Elimination of esophageal multiple precancerous lesions by chemotherapy: potential chemoprevention of metachronous multiple cancer development after curative treatment

Background

Dysplastic squamous epithelium is a precancerous lesion for squamous cell carcinoma. It is often present in the esophagus and head and neck region, and can be visualized as a Lugol-voiding lesion (LVL) by iodine chromoendoscopy. However, effective treatment for such dysplastic epithelia has not yet been developed.

Methods

Between March 2008 and July 2011, 40 consecutive patients with advanced esophageal squamous cell carcinoma were treated by two cycles of neoadjuvant chemotherapy (NAC) (5-fluorouracil, 800?mg/m², d 1?C5; cisplatin, 80?mg/m², d 1: q 21?days) at Kyoto University Hospital, and received iodine chromoendoscopy both before and after NAC. Iodine chromoendoscopy findings were divided into 4 groups: group?A, absence of LVLs; group?B, several (??10/one endoscopic view) small (??5?mm) LVLs; group?C, many (??10/one endoscopic view) small (??5?mm) LVLs; group?D, numerous irregular-shaped multiform LVLs. Group?C and D are defined as multiple LVLs. Endoscopic changes of LVLs before and after NAC were investigated retrospectively.

Results

Before NAC, 6, 12, 9, and 13 cases were classified in group?A, B, C, and D, respectively. All cases in group?A before NAC remained in group?A after NAC. Multiple LVLs (group?C and D) were significantly improved in 17 of 22 patients (77.3?%), while several small LVLs (group?B) were improved in only 4 of 12 cases (33.3?%) (p?=?0.025 by Fisher??s exact test).

Conclusions

Multiple dysplastic lesions tended to improve by chemotherapy. In contrast, there was little change in the mucosa with fewer dysplastic lesions after chemotherapy. These data show that chemotherapy has the potential to eliminate precancerous lesions.     

Comparison of the Loss of Renal Function after Cold Ischemia Open Partial Nephrectomy,Warm Ischemia Laparoscopic Partial Nephrectomy and Laparoscopic Partial Nephrectomy Using Microwave Coagulation

Purpose

Nephron sparing surgery is an effective surgical option in patients with renal cell carcinoma. Laparoscopic partial nephrectomy involves clamping and unclamping techniques of the renal vasculature. This study compared the postoperative renal function of partial nephrectomy using an estimation of the glomerular filtration rate (eGFR) for a Japanese population in 3 procedures; open partial nephrectomy in cold ischemia (OPN), laparoscopic partial nephrectomy in warm ischemia (LPN), and microwave coagulation using laparoscopic partial nephrectomy without ischemia (MLPN).

Materials and Methods

A total of 57 patients underwent partial nephrectomy in Yokohama City University Hospital from July 2002 to July 2008. 18 of these patients underwent OPN, 17 patients received MLPN, and 22 patients had LPN. The renal function evaluation included eGFR, as recommended by The Japanese Society of Nephrology.

Results

There was no significant difference between the 3 groups in the reduction of eGFR. eGFR loss in the OPN group was significantly higher in patients that experienced over 20 minutes of ischemia time. eGFR loss in LPN group was significantly higher in patients that experienced over 30 minutes of ischemia time.

Conclusion

This study showed that all 3 procedures for small renal tumor resection were safe and effective for preserving postoperative renal function.Key Words: eGFR, Partial nephrectomy, Renal function, Laparoscopic partial nephrectomy     

COX‐1‐dependent prostaglandin D2 in microglia contributes to neuropathic pain via DP2 receptor in spinal neurons

Cyclooxygenase (COX) enzyme synthesizes prostaglandins (PGs) from arachidonic acid and exists as two major isozymes, COX‐1 and COX‐2. The crucial role of prostaglandins in the pathogenesis of inflammatory pain in peripheral tissue and the spinal cord has been established; however its expression dynamics after peripheral nerve injury and its role in neuropathic pain are not clear. In this study, we examined the detailed expression patterns of genes for COX, PGD2 and thromboxane A2 synthases and their receptors in the spinal cord. Furthermore, we explored the altered gene expression of these molecules using the spared nerve injury (SNI) model. We also examined whether these molecules have a role in the development or maintenance of neuropathic pain. We found a number of interesting results in this study, the first was that COX‐1 was constitutively expressed in the spinal cord and up‐regulated in microglia located in laminae I‐II after nerve injury. Second, COX‐2 mRNA expression was induced in blood vessels after nerve injury. Third, TXA2 synthase and hematopoietic PGD synthase mRNAs were dramatically increased in the microglia after nerve injury. Finally, we found that intrathecal injection of a COX‐1 inhibitor and DP2 receptor antagonist significantly attenuated the mechanical allodynia. Our findings indicate that PGD2 produced by microglia is COX‐1 dependent, and that neurons in the spinal cord can receive PGD2 from microglia following peripheral nerve injury. We believe that PGD2 signaling via DP2 signaling pathway from microglia to neurons is one of the triggering factors for mechanical allodynia in this neuropathic pain model.     

Review of Cognitive Characteristics of Autism Spectrum Disorder Using Performance on Six Subtests on Four Versions of the Wechsler Intelligence Scale for Children

Journal of Autism and Developmental Disorders - This study was a systematic review of research using the Wechsler Intelligence Scale for Children (WISC) with Autism Spectrum Disorder (ASD) to...     

The usefulness of day-service in maintaining general nutritional status in elderly Japanese: a longitudinal study

Day-service, commuting service for elderly people requiring care at home, is one healthcare option in Japan. To date, however, there exist no studies that have examined the effects of day-service use on health outcomes in Japan. The objective of the present longitudinal study was to determine whether there is an association between day-service use and various physical and mental health outcomes in elderly people requiring care. The subjects were 61 elderly persons who required between 25 and 49 min of assistance per day and used long-term care insurance. Measurements included demographic characteristics, activities of daily living, frequency of day-service use, body weight, height, grip strength, thigh muscle volume, degree of depression (Geriatric Depression Scale), the mini-mental state examination, and serum albumin and blood hemoglobin levels in the baseline and follow-up surveys two years later. In the day-service user group, the mean changes in serum albumin concentrations using day-service once, twice and three < or = times/week were -0.2, -0.3, and 0 g/dl, respectively, and the mean changes in blood hemoglobin were -0.7, -0.5, and 0.2 g/dl, respectively. The two-year change in serum albumin concentrations was less (p = 0.024) in subjects using day-service "three < or = times" (0 g/dl) than "twice" (-0.3 g/dl). The two-year change in blood hemoglobin was also less (p = 0.043) in subjects using day-service "three < or = times" (0.2 g/dl) than "twice" (-0.5 g/dl). The present study has shown that frequent use of day-service is useful in maintaining general nutritional status in elderly people.     

Restoration of spermatogenesis by lentiviral gene transfer: offspring from infertile mice

Disruption of spermatogenesis found in azoospermia and oligozoospermia is thought to be of primarily genetic origin. Sl/Sl(d) mutant mice offer a model system in which lack of transmembrane type c-kit ligand (KL2) expression on the somatic Sertoli cell surface results in disruption of spermatogenesis. We investigated the ability of adeno-, adeno-associated-, retro-, and lentiviral vectors to transduce Sertoli cells and found that transduction with either adeno- or lentiviral vectors led to reporter gene expression for more than 2 mo after testicular tubule injection. Because adenoviral vectors showed toxicity, lentiviral vectors were used to express the c-kit ligand in Sl/Sl(d) Sertoli cells. Restoration of spermatogenesis was observed in all recipient testes. Furthermore, the sperm collected from recipient testes were able to generate normal pups after intracytoplasmic sperm injection. None of the offspring carried the transgene, suggesting the inability of lentiviral vectors to infect spermatogenic cells in vivo. We propose that lentiviral vectors can be used for gene therapy of male infertility without the risk of germ-line transmission.     

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility

For normal fertilization in mammals, it is important that functionally mature sperm are motile and have a fully formed acrosome. The glycosyltransferase-like gene, human polypeptide N-acetylgalactosaminyltransferase-like protein 5 (GALNTL5), belongs to the polypeptide N-acetylgalactosamine-transferase (pp-GalNAc-T) gene family because of its conserved glycosyltransferase domains, but it uniquely truncates the C-terminal domain and is expressed exclusively in human testis. However, glycosyltransferase activity of the human GALNTL5 protein has not been identified by in vitro assay thus far. Using mouse Galntl5 ortholog, we have examined whether GALNTL5 is a functional molecule in spermatogenesis. It was observed that mouse GALNTL5 localizes in the cytoplasm of round spermatids in the region around the acrosome of elongating spermatids, and finally in the neck region of spermatozoa. We attempted to establish Galntl5-deficient mutant mice to investigate the role of Galntl5 in spermiogenesis and found that the heterozygous mutation affected male fertility due to immotile sperm, which is diagnosed as asthenozoospermia, an infertility syndrome in humans. Furthermore, the heterozygous mutation of Galntl5 attenuated glycolytic enzymes required for motility, disrupted protein loading into acrosomes, and caused aberrant localization of the ubiquitin–proteasome system. By comparing the protein compositions of sperm from infertile males, we found a deletion mutation of the exon of human GALNTL5 gene in a patient with asthenozoospermia. This strongly suggests that the genetic mutation of human GALNTL5 results in male infertility with the reduction of sperm motility and that GALNTL5 is a functional molecule essential for mammalian sperm formation.O-glycosylation begins by the addition of N-acetylgalactosamine to the serine or threonine residues in the target protein. This first step occurs in the Golgi apparatus, and is mediated by UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (pp-GalNAc-T; EC 2.4.1.41), which transfer GalNAc from the nucleotide sugar to the acceptor residues (1). Polypeptide N-acetylgalactosaminyltransferase-like protein 5 [GALNTL5, also described as pp-GalNac-T19 (2) or GalNac-T20 (3); Refseq accession no.: {"type":"entrez-protein","attrs":{"text":"NP_660335.2","term_id":"281485547","term_text":"NP_660335.2"}}NP_660335.2] is classified as a member of the pp-GalNAc-T family because GALNTL5 possesses highly conserved catalytic domains of pp-GalNAc-T, whereas it uniquely lacks the conserved lectin domain at the C terminus. Thus far, 20 distinct pp-GalNAc-T genes have been identified in the human genome (2, 4–6). The in vitro enzymatic activities as a glycosyltransferase have been confirmed for 14 members of this family using acceptor peptide substrates (2, 7), but not identified for the other 6 members, including GALNTL5. During the preparation of this paper, it was reported that the transferase activity of GALNTL5 (GalNAc-T20) could not be detected using in vitro assays (3). The in vivo functions of these isoforms are poorly understood because of the absence of specific enzymatic activity. Meanwhile, O-fucosyltransferase 1, a member of a fucosyltransferase family, exhibits chaperon activity specific to Notch folding in Drosophila (8). One possibility is that the isoforms lacking enzymatic activities may have functions other than characteristics of glycosyltransferases, despite having typical glycosyltransferase motifs.Spermatogenesis is a complex process in which spermatogonial stem cells form spermatozoa through the proliferative phase (spermatogonia), the meiotic phase (spermatocytes), and the differentiation or spermiogenic phase (spermatids). Spermatids are connected by intercellular bridges, through which cytoplasmic constituents are shared among haploid spermatids (9). In the last spermiogenic phase, the round haploid spermatids differentiate into spermatozoa where acrosomes and tails unique and necessary for fertilization are developed. Spermatozoa are released through the seminiferous lumen into the epididymis, where they undergo further maturation and acquire motility. Sperm motility is an important factor in normal fertilization, whereas over 80% of sperm samples from infertile men demonstrate asthenozoospermia, poor sperm motility (10). Although defects of many potential genes are reported in mouse models exhibiting asthenozoospermia (11), it is rare that mutations in these genes are identified in human patients with asthenozoospermia.To investigate the biochemical machineries and biological functions of glycosylation, we performed comprehensive identification of the mammalian glycosyltransferase genes using various approaches and confirmed their enzymatic activity in vitro using biochemical methods (12). During these studies, we identified a unique isoform of the human GALNTL5 gene restricted to the human testis. However, we could not confirm the glycosyltransferase activity of GALNTL5, including whether it is a functional molecule in spermatogenesis. Therefore, using the mouse Galntl5 gene, we attempted to elucidate the biological role of GALNTL5 in spermatogenesis and found that the heterozygous mutation of Galntl5 causes male infertility by reducing sperm motility, which highly resembles human asthenozoospermia. In reference to the aberrant protein compositions of sperm from the Galntl5 heterozygous mutant mice (Ht mice), we found a patient with asthenozoospermia carrying one heterozygous nucleotide deletion at the sixth exon of the human GALNTL5 gene. Together with these data, we speculate that the function of GALNTL5 is indispensable for mature sperm formation and that GALNTL5 might have a unique role in mammalian spermiogenesis.