Lymph node metastasis is a poor prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). However, its molecular mechanism has not yet been fully understood. In our study, we ...investigated the expression of CCR4 and its ligand CCL22 in the HNSCC tumor microenvironment and found that the CCR4/CCL22 axis was involved in lymph node metastasis of HNSCC. CCR4 was expressed in 20 of 31 (64.5%) human tongue cancer tissues, and its expression was significantly correlated with lymph node metastasis (p < 0.01) and lymphatic invasion (p < 0.05). CCR4 was expressed in three of five human HNSCC cell lines tested. CCR4+ HNSCC cells, but not CCR4− cells, showed enhanced migration toward CCL22, indicating that functional CCR4 was expressed in HNSCC cell lines. CCL22 was also expressed in cancer cells (48.4% of tongue cancer tissues) or CD206+ M2‐like macrophages infiltrated in tumors and draining lymph nodes. CCL22 produced by cancer cells or CD206high M2‐like macrophages increased the cell motility of CCR4+ HNSCC cells in vitro in an autocrine or paracrine manner. In the mouse SCCVII in vivo model, CCR4+ cancer cells, but not CCR4− cells, metastasized to lymph nodes which contained CCL22 producing M2‐like macrophages. These results demonstrate that lymph node metastasis of CCR4+ HNSCC is promoted by CCL22 in an autocrine or M2‐like macrophage‐dependent paracrine manner. Therefore, the CCR4/CCL22 axis may be an attractive target for the development of diagnostic and therapeutic strategies for patients with HNSCC.
What's new?
Chemokines are major regulators of cell motility previously implicated in cancer metastasis. Here, the authors link the C‐C chemokine receptor 4 (CCR4) and its ligand CCL22 to lymph node metastasis of head and neck cancer cells by analyzing samples from patients and a mouse model. They find that the metastasis of cancer cells expressing CCR4 on their surface was promoted via the CCR4/CCL22 interaction in an autocrine and paracrine manner involving M2‐like macrophages. These findings point to the CCR4/CCL22 axis as a potential new target for diagnostic and therapeutic development in head and neck cancer patients with lymph node metastases, a condition with otherwise poor prognosis.
In vertebrates, the initial step in heme biosynthesis is the production of 5-aminolevulinic acid (ALA) by ALA synthase (ALAS). ALA formation is believed to be the rate-limiting step for cellular heme ...production. Recently, several cohort studies have demonstrated the potential of ALA as a treatment for individuals with prediabetes and type-2 diabetes mellitus. These studies imply that a mechanism exists by which ALA or heme can control glucose metabolism. The ALAS1 gene encodes a ubiquitously expressed isozyme. Mice heterozygous null for ALAS1 (A1+/-s) experience impaired glucose tolerance (IGT) and insulin resistance (IR) beyond 20-weeks of age (aged A1+/-s). IGT and IR were remedied in aged A1+/-s by the oral administration of ALA for 1 week. However, the positive effect of ALA proved to be reversible and was lost upon termination of ALA administration. In the skeletal muscle of aged A1+/-s an attenuation of mitochondrial function is observed, coinciding with IGT and IR. Oral administration of ALA for 1-week brought about only a partial improvement in mitochondrial activity however, a 6-week period of ALA treatment was sufficient to remedy mitochondrial function. Studies on differentiated C2C12 myocytes indicate that the impairment of glucose metabolism is a cell autonomous effect and that ALA deficiency ultimately leads to heme depletion. This sequela is evidenced by a reduction of glucose uptake in C2C12 cells following the knockdown of ALAS1 or the inhibition of heme biosynthesis by succinylacetone. Our data provide in vivo proof that ALA deficiency attenuates mitochondrial function, and causes IGT and IR in an age-dependent manner. The data reveals an unexpected metabolic link between heme and glucose that is relevant to the pathogenesis of IGT/IR.
Forage rice (Oryza sativa L.) must be cost competitive with other fodders, and thus an important goal is increasing its dry matter (DM) and total digestible nutrient (TDN) yields, while reducing ...labor and costs. Although the direct seeding of rice does not have higher yield stability than transplanting, it has the potential to reduce labor and costs. The objective of this study was to determine the effects of seeding rate (2, 4, or 6 g m–2) and row spacing (10 or 30 cm) on DM and TDN yields in direct-seeded and double-harvested forage rice in a well-drained paddy field. The seeding rate did not affect the total DM and TDN yields of the first and second crops, although those total yields were higher at 10 cm row spacing than at 30 cm row spacing. The DM yield and tiller number of the first crop increased with increasing seeding rate. Both were higher at 10 cm row spacing than at 30 cm row spacing. The seeding rate did not affect the DM and TDN yields of the second crop harvested at heading, although those yields were higher at 10 cm row spacing than at 30 cm row spacing. Neither seeding rate nor row spacing affected the DM and TDN yields of the second crop harvested at dough ripe. Thus, increasing the seeding rate is effective for increasing the DM and TDN yields of the first crop and reducing row spacing is effective for increasing total DM and TDN yields of the first and second crops. This cultivation method is expected to facilitate forage rice production by reducing labor and costs in temperate regions.
This study aimed to determine the consequences of snoring independent of obstructive sleep apnea (OSA) and hypothesized that snoring sound intensity, as assessed by mean tracheal sound (TS) energy ...(Leq), is related to morning blood pressure (BP).
A home-based TS monitoring study was performed for two nights on 191 workers in Japan using an IC recorder. Leq and the respiratory disturbance index (RDI) were calculated from the TS data. RDI was used as a marker of OSA severity. Systolic and diastolic BP measurements in the evening and morning (eSBP/eDBP and mSBP/mDBP, respectively) were done before and after TS recording. The data of the second night were analyzed.
Leq was significantly related to both mSBP and mDBP (r = 0.32, p < 0.0001; r = 0.34, p < 0.0001, respectively). Leq was also significantly related to morning BP after adjustment for age, sex, and body mass index. However, the relationship was no longer significant when both RDI and Leq were included in the multiple regression model. In non-apneic, non-obese subjects, Leq was significantly related to both mSBP and mDBP (r = 0.38, p < 0.0001; r = 0.33, p = 0.0004, respectively). In this group, Leq was associated with mSBP after adjusting for all confounding factors (n = 106, p = 0.022).
The association between night TS intensity and morning BP suggests a pathological role of heavy snoring. To understand this association, a prospective cohort study in a general population is warranted.
A commentary on this article appears in this issue on page 1581.
Increasing rice yield potential is a major objective in rice breeding programs, given the need for meeting the demands of population growth, especially in Asia. Genetic analysis using genomic ...information and high-yielding cultivars can facilitate understanding of the genetic mechanisms underlying rice yield potential. Chromosome segment substitution lines (CSSLs) are a powerful tool for the detection and precise mapping of quantitative trait loci (QTLs) that have both large and small effects. In addition, reciprocal CSSLs developed in both parental cultivar backgrounds may be appropriate for evaluating gene activity, as a single factor or in epistatic interactions.
We developed reciprocal CSSLs derived from a cross between Takanari (one of the most productive indica cultivars) and a leading japonica cultivar, Koshihikari; both the cultivars were developed in Japan. Forty-one CSSLs covered most of the Takanari genome in the Koshihikari background and 39 CSSLs covered the Koshihikari genome in the Takanari background. Using the reciprocal CSSLs, we conducted yield trials under canopy conditions in paddy fields. While no CSSLs significantly exceeded the recurrent parent cultivar in yield, genetic analysis detected 48 and 47 QTLs for yield and its components in the Koshihikari and Takanari backgrounds, respectively. A number of QTLs showed a trade-off, in which the allele with increased sink-size traits (spikelet number per panicle or per square meter) was associated with decreased ripening percentage or 1000-grain weight. These results indicate that increased sink size is not sufficient to increase rice yield in both backgrounds. In addition, most QTLs were detected in either one of the two genetic backgrounds, suggesting that these loci may be under epistatic control with other gene(s).
We demonstrated that the reciprocal CSSLs are a useful tool for understanding the genetic mechanisms underlying yield potential in the high-yielding rice cultivar Takanari. Our results suggest that sink-size QTLs in combination with QTLs for source strength or translocation capacity, as well as careful attention to epistatic interactions, are necessary for increasing rice yield. Thus, our findings provide a foundation for developing rice cultivars with higher yield potential in future breeding programs.
The tumor microenvironment (TME) plays a key role in the efficacy of neoadjuvant chemotherapy (NAC) in solid tumors including esophageal squamous cell carcinoma (ESCC). However, the TME profile of ...ESCC treated with NAC is not fully understood. In this study, we investigated the effect of NAC on the TME especially tumor-associated macrophages (TAM), the important immunosuppressive components of the TME, in ESCC. We quantified the expression of CD163, a crucial marker of TAM, in pretherapeutic biopsy and surgically resected ESCC specimens from patients who received NAC (
= 33) or did not receive NAC (
= 12). We found that NAC dramatically increased the expression of CD163 on TAMs in ESCC. Colony-stimulating factor 1 (CSF-1) and IL34 are crucial cytokines that recruit monocytes into tumor sites and differentiate them into TAMs. Interestingly, NAC significantly upregulated the expression of IL34 but not CSF-1 on tumor cells, and the frequencies of CD163
TAMs were significantly correlated with IL34 expression in ESCC after NAC. The expression of IL34 in NAC-nonresponsive patients was significantly higher than that in NAC-responsive patients, and patients with IL34-high ESCC exhibited worse prognosis as compared with patients with IL34-low ESCC. We also demonstrated that 5-fluorouracil (5-FU)/cisplatin preferentially increased mRNA expression of IL34 on human ESCC cell lines. Human peripheral blood monocytes co-cultured with ESCC cells treated with 5-FU/cisplatin increased the expression of CD163, which was attenuated by the treatment with CSF-1R inhibitors. These data suggest that IL34 expression by NAC shifts the TME toward CD163
TAM-rich immunosuppressive and chemo-insensitive microenvironment in ESCC. IMPLICATIONS: The blockade of IL34 signaling may offer a novel therapeutic strategy against chemoresistance in ESCC by inhibiting M2-TAM polarization.
Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) encodes an enzyme that catalyzes de novo purine biosynthesis. Although PAICS has been ...implicated as a potential therapeutic target in several cancers, its clinical and prognostic significance in colorectal cancer (CRC) is not fully understood. To elucidate the roles of PAICS in CRC, we investigated PAICS expression in four cohorts consisting of a total of 1659 samples based on quantitative RT-PCR, microarray and RNA-seq analysis. Despite upregulated PAICS levels in tumor compared to those of normal mucosa, we found a decreasing trend of PAICS expression during tumor progression and metastasis. We conducted immunohistochemistry on 252 specimens, showing that PAICS protein was strongly expressed in the majority of CRCs, but not in adjacent mucosa. Notably, 29.0% of tumors lacked PAICS staining, and PAICS-negative expression in tumor had significant prognostic impact on poor cancer-specific survival in stage III CRC. Correspondingly, decreased levels of PAICS transcript were also correlated with poor relapse-free survival particularly in stage III patients, and this finding was robustly confirmed in three microarray datasets of a total of 802 stage II-III patients. Bioinformatics analysis of CRC tissues and cell lines consistently indicated a correlation between decreased PAICS expression and copy number loss of chromosome arm 4q. In conclusion, our results suggest that PAICS expression is downregulated during tumor progression due to genetic deletion of chromosome 4q in microsatellite stable but chromosomally unstable tumors. Furthermore, decreased expression of PAICS transcript or loss of PAICS protein may provide prognostic stratification for postoperative patients with stage III CRC.
The pathophysiological mechanisms of cisplatin nephrotoxicity include the reduction of renal blood flow, as well as tubular epithelial cell toxicity. The objective of this study was to investigate ...the influence of lower blood pressure and decreased food intake on the incidence of cisplatin nephrotoxicity.
We conducted a retrospective cohort study at a university hospital between 2011 and 2012. We identified hospitalized adult patients with head and neck cancer, esophageal cancer, or gastric cancer, who received intravenous cisplatin administration. The primary outcome was the incidence of cisplatin nephrotoxicity defined as the increase in serum creatinine after cisplatin administration more than 1.5 times from baseline.
The study participants included 182 patients, in whom we observed a total of 442 cycles of cisplatin chemotherapy. The incidence of cisplatin nephrotoxicity was observed in 41 of 182 cycles with initial administration. Multivariate logistic regression analysis showed that systolic blood pressure was independently associated with cisplatin nephrotoxicity (adjusted odds ratio 0.75, 95% confidence interval 0.57 to 0.95 for each 10 mmHg). The use of renin-angiotensin system (RAS) inhibitors was also associated with cisplatin nephrotoxicity (3.39, 1.30 to 8.93). Among quartiles of systolic blood pressure in all cycles of chemotherapy, the incidence of nephrotoxicity in the lower blood pressure group was significantly higher than that in the higher blood pressure group for patients taking non-solid food (P = 0.037), while there was no significant difference for patients taking solid food (P = 0.67).
Lower blood pressure and the use of RAS inhibitors were associated with the incidence of cisplatin nephrotoxicity, and lower blood pressure had a greater influence on nephrotoxicity in patients who could not take solid food. Discontinuation of antihypertensive medication including RAS inhibitors before cisplatin chemotherapy should be considered, which may be beneficial for patients with lower blood pressure.
Accurate and long-term transposition of offending vessels is required in microvascular decompression (MVD) for the treatment of hemifacial spasm (HFS) and trigeminal neuralgia (TN). We created ...ion-beam implanted of an expanded-polytetrafluoroethylene (i-ePTFE) surface to transpose offending vessels in MVD. In 13 patients with MVD, we concealed and transposed offending vessels with tape-shaped i-ePTFE, and relieved facial and trigeminal nerve compression by attaching the i-ePTFE to the dura with fibrin glue. After surgery, none of the patients reported further symptoms or experienced recurrence of symptoms up to 12 months post-surgery. Favorable surgical outcomes are obtainable, since i-ePTFE has high tissue affinity and is easy to manipulate, even under a narrow and deep operative field. Our results suggested that i-ePTFE is very useful for transposition in MVD.
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