Hedgehog signaling is highly conserved across species and governs proper embryonic development. Germline gene mutations that reduce this signaling activity cause a variety of developmental ...abnormalities such as holoprosencephaly, while those that enhance Hedgehog signaling activity induce a tumor‐predisposition condition Nevoid basal cell carcinoma syndrome. Furthermore, dysregulated activation of Hedgehog signaling has been recognized in various sporadic malignancies, including pancreatic adenocarcinoma. Pancreatic adenocarcinoma develops through a multistep carcinogenesis starting with oncogenic mutation of the KRAS gene. During this process, precancerous or cancer cells secrete Hedgehog ligand proteins to promote characteristic desmoplastic stroma around the cells, which in turn activates the expression of the downstream transcription factor GLI1 inside the cells. The quantitative and spatiotemporal dysregulation of GLI1 subsequently leads to the expression of transcriptional target genes of GLI1 that govern the hallmark of malignant properties. Here, after a brief introductory outline, a perspective is offered of Hedgehog signaling with a special focus on the role of GLI1 in pancreatic carcinogenesis.
Cell motility is a tightly regulated phenomenon that supports the accurate formation of organ structure during development and homeostasis, including wound healing and inflammation. Meanwhile, cancer ...cells exhibit dysregulated motility, which causes spreading and invasion. The Dbl family RhoGEF ARHGEF7/β-PIX and its binding partner p21-activated kinase PAK1 are overexpressed in a variety of cancers and have been shown to be responsible for cancer cell migration. A key step in motility is the intracellular transport of ARHGEF7-PAK1 complex to the migrating front of cells, where lamellipodia protrusion and cytoskeletal remodeling efficiently occur. However, the molecular mechanisms of the intracellular transport of this complex are not fully understood. Here we revealed that SCL/TAL1-interrupting locus (STIL) is indispensable for the efficient migration of cancer cells. STIL forms a ternary complex with ARHGEF7 and PAK1 and accumulates with those proteins at the lamellipodia protrusion of motile cells. Knockdown of STIL impedes the accumulation of ARHGEF7-PAK1 complex within membrane ruffles and attenuates the phosphorylation of PAK1 substrates and cortical actin remodeling at the migrating front. Intriguingly, ARHGEF7 knockdown also diminishes STIL and PAK1 accumulation in membrane ruffles. Either STIL or ARHGEF7 knockdown impedes cell migration and Rac1 activity at the migrating front of cells. These results indicate that STIL is involved in the ARHGEF7-mediated positive-feedback activation of cytoskeletal remodeling through accumulating the ARHGEF7-PAK1 complex in lamellipodia. We conclude that its involvement is crucial for the polarized formation of Rac1-mediated leading edge, which supports the efficient migration of cancer cells.
The anticancer effects of immune checkpoint inhibitors against CTLA4 and CD274-PDCD1 axes are evident. However, these immunotherapies for colorectal cancers (CRCs) are now limited to a small subset ...of patients with microsatellite unstable tumors. Thus, therapeutics targeting other types of CRCs is desired. The CD70–CD27 axis plays a co-stimulatory role in promoting the expansion and differentiation of T-lymphocytes through the activation of NFκB pathway. Aberrant activation of the CD70–CD27 axis accelerates tumor cell proliferation, survival, and immune evasion of tumor cells. Based on these observations, drugs modulating the CD70–CD27 axis have been developed with expectation of anticancer effects. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD70, CD27, and FOXP3 expression to assess their clinical usage and the application of CD70–CD27 axis modulating drugs. CRC tumor cells rarely (2.2%) expressed CD70. In contrast, tumor-surrounding fibroblasts showed various CD70 expressions (fCD70) in 14.9%. The logistic regression analysis revealed significant association of fCD70 expression with incomplete resection status (OR, 2.60; 95% CI, 1.10–6.13;
P
= 0.029). Overall survival was significantly decreased in the cohort of the patients with fCD70-positive tumor (
P
= 0.0078). Furthermore, significantly more CD27+ tumor-associated lymphocytes were detected within the primary CRCs without metastases (
P
= 0.024). Thus, the CD70–CD27 axis may have several roles in CRCs independent from their mismatch repair (MMR) system status. CD70–CD27 pathway-modulating therapies may be applied to CRC patients regardless of their tumor MMR status.
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide with high morbidity and mortality rates. The discovery of small molecule anticancer reagents has significantly ...affected cancer therapy. However, the anticancer effects of these therapies are not sufficient to completely cure CRC. PDZ-binding kinase (PBK) was initially identified as a mitotic kinase for mitogen-activated protein kinase and is involved in cytokinesis and spermatogenesis. Aberrant expression of PBK has been reported to be closely associated with malignant phenotypes of many cancers and/or patient survival. However, the expression of PBK and its association to patient survival in CRC have not been fully elucidated. In the present study, 269 primary CRCs were evaluated immunohistochemically for PBK expression to assess its ability as a prognostic factor. CRC tumor cells variably expressed PBK (range, 0–100%; median, 32%) in the nucleus and cytoplasm. Univariate analyses identified a significant inverse correlation between PBK expression and pT stage (
P
<0.0001). Furthermore, patients carrying CRC with higher PBK expression showed significantly favorable survival (
P
=0.0094). Multivariate Cox proportional hazards regression analysis revealed high PBK expression (HR, 0.52;
P
=0.015) as one of the potential favorable factors for CRC patients. PBK expression showed significant correlation to Ki-67 labeling indices (
ρ
=0.488,
P
<0.0001). In vitro, the PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells with PBK expression through downregulation of P-ERK and induction of apoptosis. These results suggest that PBK-targeting therapeutics may be useful for the treatment of PBK-expressing CRC patients.
Encapsulating peritoneal sclerosis (EPS) is a serious complication of peritoneal dialysis (PD). Over the past decade in Japan, a multidisciplinary approach has been adopted to minimize the incidence ...and improve outcomes of EPS. This strategy includes planned PD discontinuation for high-risk patients and the introduction of biocompatible solutions. This study examined the current clinical status of EPS in representative PD centers in Japan.
Patients (n = 1,338) from 55 PD centers in Japan who were using neutral-pH solutions from the initiation of therapy (mean age, 62 years; median PD duration, 32 months; concomitant use of icodextrin, 35.2%; PD and hemodialysis combination therapy, 12.2%) were assessed every 6 months to ascertain the reasons for PD discontinuation and the development of EPS development. Outcomes were also recorded. The study period was from November 2008 to March 2012.
There were 727 patients who discontinued PD, including 163 deaths. Among all causes of PD withdrawal except for death, planned PD discontinuation to avoid EPS was utilized in 58 cases (7.1% in total). The strategy was increasingly utilized in proportion to the duration of PD: 0.5% for patients undergoing PD for < 3 years, 0.6% for patients undergoing PD for 5 years, 14.7% for patients undergoing PD for 8 years, and 35.5% for patients undergoing PD for > 8 years. Fourteen patients developed EPS (three cases after PD), which corresponded with an overall incidence of 1.0%. The incidence according to the duration of PD was 0.3% for PD < 3 years, 0.6% for PD = 5 years, 2.3% for PD = 8 years, and 1.2% for PD > 8 years. In terms of therapy, 11 patients were treated with prednisolone (PSL), and surgical enterolysis was utilized in two cases. Complete remission of abdominal symptoms was achieved in twelve patients (85.7%), and three died due to EPS (mortality rate of 21.4%).
Use of the multidisciplinary approach described above reduces the risk of the development of EPS according to PD duration. In cases of de novo EPS cases in Japan, this strategy can also attenuate the clinical course of the condition.
Abstract
Background
Patients with chronic kidney disease (CKD) present high mortality and morbidity rates despite the availability of various therapies. Although CKD-mineral and bone disorder (MBD) ...and renal anemia are important factors in patients with CKD, only few studies have analyzed the relationship between them. Therefore, this study aimed to evaluate the relationship between CKD-MBD and anemia in patients with CKD who did not receive erythropoiesis-stimulating agent or iron therapies.
Methods
This retrospective cross-sectional study included patients with CKD aged ≥ 20 years with estimated glomerular filtration rate (eGFR) categories G2a to G5 who were referred to the Fuji City General Hospital between April 2018 and July 2019. The exclusion criterion was ongoing treatment for CKD-MBD and/or anemia.
Results
The data of 300 patients with CKD were analyzed in this study. The median age of patients was 71 (range, 56.5–79) years. The median eGFR was 34 (range, 20–48) mL/min/1.73 m
2
, and the mean hemoglobin (Hb) level was 12.7 g/dL (standard deviation, 2.3), which decreased as the CKD stage increased. In a multivariate linear regression analysis of anemia-related factors, including age, renal function (eGFR), nutritional status, inflammation, and iron dynamics (serum iron level, total iron-binding capacity, ferritin levels), the serum phosphate levels were significantly associated with the Hb levels (coefficient 95% confidence interval, -0.73 -1.1, -0.35;
P
< 0.001). Subgroup analysis revealed a robust association between serum phosphate levels and Hb levels in the low-ferritin (coefficient 95% confidence interval, -0.94 -1.53, -0.35;
P
= 0.002) and advanced CKD groups (coefficient 95% confidence interval, -0.89 -1.37, -0.41;
P
< 0.001).
Conclusions
We found an association between high serum phosphate levels and low Hb levels in patients with CKD not receiving treatment for anemia. These results underscore the possibility of a mechanistic overlap between CKD-MBD and anemia.
Pneumothorax secondary to septic pulmonary embolism (SPE) is rare but life-threatening. We herein report a long-term hemodialysis patient with psoas abscess caused by methicillin-resistant ...Staphylococcus aureus, associated with other muscle and splenic abscesses and SPE. Intravenous vancomycin treatment and percutaneous drainage of the psoas abscess rapidly improved her condition. However, the SPE lesions continued to increase, and right-sided pneumothorax occurred 10 days after treatment. The pneumothorax resolved after two months and SPE and all abscesses after four months of treatment. Since late-onset pneumothorax caused by SPE can occur despite successful treatment of the primary infection, care should be taken with such patients.
Archaeological evidence indicates that dogs appeared in Japan at least 9300 years ago, during the Jomon period. The Jomon period dogs (Jomon dogs) retained the morphological characteristics of ...ancient domestic dogs throughout the Jomon period, possibly due to their geographical isolation from continental dogs. Therefore, we expect them to retain the genetic characteristics of ancient domestic dogs. To explore this possibility, we determined the mitochondrial genomes of five Jomon dogs, including one of the oldest dogs in Japan (7400–7200 cal BP), and seven late-8th-century Japanese dogs (Suwada dogs). We analyzed these sequences with 719 mitochondrial genomes of ancient and modern canids. The dog mitochondrial DNA (mtDNA) sequences have been grouped into six clades (haplogroups A–F), and clade A comprises six sub-clades (sub-haplogroups A1–A6). Classification of the Jomon dogs’ mtDNA haplotypes revealed that these dogs belong to a nested A2/A3 sub-haplogroup not shared by other modern or ancient samples. The mtDNA sequences of Jomon dogs form a monophyletic clade which is sister to the A3 sub-clade in the phylogenetic trees. Network analysis showed that the Jomon dogs’ mtDNA sub-clade diverged close to the base of the A2 and A3 haplotype network, which was centered by an ancient dog from South China. The Jomon dog mtDNAs diverged from A3 (~11500 years ago) soon after the A2 and A3 divergence (~12800 years ago), indicating early divergence of the Jomon dogs’ sub-clade. These results suggest that the Jomon dogs were possibly introduced into the Japanese archipelago 11500–9300 years ago. The mtDNAs of late-8th-century dogs were more diverse and were different haplogroups than that of Jomon dogs, suggesting that other haplogroups likely replaced the haplogroup of Jomon dogs through the introduction of dogs that accompanied the migration of people into Japan in later periods.
Thrombophilia is a serious unpredictable complication caused by gene mutations, resulting in anticoagulant deficiencies. We herein report a single-family case series of protein C (PC) deficiency. ...Case 1 involved a Japanese man whose PC deficiency resulted in severe systemic thrombosis. The patients in cases 2 and 3 were his daughters who were diagnosed with PC deficiency via carrier screening in 2001 and later both became pregnant. Owing to appropriate treatments during pregnancy, they did not develop thrombosis and safely gave birth to healthy infants. This family case series suggests that appropriate knowledge concerning thrombophilia helps prevent future emergencies.
p53 immunohistochemistry is considered an accurate surrogate marker reflecting the underlying TP53 mutation status and has utility in tumor diagnostics. In the present study, 269 primary CRCs were ...immunohistochemically evaluated for p53 expression to assess its utility in diagnostic pathology and prognostication. p53 expression was wild-type in 59 cases (23%), overexpressed in 143 cases (55%), completely lost in 50 cases (19%), and cytoplasmic in 10 cases (4%). p53 immunoreactivity was associated with tumor size (p = 0.0056), mucus production (p = 0.0015), and mismatch repair (MMR) system status (p < 0.0001). Furthermore, among CRCs with wild-type p53 expression, a significantly higher number of cases had decreased CDX2 than those with p53 overexpression (p = 0.012) or complete p53 loss (p = 0.043). In contrast, among CRCs with p53 overexpression, there were significantly fewer ALCAM-positive cases than p53 wild-type cases (p = 0.0045). However, no significant association was detected between p53 immunoreactivity and the “stem-like” immunophenotype defined by CDX2 downregulation and ALCAM-positivity. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio HR = 0.17, p < 0.0001), younger age (HR = 0.52, p = 0.021), and female sex (HR = 0.55, p = 0.046) as potential favorable factors. The analysis also revealed complete p53 loss (HR = 2.16, p = 0.0087), incomplete resection (HR = 2.65, p = 0.0068), and peritoneal metastasis (HR = 5.32, p < 0.0001) as potential independent risk factors for patients with CRC. The sub-cohort survival analyses classified according to chemotherapy after surgery revealed that CRC patients with wild-type p53 expression tended to have better survival than those with overexpression or complete loss after chemotherapy. Thus, immunohistochemistry for p53 could be used for the prognostication and chemotherapy target selection of patients with CRC.
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