Newly developed humanized anti-CKAP4 antibody suppresses pancreatic cancer growth by inhibiting DKK1-CKAP4 signaling.

Cytoskeleton-associated protein 4 (CKAP4) is a cell surface receptor for Dickkopf 1 (DKK1), a secreted protein. The DKK1-CKAP4 pathway is activated in various malignant tumors, including pancreatic, lung, esophageal, and liver cancers, to promote tumor growth. Thus, CKAP4 has been expected to represent a novel molecular target of cancer therapy. Recombinant mouse anti-CKAP4 antibodies were generated based on an original mouse antibody (3F11-2B10) and inhibited DKK1-CKAP4 signaling and xenograft tumor formation induced by pancreatic cancer cells, which was comparable with 3F11-2B10. From the 3F11-2B10 nucleotide sequence, humanized anti-CKAP4 antibody (Hv1Lt1) was subsequently developed. The binding affinity of Hv1Lt1 for CKAP4 was superior to that of 3F11-2B10. Hv1Lt1 inhibited DKK1 binding to CKAP4, AKT activity, and sphere formation of pancreatic cancer cells, which was comparable with 3F11-2B10. Hv1Lt1 also suppressed xenograft tumor formation induced by human pancreatic cancer cells and tumor growth in murine cancer models, in which murine pancreatic cancer organoids were orthotopically transplanted into the pancreas. In resected tumor samples from mice treated with Hv1Lt1, anti-tumor immune reactions were modulated and cytotoxic T cells were highly infiltrated in the tumor microenvironment. Additionally, combination of Hv1Lt1 and other chemotherapy drugs exhibited stronger effects compared with monotherapy. These results suggest that Hv1Lt1 represents a promising anti-cancer therapy.

Association between neutrophil-to-lymphocyte ratio and length of hospital stay in an acute psychiatric hospital: A cross-sectional study.

Aim: The available evidence for predicting length of stay in acute psychiatric hospitals includes demographics, diagnosis, and treatment variables. This study aimed to evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and length of hospital stay in an acute psychiatric hospital. Methods: A total of 116 patients who were admitted to an acute psychiatric ward at Urawa Neuropsychiatric Sanatorium (Saitama, Japan) from August 2022 to December 2022 were eligible for this study. Laboratory data of lymphocytes and neutrophils were assessed on the first day of admission and NLR was calculated based on the data. Participants were categorized into two groups, high NLR and low NLR, which were set as predictor variables, as well as using NLR as a continuous variable. Multiple linear regression was performed to determine the association between NLR and length of hospital stay, adjusting for confounding factors. Results: A total of 90 participants were included in this study. The association of NLR as a continuous variable and length of hospital stay was not significant. When we categorized participants into high- and low-NLR groups, the association was significant even after adjusting by covariates (p < 0.05). Conclusion: Categorized NLR was positively associated with the length of hospital stay in patients admitted to an acute psychiatric hospital. Categorized NLR may predict the length of hospital stay for patients who are admitted to an acute psychiatric hospital.

Increasing survivors of anthracycline-related cardiomyopathy with breast cancer in trastuzumab era: thirty-one-year trends in a Japanese Community.

BACKGROUND: Trastuzumab has improved breast cancer (BC) prognosis and reduced anthracycline use. However, the characteristic changes of anthracycline-related cardiomyopathy (ARCM) in patients with BC remain unclear. We aimed to update our understanding of ARCM in the trastuzumab era. METHODS: This retrospective observational cohort study included 2959 patients with BC treated with anthracyclines at three regional cancer centers in Niigata City between 1990 and 2020. Seventy-five patients (2.5%) developed ARCM and were categorized into two groups: pre- 2007 (early phase) and post-2007 (late phase), corresponding to before and during the trastuzumab era in Japan. RESULTS: ARCM incidence peaked at 6% in the 1990s, then decreased and stabilized at 2% until the 2010s. Survivors of anthracycline-treated BC increased more rapidly in the late phase, with four times as many patients with ARCM compared to the end of the early phase (26 and six, respectively). Although the rate of change in accumulation from the early phase to the late phase was slight in the anthracycline-treated BC group, it was more pronounced in the ARCM group (P < 0.001). Mean anthracycline use in the late phase was significantly lower than in the early phase (307 vs. 525 mg/m2, P < 0.001). Five-year survival rates in the late phase tended to be higher than early phase (45% and 28%, respectively. P = 0.058). Human epidermal growth factor receptor type 2 (HER2) positivity with trastuzumab therapy in the late phase was an independent predictor for mortality within 10 years (hazard ratio = 0.24, 95% confidence interval: 0.10-0.56; P = 0.001). CONCLUSIONS: HER2-positive patients with ARCM receiving trastuzumab therapy had a better prognosis than HER2-positive and HER2-negative patients with ARCM not receiving trastuzumab therapy, and this trend has been increasing in the trastuzumab era. These findings highlight the importance of HER2-targeted treatments in improving prognosis for BC patients with ARCM.

Role of Wnt5b-Ror1 signaling in the proliferation of pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory cancers with the worst prognosis. Although several molecules are known to be associated with the progression of PDAC, the molecular mechanisms underlying the progression of PDAC remain largely elusive. The Ror-family receptors, Ror1 and Ror2, which act as a receptor(s) for Wnt-family ligands, particularly Wnt5a, are involved in the progression of various types of cancers. Here, we show that higher expression of Ror1 and Wnt5b, but not Ror2, are associated with poorer prognosis of PDAC patients, and that Ror1 and Wnt5b are expressed highly in a type of PDAC cell lines, PANC-1 cells. Knockdown of either Ror1 or Wnt5b in PANC-1 cells inhibited their proliferation significantly in vitro, and knockout of Ror1 in PANC-1 cells resulted in a significant inhibition of tumor growth in vivo. Furthermore, we show that Wnt5b-Ror1 signaling in PANC-1 cells promotes their proliferation in a cell-autonomous manner by modulating our experimental setting in vitro. Collectively, these findings indicate that Wnt5b-Ror1 signaling might play an important role in the progression of some if not all of PDAC by promoting proliferation.

Trends in endometrial carcinoma: experience of a single institute for four decades.

OBJECTIVE: To determine the current prognosis of endometrial carcinoma in Japan by analyzing long-term trends in endometrial carcinoma at our hospital. METHODS: We divided 1463 patients with endometrial carcinoma who visited our hospital between 1984 and 2022 into group 1984-1991, group 1992-1999, group 2000-2006, group 2007-2014 and group 2015-2022. Trends were determined using the Jonckheere-Terpstra and Cochran-Armitage tests. Data were analyzed using Cox regression analysis. RESULTS: When group 2015-2022 was used as a reference in the univariate analysis, the hazard ratios for the other groups were <1. In particular, the hazard ratio for group 2007-2014 was 0.65 (95% confidence interval, 0.47-0.90, P = 0.009), suggesting that the prognosis of group 2015-2022 was worse than that of group 2007-2014 and seemed to be the worst among all prognoses. In multivariate analysis, the hazard ratios for each group were 1.38, 1.42, 1.88, 1.16 and 1, respectively; the group with the worst prognosis changed from group 2015-2022 to group 2000-2006 (hazard ratio, 1.88; 95% confidence interval, 1.27-2.78, P = 0.001). Age and the rate of non-endometrioid carcinoma exhibited significantly increasing trends (P < 0.001 and P < 0.001, respectively), as did the rates of serous and mixed carcinomas (P = 0.001 and 0.024, respectively). The rates of non-endometrioid carcinoma, serous carcinoma and mixed carcinoma were 19.0%, 5.5% and 3.1% in group 2007-2014 and 28.2%, 10.8% and 4.6% in group 2015-2022, respectively. CONCLUSIONS: The increasing rates of non-endometrioid carcinoma-especially serous and mixed carcinoma-may be associated with the worsening prognosis of endometrial carcinoma at our institution. Careful monitoring is needed to confirm whether this phenomenon is observed throughout Japan.

Wnt/ß-catenin signaling pathway in liver biology and tumorigenesis.

The Wnt/ß-catenin pathway is an evolutionarily conserved signaling pathway that controls fundamental physiological and pathological processes by regulating cell proliferation and differentiation. The Wnt/ß-catenin pathway enables liver homeostasis by inducing differentiation and contributes to liver-specific features such as metabolic zonation and regeneration. In contrast, abnormalities in the Wnt/ß-catenin pathway promote the development and progression of hepatocellular carcinoma (HCC). Similarly, hepatoblastoma, the most common childhood liver cancer, is frequently associated with ß-catenin mutations, which activate Wnt/ß-catenin signaling. HCCs with activation of the Wnt/ß-catenin pathway have unique gene expression patterns and pathological and clinical features. Accordingly, they are highly differentiated with retaining hepatocyte-like characteristics and tumorigenic. Activation of the Wnt/ß-catenin pathway in HCC also alters the state of immune cells, causing "immune evasion" with inducing resistance to immune checkpoint inhibitors, which have recently become widely used to treat HCC. Activated Wnt/ß-catenin signaling exhibits these phenomena in liver tumorigenesis through the expression of downstream target genes, and the molecular basis is still poorly understood. In this review, we describe the physiological roles of Wnt/b-catenin signaling and then discuss their characteristic changes by the abnormal activation of Wnt/b-catenin signaling. Clarification of the mechanism would contribute to the development of therapeutic agents in the future.

Refractory ovarian squamous cell carcinoma arising from a seromucinous borderline tumor with squamous overgrowth: A case report.

Ovarian squamous cell carcinoma (SCC) is rare, and most cases arise from ovarian teratomas. Herein, we present a case of ovarian SCC arising from an ovarian seromucinous borderline tumor (SMBT) with squamous overgrowth. A 71-year-old woman an underwent emergency laparotomy due to the rupture of a right ovarian tumor suspected to be a borderline or malignant tumor. We performed a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and partial omentectomy. The postoperative diagnosis was stage IC3 ovarian SCC arising from the SMBT with a squamous overgrowth. Subsequently, she underwent six cycles of combination therapy comprising paclitaxel and carboplatin. Two months after the last chemotherapy treatment, she presented with back pain. A CT scan showed a 14 mm pelvic tumor affecting the ureter, leading to right hydronephrosis. The patient underwent tumor resection and ureteroureterostomy. The pathological diagnosis was keratinizing SCC, representing ovarian cancer recurrence. Eight months after the removal of the recurrent tumor, we found a 35 mm recurrent pelvic tumor causing right hydronephrosis. Additionally, a 20 mm pleural dissemination was identified. Comprehensive genome profiling of recurrent tumor revealed genomic abnormalities in TP53, ARID1A, PTEN, PIK3R1, and CDKN2A/2B. Regarding immunotherapy biomarkers, the microsatellite instability test result was negative, the tumor mutation burden was low, and PD-L1 was highly expressed. The patient was referred to another hospital for participation in an immunotherapy clinical trial for ovarian SCC. This case indicates that refractory ovarian SCC can arise from SMBT. Further evaluation of additional cases is required to identify the molecular biological characteristics of ovarian SCC.

Heterogeneous Expression of Arabidopsis Subclass II of SNF1-Related Kinase 2 Improves Drought Tolerance via Stomatal Regulation in Poplar.

Abscisic acid (ABA) is the most important phytohormone involved in the response to drought stress. Subclass II of SNF1-related kinase 2 (SnRK2) is an important signaling kinase related to ABA signal transduction. It regulates the phosphorylation of the target transcription factors controlling the transcription of a wide range of ABA-responsive genes in Arabidopsis thaliana. The transgenic poplars (Populus tremula × P. tremuloides, clone T89) ectopically overexpressing AtSnRK2.8, encoding a subclass II SnRK2 kinase of A. thaliana, have been engineered but almost no change in its transcriptome was observed. In this study, we evaluated osmotic stress tolerance and stomatal behavior of the transgenic poplars maintained in the netted greenhouse. The transgenic poplars, line S22, showed a significantly higher tolerance to 20% PEG treatment than non-transgenic controls. The stomatal conductance of the transgenic poplars tended to be lower than the non-transgenic control. Microscopic observations of leaf imprints revealed that the transgenic poplars had significantly higher stomatal closures under the stress treatment than the non-transgenic control. In addition, the stomatal index was lower in the transgenic poplars than in the non-transgenic controls regardless of the stress treatment. These results suggested that AtSnRK2.8 is involved in the regulation of stomatal behavior. Furthermore, the transgenic poplars overexpressing AtSnRK2.8 might have improved abiotic stress tolerance through this stomatal regulation.

Intraperitoneal Carboplatin for Ovarian Cancer - A Phase 2/3 Trial.

BACKGROUND: Intraperitoneal chemotherapy has been shown to be effective at reducing mortality for patients with advanced epithelial ovarian cancer but is not widely used in practice. METHODS: We performed the Intraperitoneal Therapy for Ovarian Cancer with Carboplatin (iPocc) trial as an open-label, international, multi-institutional, randomized phase 2/3 clinical trial in women with newly diagnosed epithelial ovarian cancer who underwent laparotomy or laparoscopy. All patients received intravenous paclitaxel (80 mg/m2 on days 1, 8, and 15 of a 21-day cycle). In addition, patients in the control group received intravenous carboplatin (dose-dense intravenous paclitaxel plus intravenous carboplatin [dd-TCiv]), whereas patients in the experimental group received dose-dense intravenous paclitaxel plus intraperitoneal carboplatin (dd-TCip). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response, treatment completion rate, and incidence of adverse events (AEs). RESULTS: Among 655 patients randomized to treatment, median (95% confidence interval [CI]) PFS was 20.7 (18.1 to 22.8) months for dd-TCiv (n=328) and 23.5 (20.5 to 26.9) months for dd-TCip (n=327; hazard ratio, 0.83; 95% CI, 0.69 to 0.99; P=0.04). The PFS benefit with dd-TCip was consistent in patients with different baseline characteristics, stage, size of residual tumor, age, and performance status. The treatment completion rates were 68.3 and 59.9% in the dd-TCiv and dd-TCip groups, respectively. The incidence of intraperitoneal catheter-related AEs in the dd-TCip group was 10.1%; there were no such AEs in the dd-TCiv group. CONCLUSIONS: In the first-line treatment of advanced epithelial ovarian cancer, intraperitoneal carboplatin resulted in a modest prolongation of PFS when given with dose-dense weekly paclitaxel regardless of residual tumor size, with no impact on noncatheter-related toxicities. (Funded by the Japan Agency for Medical Research and Development, and others; Japan Registry of Clinical Trials number, jRCTs031180141.)

Planificación pre-operatoria digital en artroplastia total de cadera / Digital templating in total hip arthroplasty

Introducción: La planificación preoperatoria favorece la realización de un acto quirúrgico sin complicaciones. Actualmente existe escasa información a nivel nacional sobre la eficacia de la planificación pre-operatoria digital por lo que el objetivo del presente estudio es el analizar los resultados de la implementación de esta estrategia en una población de pacientes con indicación de artroplastia total de cadera. Materiales y métodos: Estudio observacional, prospectivo, analítico. Se realizó un muestreo no probabilístico de casos consecutivos atendidos en la Cátedra de Ortopedia y Traumatología de la Facultad de Ciencias Médicas (U.N.A). Fueron captados pacientes >18 años con indicación de ATC, entre diciembre 2018 ­ octubre 2019, previo consentimiento informado. Se relevaron datos cuya caracterización fue posible mediante un instrumento establecido previamente, ingresado en base Excel. Se utilizó el software TraumaCad® versión 2.5 de Brainlab y marcadores radiológicos King Mark®. Fueron comparados ambos tipos de planificación ejecutando análisis estadísticos con el software R.v3.4.2., siendo un valor p ˂0.05, considerado estadísticamente significativa. Resultados: 57 pacientes fueron evaluados con el método digital y los resultados fueron comparados con los de 42 pacientes en los que se utilizó una planificación manual. La relación masculino-femenino fue 1/1, siendo los del grupo de 50 a 60 años, los más afectados. La coxartrosis primaria y la necrosis ósea aséptica fueron los diagnósticos más frecuentes. El tiempo quirúrgico, la correlación entre planificación y resultados para componentes acetabular, femoral, presentaron mejores resultados en el grupo de pacientes con planificación digital. Conclusión: La planificación digital comparada con la manual presentó mayor eficacia.

Introduction: Preoperative planning allows a surgical act without complications. It can be manual or digital. Its usefulness in total hip arthroplasty (ATC) is important, being digital seemingly more beneficial since it reduces surgical time and complications. The present study analyzed the effectiveness of the digital modality. Materials and methods: Observational, prospective, analytical study. Non-probabilistic sampling of consecutive cases attended in Department of Orthopedics and Traumatology of the Medicine Scholl (Universidad Nacional de Asunción). Patients> 18 years of age were indicated with ATC indication, between december 2018 to october 2019, with prior informed consent. Data whose characterization was made possible by means of a previously established instrument, entered in Excel basis, were released. Each patient had both types of planning: manual and digital. For TraumaCad® version 2.5 Brainlab software and King Mark® radiological markers were used for the digital. Both types of planning were compared by executing statistical analyzes with the software R.v3.4.2., being a value p <0.05, considered statistically significant. Results: 57 patients were evaluated with the digital method and 42 with the manual. The male-female ratio was 1/1, with those in the 50-60 age group being the most affected. The most frequent reason for consultation was hip pain, with primary coxarthrosis and aseptic bone necrosis being their cause. The consultation time 1 and surgery was 12.5 days. The surgical time, the correlation between planning and results for acetabular, femoral components, were more effective with digital planning. Conclusion: Digital planning compared to the manual is more effective.

Characterization of the genetic structure of mango ginger (Curcuma amada Roxb) from Myanmar in farm and genebank collection by the neutral and functional genomic markers

A preliminary characterization was undertaken to describe genetic structure of mango ginger (Curcuma amada) acquired from farmers and ex situ genebank in Myanmar using neutral (rice SSR based RAPDs) and functional genomic (P450 based analog) markers. The high polymorphism (> 91 percent) depicted has displayed existence of genetic variability in the germplasm investigated. Large number of source-specific alleles (neutral-markers = 78, functional-markers = 63) was amplified which revealed that neutral regions of the mango ginger were more variable compared with the functional regions. The major fraction of the molecular variance (neutral-markers = 85 percent, functional-markers = 93 percent) was explained within germplasm acquisition sources and this tendency was also supported by the estimate of gene diversity. The genebank accessions have shown comparatively more genetic variability than farmers' accessions. The variability observed in mango ginger may possibly be associated with the long history of its cultivation under diverse ecological conditions. The two marker systems elucidated their high resolving power which detected variability even in fewer genotypes assayed. As the target sites of these markers are different, therefore, the variability detected is believed to cover diverse part of the genome together with neutral and functional regions. We found the concurrent use of the different types of molecular markers valuable to comprehend a dependable variability pattern in the germplasm assayed.