those with a nuclear translocation rate of ≤50%. The nuclear translocation rate of >50% group had a significantly better recurrence­free survival than the nuclear translocation rate of ≤50% group (P=0.037). Subsequent in vitro experiments were conducted; notably, the nuclear translocation rate of SRP9 was reduced under amino acid­deficient conditions, suggesting that multiple factors are involved in this phenomenon. To further study the function of SRP9 nuclear translocation, in vitro experiments were performed by introducing SRP9 splicing variants (v1 and v2) and their deletion mutants lacking C­terminal regions into MiaPaCa pancreatic cancer cells. The results demonstrated that both splicing variants showed nuclear translocation regardless of the C­terminal deletions, suggesting the role of the N­terminal regions. Given that SRP9 is an RNA­binding protein, the study of RNA immunoprecipitation revealed that signaling pathways involved in cancer progression and protein translation were downregulated in nuclear­translocated v1 and v2. Undoubtedly, further studies of the nuclear translocation of SRP9 will open an avenue to optimize the precise evaluation and therapeutic control of pancreatic cancer.

RN7SL1 may be translated under oncogenic conditions.

RN7SL1 (RNA component of signal recognition particle 7SL1), a component of the signal recognition particle, is a non-coding RNA possessing a small ORF (smORF). However, whether it is translated into peptides is unknown. Here, we generated the RN7SL1-Green Fluorescent Protein (GFP) gene, in which the smORF of RN7SL1 was replaced by GFP, introduced it into 293T cells, and observed cells emitting GFP fluorescence. Furthermore, RNA-seq of GFP-positive cells revealed that they were in an oncogenic state, suggesting that RN7SL1 smORF may be translated under special conditions.

Revealing neuropilin expression patterns in pancreatic cancer: From single­cell to therapeutic opportunities (Review).

Pancreatic cancer, one of the most fatal types of human cancers, includes several non-epithelial and stromal components, such as activated fibroblasts, vascular cells, neural cells and immune cells, that are involved in different cancers. Vascular endothelial cell growth factor 165 receptors 1 [neuropilin-1 (NRP-1)] and 2 (NRP-2) play a role in the biological behaviors of pancreatic cancer and may appear as potential therapeutic targets. The NRP family of proteins serve as co-receptors for vascular endothelial growth factor, transforming growth factor ß, hepatocyte growth factor, fibroblast growth factor, semaphorin 3, epidermal growth factor, insulin-like growth factor and platelet-derived growth factor. Investigations of mechanisms that involve the NRP family of proteins may help develop novel approaches for overcoming therapy resistance in pancreatic cancer. The present review aimed to provide an in-depth exploration of the multifaceted roles of the NRP family of proteins in pancreatic cancer, including recent findings from single-cell analysis conducted within the context of pancreatic adenocarcinoma, which revealed the intricate involvement of NRP proteins at the cellular level. Through these efforts, the present study endeavored to further reveal their relationships with different biological processes and their potential as therapeutic targets in various treatment modalities, offering novel perspectives and directions for the treatment of pancreatic cancer.

[Colitis Suggested to be Related to Nivolumab in a Gastric Cancer Patient with a History of Ulcerative Colitis: A Case Report].

We experienced a case in which long-term use of nivolumab in a patient with a history of ulcerative colitis led to disease control of gastric cancer. The case is a 77-year-old man. The patient had a history of ulcerative colitis and remained in remission on mesalazine 1500 mg/d. With continuous monitoring, nivolumab could be continued up to 16 courses, but was withdrawn due to the appearance of diarrhea (grade 1) and bloody stools, which was relieved with prednisolone (PSL) 40 mg/d. After two more courses, diarrhea (grade 3) appeared again, which improved with PSL 60 mg/d and increased dose of mesalazine. It is difficult to distinguish whether colitis that occurs after nivolumab administration is due to relapse exacerbation or irAE. The onset of irAE colitis is often reported within 3 months, and the fact that this patient developed irAE colitis after 8 months, despite having ulcerative colitis, is considered novel. In the future, we hope to accumulate cases so that immune checkpoint inhibitors can be used safely in patients with ulcerative colitis, and to establish appropriate methods for their use.

Reproductive outcomes following abdominal repair for cesarean scar defect in women who desire subsequent pregnancies: A single-center retrospective study.

OBJECTIVE: To clarify the reproductive outcomes of women who underwent abdominal repair surgery for cesarean scar defect (CSD). STUDY DESIGN: This is a retrospective observational study performed in a tertiary center. We retrospectively reviewed 20 women who underwent abdominal repair between 2007 and 2021. The indication for the repair was a minimal residual myometrial thickness (RMT) of ≦3.0 mm. We investigated surgical complications, changes in minimal RMT before and three-months after the repair, and reproductive outcomes. RESULTS: The median age at the time of repair was 36 years (27-40), with a median body mass index of 21.0 (17.7-28.7) and a median of 1 prior cesarean section (1-5). Twelve women reported secondary infertility, while eight women were concerned about the potential risk of uterine rupture in future pregnancies due to thin RMT. Additionally, one woman had a co-existing vesicouterine fistula, two had abscess and hematoma formation at the precedent cesarean section, and three showed remarkable dehiscence of the defect. The median minimal RMT significantly increased to 5.05 mm (range; 2.5-14.2 mm) after the repair. Seven women had a total of eight live births, with a median duration from the repair to a live-birth pregnancy of 11.5 months (range; 4-20 months). No surgical complications occurred during the repair, and there were no instances of uterine rupture in subsequent pregnancies. However, one woman who became pregnant with twins following double blastocyst transfer required a cesarean section at 25 weeks of pregnancy due to bulging towards the bladder side of the repaired CSD. CONCLUSION: Abdominal repair for CSD is feasible in women with thin RMT who experience secondary infertility. Twin pregnancies can promote thinning of the CSD repair site, potentially increasing the risk of uterine rupture.

RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids.

Abstract: Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized by accumulation of abundant extracellular matrix (ECM) and sex steroid-dependent growth. Women with symptomatic UFs have reduced quality of life and decreased labor productivity. Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs. They are gain-of-function mutations and are more frequently observed in Black women and commonly observed even in small UFs. MED12 mutation-positive UFs (MED12-UFs) often develop multiple rather than solitary and have distinct gene expression profiles, DNA methylomes, transcriptomes, and proteomes. Gene expressions related to ECM organization and collagen-rich ECM components are upregulated, and impaired Mediator kinase activity and dysregulation of Wnt/ß-catenin signaling are identified in MED12-UFs. Clinically, the UF shrinking effect of gonadotropin-releasing hormone agonists and ulipristal acetate is dependent on the MED12 mutation status. Understanding of characteristics of MED12-UFs and functions of MED12 mutations for UF tumorigenesis may elucidate the pathophysiology of UFs, leading to the development of new therapeutic options in women with symptomatic UFs.

Multifaced roles of desmoplastic reaction and fibrosis in pancreatic cancer progression: Current understanding and future directions.

Desmoplastic reaction is a fibrosis reaction that is characterized by a large amount of dense extracellular matrix (ECM) and dense fibrous stroma. Fibrotic stroma around the tumor has several different components, including myofibroblasts, collagen, and other ECM molecules. This stromal reaction is a natural response to the tissue injury process, and fibrosis formation is a key factor in pancreatic cancer development. The fibrotic stroma of pancreatic cancer is associated with tumor progression, metastasis, and poor prognosis. Reportedly, multiple processes are involved in fibrosis, which is largely associated with the upregulation of various cytokines, chemokines, matrix metalloproteinases, and other growth factors that promote tumor growth and metastasis. Fibrosis is also associated with immunosuppressive cell recruitment, such as regulatory T cells (Tregs) with suppressing function to antitumor immunity. Further, dense fibrosis restricts the flow of nutrients and oxygen to the tumor cells, which can contribute to drug resistance. Furthermore, the dense collagen matrix can act as a physical barrier to block the entry of drugs into the tumor, thereby further contributing to drug resistance. Thus, understanding the mechanism of desmoplastic reaction and fibrosis in pancreatic cancer will open an avenue to innovative medicine and improve the prognosis of patients suffering from this disease.

[Side Effect Management in the Early Stages of Cabozantinib Administration].

In 2 patients with postoperative lung metastases from renal cell carcinoma, we administered cabozantinib at a starting dose of 40 mg. The side effects were proteinuria(Grade 2), hand-foot syndrome(Grade 2), and hypertension(Grade 3), which subsided following dose reduction and drug suspension. We believe that a low starting dose of cabozantinib might be a suitable regimen for advanced renal cell carcinoma.

Time-lapse monitoring of fertilized human oocytes focused on the incidence of 0PN embryos in conventional in vitro fertilization cycles.

We aimed to investigate why the incidence of embryos derived from oocytes with no pronuclei (0PN) decreases using time-lapse monitoring (TLM) versus fixed-point assessment in conventional IVF cycles. We analyzed 514 embryos monitored with TLM 6-9 h after insemination and 144 embryos monitored using microscopic assessment 18-21 h after insemination. The primary endpoint of this study was the incidence of 0PN-derived embryos in short insemination followed by TLM. The secondary endpoint was the duration of insemination. As exploratory endpoints, we analyzed the blastulation rate and cryo-warmed blastocyst transfer outcome of embryos with early PN fading, whereby PN disappeared within < 20 h following the initiation of insemination. The incidence of 0PN-derived embryo reduced more significantly through TLM than through fixed-point observation. The microscopic assessment time was more significantly delayed in the 0PN-derived embryo than that in the 2PN-derived embryo. The embryo with early PN fading formed good-quality blastocysts, and their pregnancy outcomes were similar to those of other embryos. Most 0PN-derived embryos in the fixed-point assessment might have resulted from missed observation of PN appearance in the early-cleaved embryos. TLM or strict laboratory schedule management may reduce 0PN-derived embryos by reducing missed PN observations.

[Project for Self-Help Tableware Involving Local Traditional Arts and Crafts of Japan].

To improve the quality ofmeals in communities, "Keiji study group on dysphagia" was founded in 2010. With the "Project for Self-Help Tableware involving Traditional Arts and Crafts," we will introduce an innovative community collaboration of cultural specialists,. The existing self-help tableware are not suitable for traditional feasts. Therefore, to produce new self-help tableware, we collaborated with cooks, designers, potters, and a lacquer ware company. To ensure a comfortable traditional feast, the backgrounds and cultural manners ofeach ofthese specialists were integrated. Finally, traditional Japanese style tableware was produced through repeated trial manufacturing. We offered patients with eating disorders a Japanese style feast that ameliorates swallowing and we had them use the produced tableware. The observers, the patients, and patients' families approved of the tableware because it increased their appetite and they developed a positive attitude toward eating. In the future, the need for food that ameliorates swallowing will increase. This new eating culture is not only concerned with the production off ood, but also with the presentation ofits tableware. We are planning to support the development ofsuch a cuisine through a sponsored project, which will encourage collaboration between local manufacturing of traditional culture and occupational therapy.

[Impact of Physician Order Support Duties on de novo Hepatitis Prevention].

"Immunosuppression and hepatitis B measures and guidelines for chemotherapy" were announced in 2009. However, a fulminant case that appeared when the guidelines were not observed was reported, and de novo hepatitis prevention is an urgent problem. The rate of compliance with these guidelines as of January 2014 was 20.4%, but this rose to 34.3%after the alert indication for de novo hepatitis prevention was set on an electronic chart system from June 2014. The rate of compliance increased to 63.9% at a hospital where de novo hepatitis alerts were put on clinical cards in April 2015, but it gradually decreased thereafter. HBV-DNA measurement was 100% in compliance with the guidelines from August 2016 when HB antigen, HB antibody, and anti-hepatitis B core antigen measurements were all performed in March 2016 because the pharmacists practiced physician order support duties at that time. This helped to reduce the burden on physicians, and the physician order support duties by the pharmacist were educational. Thus, de novo hepatitis prevention may contribute to safe cancer chemotherapy.

[A Case of Rectal Cancer and Multiple Liver Metastases Treated Using mFOLFOX and Bevacizumab under Maintenance Dialysis].

A 50s man receiving dialysis for chronic kidney disease due to IgA nephropathy underwent laparoscopic reversal via Hartmann 's procedure for rectal cancer and multiple liver metastases, followed by chemotherapy for the liver metastases. Following a single course of mFOLFOX therapy, bevacizumab was administered for 8 courses, resulting in tumor shrinkage and a decrease in tumor marker levels. The initial doses were 60mg/m2 oxaliplatin and 280(bolus injection)and 1,680mg/m2 (continuous infusion)of 5-FU. Subsequently, these doses were adjusted to be administered every 3 weeks. No serious adverse events other than neutropenia(Grade3 ), anorexia(Grade1 ), and hiccups(Grade1)were noted.

[Outcomes of an Independent Clinical Study to Compare Branded and Generic Formulations of Sustained-Release Oxycodone].

To evaluate the potential for the adoption of a generic formulation of sustained-release oxycodone(Oxycodone SR Capsules), an independent clinical study was planned to accurately evaluate the efficacy and safety during a 9-day period. After a 3-day pretreatment period, the generic formulation was administered to patients with progressive cancer, who had been treated with a branded formulation(OxyContin®Tablets)of the drug for 5 days at the same dose. This was followed by a 1- day observation period. Drug administration to 3 patients with pulmonary cancer achieved the primary(dose, pain level, and adverse drug reactions)and secondary(rescue dose frequency and quality of life)endpoints, as well as safety goals. The merits of adopting a different dosage form were also noted. Independent data collection using an appropriate evaluation method consequently promoted the understanding of generic opioids in the clinical setting.

Noninvasive early detection of anthracycline-induced cardiotoxicity in patients with hematologic malignancies using the phased tracking method.

Anthracyclines are among the most effective and widely used anticancer drugs; however, their use is limited by serious cardiotoxicity. Early detection is necessary to prevent the high mortality rate associated with heart failure (HF). We evaluated cardiac function in 142 patients using conventional echocardiography and the phased tracking method (PTM), which was measured using the minute vibration and the rapid motion components, neither of which is recognized in standard M-mode nor in tissue Doppler imaging. For systolic function comparison, we compared left ventricular ejection fraction (LVEF) in conventional echocardiography with the average velocity of ventricular septum myocytes (Vave ) in the PTM. The Vave of 12 healthy volunteers was 1.5 (m/s)/m or more. At baseline of 99 patients, there was a positive correlation between LVEF and Vave in all patients. There were no significant differences in baseline cardiac function between patients with and without HF. There was a negative correlation between the cumulative anthracycline dose and LVEF or Vave among all patients. We determined that Vave 1.5 (m/s)/m was equivalent to LVEF 60%, 1.25 (m/s)/m to 55%, and 1.0 (m/s)/m to 50%. During the follow-up period, there was a pathological decrease in LVEF (<55%) and Vave (<1.25 m/s/m) in patients with HF; decreases in Vave were detected significantly earlier than those in LVEF (P < 0.001). When Vave declined to 1.5 (m/s)/m or less, careful continuous observation and cardiac examination was required. When Vave further declined to 1.0 (m/s)/m or lower, chemotherapy was postponed or discontinued; thus, serious drug-induced cardiomyopathy was avoided in patients who did not relapse. The PTM was superior to echocardiography for early, noninvasive detection and intermediate-term monitoring of left ventricle systolic function associated with anthracycline chemotherapy, among patients with hematologic malignancies. The PTM was an effective laboratory procedure to avoid the progression to serious cardiomyopathy.

[Team Approaches for and Future Challenges to Promoting Perioperative Oral Management].

When the medical fee system was revised in 2012, the category of perioperative oral management was newly organized. However, the calculation of additional fees for such management required referral from medical to dental departments. In addition, requests for such management were limited, possibly owing to an increased burden on doctors engaged in outpatient services. This study examined the usefulness of an approach to promote patients' use of dental services by increasing their awareness of the importance of oral management. In this approach, pharmacists explained doctors' instructions to patients at a chemotherapy center within the study facility. Explanations were provided to 114 patients, 75 (65.8%) of whom subsequently used dental services in the facility. For patients using dental services, oral care was performed most frequently (40; 53.3%), followed by invasive procedures (23; 30.7%). Furthermore, the facility's ethics committee approved a survey to measure the satisfaction of patients undergoing chemotherapy at the center. Of the 110 patients invited to participate in the survey, 77(70.0%) did not respond. Researchers concluded the low response rate was associated with patients' belief that dental services were intended primarily for treating oral cavities and their lack of awareness of the importance of preventive dental care. However, in 2014, the number of calculations of additional fees for perioperative oral management markedly increased each month after the above-mentioned approach, from 62 (January) to 162 (December). Both the hospital-to family and family-to-hospital dentist referral rates significantly increased, from 11.2% and 10.7%, respectively (June 2013), to 21.0% and 41.9%, respectively(June 2014). Future evaluations of the outcomes of perioperative oral management and promoting cooperation between medical and dental communities may be necessary.

[Initial Evaluation of the Efficacy and Safety of Tablets Containing Trifluridine and Tipiracil Hydrochloride--Safety Measures Devised by a Multidisciplinary Team Including a Pharmaceutical Outpatient Clinic].

In May 2014, tablets containing both trifluridine and tipiracil hydrochloride (Lonsurf® tablets) were launched in Japan ahead of other countries, for the treatment of advanced/relapsed unresectable colorectal cancer. The benefits of these tablets in terms of a new therapeutic option have been demonstrated. However, the manufacturer has requested healthcare professionals to help develop safety measures for the appropriate and safe use of the tablets. In this study, we evaluated the efficacy and safety of the tablets in 16 patients who received the tablets at our hospital. Among the 4 evaluable patients, none achieved a complete or partial response. One patient (25.0%) had stable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines outlined in the General Rules of the Study of Colorectal Cancer (The 8th Edition). Lonsurf® is considered to be a third-line (or later) treatment. Among the 16 cases studied, Lonsurf® was used as a third-, fourth-, and fifth-line treatment in 9, 6, and 1 cases, respectively. Therefore, Grade 3 or worse toxicities were a potential concern. Despite a high incidence of Grade 3 or worse neutropenia (7 of the 16 patients [43.8%]), none of the patients were hospitalized due to neutropenia or other treatment-related adverse events. Pharmacists have made 126 proposals to physicians regarding the use of Lonsurf®, 121 (96.0%) of which have been adopted. All of the adverse reactions experienced by our patients were resolved after supportive therapy.

[Appropriate dosing of fosaprepitant for colon cancer patients].

After fosaprepitant (FOS)was added to the National Health Insurance drug reimbursement price list, we switched the route of administration of antiemetics from oral to intravenous in chemotherapy regimens for colon cancer to improve patient medication adherence. However, because the number of patients reporting application-site disorders after administration of FOS increased, we monitored the incidence of these disorders in patients with colon cancer to identify ways to avoid them. In our prospective study, patients receiving conventional FOS dosing regimens (control group)were compared with those receiving diluted FOS solutions (study group). There were no significant differences between the two groups with respect to the incidence of application-site disorders, and contrary to expectations, the incidence was higher in the study group than in the control group. On the basis of the principle of non-maleficence and the availability of alternative therapies using oral aprepitant (APR), we terminated this study early and adopted the basic strategy that all patients with application-site disorders, except for those with central venous access devices, should be treated with oral APR after confirming their preferences.

[An assessment tool for chemotherapy-induced nausea and vomiting and intervention outcomes].

Chemotherapy-induced nausea and vomiting(CINV)is the most unpleasant side effect for patients receiving cancer chemotherapy. Moderately emetic anticancer drugs show a wide range of emetic frequencies, and the use or nonuse of antiemetics is optionally described without specifics. In the present study, we clarified the state of CINV presentation caused by moderately emetic anticancer drugs using the MASCC Antiemesis Tool, a nausea-and-vomiting evaluation tool developed by the Multinational Association of Supportive Care in Cancer(MASCC)for patients with colorectal cancer. Of the 32 subjects, 5 (15.6%)had vomiting and 22(68.8%)experienced nausea. The timing of their occurrence and their nausea scores were accurately and easily clarified. This study's findings suggested that the current regimens need to be reviewed, particularly because all patients exhibited late nausea; therefore, we modified our antiemetic regimens through the Cancer Chemotherapy Regimen Review Board of this hospital. After the modification was introduced, significant improvement was seen in the control of both acute and late nausea/vomiting.

[Examination of the usefulness of the pharmacists' outpatient clinic for treatment with oral molecule-targeting drugs].

BACKGROUND: In the author's hospital, pharmacists' outpatient clinics were initiated in April 2010, and the department of breast surgery there has provided guidance on oral anti-cancer medication, but with difficulty in adopting proposals for supportive therapy made after the doctor's consultation on the same day. Under such circumstances, this study examined methods for conducting interviews with patients before the doctor's consultation in cases where oral molecular-targeted drugs are necessary. OBJECTIVE: To promote next-generation skill-mix team medicine in order to improve the continuity of treatment and optimize therapeutic effects. METHODS: Patients being treated with oral molecular-targeted drugs in Hitachi General Hospital were studied. INTERVENTION: Outcomes were assessed through medication-monitoring reports, while conducting a questionnaire regarding duties of pharmacists coordinating molecular-targeted drugs. RESULTS: Within the study period, 245/259(94. 6%)of proposals for prescriptions were adopted in 95 patients, among which 212/245(86. 5%) proposed supportive therapy. Improvement in conditions was observed in all patients treated with supportive therapy. The mean duration of sorafenib administration among 19 patients before and after the pharmacist's intervention was 66±20. 3 and 102±30. 8 days, respectively. The main reason for the need of pharmacists coordinating molecular-targeted drugs was: security among all patients; "support for adverse event management"among all doctors; and "proposals for prescription" among all nurses. DISCUSSION: The mean duration of sorafenib administration prolonged by the pharmacist's intervention and consequent reduction in side effects may have directly improved the continuity of treatment. Furthermore, when reflecting on each prescription, the pharmacist's expertise may have facilitated pharmacological intervention. In the future, it may also be necessary to promote pharmacist-led consultations supporting patients' informed choice of drugs.

[Nutritional assessment using MUST(Malnutrition Universal Screening Tool) in outpatient chemotherapy].

OBJECTIVE: We set out to see if nutritional assessment(management)using MUST could be useful for patients undergoing outpatient chemotherapy. METHODS: The study sample consisted of 197 patients undergoing outpatient chemotherapy between June 2010 and November 2010. The results of MUST, serum albumin levels, and nutritional intervention were investigated. RESULTS: High- and medium-risk patients requiring nutritional therapy was comprised of 17/78 breast cancer(21. 8%), 16/63 hematologic malignancy(25. 4%), and 26/56 colonic cancer(46. 4%)patients.Moreover, the serum albumin level in high- and medium-risk patients was likely to decrease compared to low-risk patients, suggesting the usefulness of MUST. DISCUSSION AND CONCLUSION: It is important to assess nutritional status focusedon simplicity, objectivity, andspeedin outpatient chemotherapy. Assessment of patients' nutritional status and cancer treatment compliance are expected to be improved using MUST.