Laparoscopic-assisted distal gastrectomy has recently come to be a standard procedure for the treatment of early gastric cancer1–5 in select patients. The minimal invasiveness associated with laparoscopic procedures for the resection of gastrointestinal cancer has been repeatedly explained in part by the short incision that is required.6–11 We used two different approaches to perform distal gastrectomies for the resection of gastric cancer as minimally invasive alternatives to a standard laparoscopic approach prior to our surgical team's complete mastery of the skills required for laparoscopic oncological surgery for gastric cancer.9,12 If the minimal invasiveness associated with laparoscopic-assisted gastrectomy can be explained by the small incision, a gastrectomy via a small incision without the use of a pneumoperitoneum may provide a similar outcome in patients. However, to our knowledge, such a comparison has not been previously made. We compared the minimal invasiveness of three different approaches (minilaparotomy, minilaparotomy approach with laparoscopic assistance, and standard laparoscopic-assisted approach) to performing a distal gastrectomy for T1N0-1 gastric cancer in nonoverweight patients (body mass index, ≤25 kg/m2) performed within a limited study period.
Laparoscopy; Minilaparotomy; Gastrectomy; Gastric cancer
In the rodent brain, certain G protein-coupled receptors and adenylyl cyclase type 3 are known to localize to the neuronal primary cilium, a primitive sensory organelle protruding singly from almost all neurons. A recent chemical screening study demonstrated that many compounds targeting dopamine receptors regulate the assembly of Chlamydomonas reinhardtii flagella, structures which are analogous to vertebrate cilia. Here we investigated the effects of dopaminergic inputs loss on the architecture of neuronal primary cilia in the rodent striatum, a brain region that receives major dopaminergic projections from the midbrain. We first analyzed the lengths of neuronal cilia in the dorsolateral striatum of hemi-parkinsonian rats with unilateral lesions of the nigrostriatal dopamine pathway. In these rats, the striatal neuronal cilia were significantly longer on the lesioned side than on the non-lesioned side. In mice, the repeated injection of reserpine, a dopamine-depleting agent, elongated neuronal cilia in the striatum. The combined administration of agonists for dopamine receptor type 2 (D2) with reserpine attenuated the elongation of striatal neuronal cilia. Repeated treatment with an antagonist of D2, but not of dopamine receptor type 1 (D1), elongated the striatal neuronal cilia. In addition, D2-null mice displayed longer neuronal cilia in the striatum compared to wild-type controls. Reserpine treatment elongated the striatal neuronal cilia in D1-null mice but not in D2-null mice. Repeated treatment with a D2 agonist suppressed the elongation of striatal neuronal cilia on the lesioned side of hemi-parkinsonian rats. These results suggest that the elongation of striatal neuronal cilia following the lack of dopaminergic inputs is attributable to the absence of dopaminergic transmission via D2 receptors. Our results provide the first evidence that the length of neuronal cilia can be modified by the lack of a neurotransmitter's input.
To identify risk factors for recurrence in patients with stage II colon cancer, Cox proportional hazards regression analysis was performed in 194 patients with stage II colon cancer who underwent curative surgery between April 1997 and December 2008. Thirteen clinical and pathologic factors, including use of fluoropyrimidine-based adjuvant chemotherapy in 113 of the patients (58.2%), were assessed. By multivariate analysis, only obstruction, perforation, and T4-level invasion were identified as independent risk factors affecting disease-free survival (DFS) (P < 0.01). The 5-year DFS rate was 70.6% in patients with one or more risk factors (n = 68) and 96.0% in patients with no risk factors (n = 126) (P < 0.01). These results suggest that obstruction, perforation, and T4-level invasion are suitable candidates for prediction of tumor recurrence in patients with stage II colon cancer. The oxaliplatin-based adjuvant chemotherapy, which has been reported to be effective in stage III colon cancer patients, may improve the prognosis in high-risk stage II colon cancer patients.
Colon cancer; High risk factor; Stage II
Recent studies have shown that the behavior of calcium in the epidermis is closely related to the conditions of the skin, especially the differentiation of the epidermal keratinocytes and the permeability barrier function, and therefore a correct understanding of the calcium dynamics is important in explaining epidermal homeostasis. Here we report on experimental observations of in vitro calcium waves in keratinocytes induced by mechanical stimulation, and present a mathematical model that can describe the experimentally observed wave behavior that includes finite-range wave propagation and a ring-shaped pattern. A mechanism of the ring formation hypothesized by our model may be related to similar calcium propagation patterns observed during the wound healing process in the epidermis. We discuss a possible extension of our model that may serve as a tool for investigating the mechanisms of various skin diseases.
The accident of the Fukushima Dai-ichi nuclear power plant in March 2011 released a large amount of radiocesium into the North Pacific Ocean. Vertical distributions of Fukushima-derived radiocesium were measured at stations along the 149°E meridian in the western North Pacific during the winter of 2012. In the subtropical region, to the south of the Kuroshio Extension, we found a subsurface radiocesium maximum at a depth of about 300 m. It is concluded that atmospheric-deposited radiocesium south of the Kuroshio Extension just after the accident had been transported not only eastward along with surface currents but also southward due to formation/subduction of subtropical mode waters within about 10 months after the accident. The total amount of decay-corrected 134Cs in the mode water was an estimated about 6 PBq corresponding to 10–60% of the total inventory of Fukushima-derived 134Cs in the North Pacific Ocean.
Antiepileptics used for treating neuropathic pain have various actions including voltage-gated Na+ and Ca2+ channels, glutamate-receptor inhibition, and GABAA-receptor activation, while local anesthetics are also used to alleviate the pain. It has not been fully examined yet how nerve conduction inhibitions by local anesthetics differ in extent from those by antiepileptics. Fast-conducting compound action potentials (CAPs) were recorded from frog sciatic nerve fibers by using the air-gap method. Antiepileptics (lamotrigine and carbamazepine) concentration dependently reduced the peak amplitude of the CAP (IC50 = 0.44 and 0.50 mM, resp.). Carbamazepine analog oxcarbazepine exhibited an inhibition smaller than that of carbamazepine. Antiepileptic phenytoin (0.1 mM) reduced CAP amplitude by 15%. On the other hand, other antiepileptics (gabapentin, sodium valproate, and topiramate) at 10 mM had no effect on CAPs. The CAPs were inhibited by local anesthetic levobupivacaine (IC50 = 0.23 mM). These results indicate that there is a difference in the extent of nerve conduction inhibition among antiepileptics and that some antiepileptics inhibit nerve conduction with an efficacy similar to that of levobupivacaine or to those of other local anesthetics (lidocaine, ropivacaine, and cocaine) as reported previously. This may serve to know a contribution of nerve conduction inhibition in the antinociception by antiepileptics.
Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a translocation, t(1;11) (q42.1;q14.3), that segregates with major psychiatric disorders, including schizophrenia, recurrent major depression and bipolar affective disorder, in a Scottish family. Here we report that mammalian DISC1 endogenously expressed in oligodendroglial lineage cells negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 expression was detected in oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA was expressed in primary cultured rat cortical oligodendrocyte precursor cells and decreased when oligodendrocyte precursor cells were induced to differentiate by PDGF deprivation. Immunocytochemical analysis showed that overexpressed DISC1 was localized in the cell bodies and processes of oligodendrocyte precursor cells and oligodendrocytes. We show that expression of the myelin related markers, CNPase and MBP, as well as the number of cells with a matured oligodendrocyte morphology, were decreased following full length DISC1 overexpression. Conversely, both expression of CNPase and the number of oligodendrocytes with a mature morphology were increased following knockdown of endogenous DISC1 by RNA interference. Overexpression of a truncated form of DISC1 also resulted in an increase in expression of myelin related proteins and the number of mature oligodendrocytes, potentially acting via a dominant negative mechanism. We also identified involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of oligodendrocyte differentiation, both well-known transcription factors involved in the regulation of myelin genes.
The inflammation-based Glasgow prognostic score (GPS) has been demonstrated to be prognostic for various tumors. We investigated the value of the modified GPS (mGPS) for the prognosis of patients undergoing curative resection for colorectal liver metastases (CRLM).
A total of 343 patients were enrolled onto this study. The mGPS was calculated as follows: mGPS-0, C-reactive protein (CRP) ≤10 mg/L; mGPS-1, CRP >10 mg/L and albumin ≥35 g/L; and mGPS-2, CRP >10 mg/L and albumin <35 g/L. Prognostic significance was retrospectively analyzed by univariate and multivariate analyses.
Of the 343 patients, 295 (86.0 %) were assigned to mGPS-0, 33 (9.6 %) to mGPS-1, and 15 (4.4 %) to mGPS-2. The median disease-free survival of patients with mGPS-0, -1, and -2 was 18.3, 15.5, and 5.2 months, respectively. The median cancer-specific survival (CSS) of patients with mGPS-0, -1, and -2 was 89.5, 62.2, and 25.8 months, respectively. The CSS of patients with mGPS-0 was significantly longer than that of patients with mGPS-2. Multivariate analysis revealed a significant association between cancer-related postoperative mortality and mGPS and carcinoembryonic antigen level.
The preoperative mGPS is a useful prognostic factor for postoperative survival in patients undergoing curative resection for CRLM.
Lamina I projection neurons respond to painful stimuli, and some are also activated by touch or hair movement. Neuropathic pain resulting from peripheral nerve damage is often associated with tactile allodynia (touch-evoked pain), and this may result from increased responsiveness of lamina I projection neurons to non-noxious mechanical stimuli. It is thought that polysynaptic pathways involving excitatory interneurons can transmit tactile inputs to lamina I projection neurons, but that these are normally suppressed by inhibitory interneurons. Vertical cells in lamina II provide a potential route through which tactile stimuli can activate lamina I projection neurons, since their dendrites extend into the region where tactile afferents terminate, while their axons can innervate the projection cells. The aim of this study was to determine whether vertical cell dendrites were contacted by the central terminals of low-threshold mechanoreceptive primary afferents.
We initially demonstrated contacts between dendritic spines of vertical cells that had been recorded in spinal cord slices and axonal boutons containing the vesicular glutamate transporter 1 (VGLUT1), which is expressed by myelinated low-threshold mechanoreceptive afferents. To confirm that the VGLUT1 boutons included primary afferents, we then examined vertical cells recorded in rats that had received injections of cholera toxin B subunit (CTb) into the sciatic nerve. We found that over half of the VGLUT1 boutons contacting the vertical cells were CTb-immunoreactive, indicating that they were of primary afferent origin.
These results show that vertical cell dendritic spines are frequently contacted by the central terminals of myelinated low-threshold mechanoreceptive afferents. Since dendritic spines are associated with excitatory synapses, it is likely that most of these contacts were synaptic. Vertical cells in lamina II are therefore a potential route through which tactile afferents can activate lamina I projection neurons, and this pathway could play a role in tactile allodynia.
Cervical disc herniation (CDH) is found more frequently at the lower cervical spine than at the upper or middle level. However, there is scarcity of data about the laterality of CDH. The aim of this study is to detect the laterality of CDH.
We retrospectively evaluated preoperative computed tomography myelograms and magnetic resonance images of 75 cases of CDH who underwent single level anterior cervical discectomy and fusion at C4–5, C5–6, or C6–7 levels from 2008 to 2010 in our institute. Statistical analyses were performed using the Chi-square test.
Eleven cases were found at C4–5 level, 42 cases at C5–6 level, and 22 cases at C6–7 level. At C4–5 level, CDH was recognized at the right side in 2 cases, at the left side in 2 cases, and at the center in 7 cases. At C5–6 level, CDH was found at the right side in 20 cases and at the left side in 22 cases. At C6–7 level, CDH was found at the right side in 3 cases and at the left side in 19 cases with significantly high frequency of left-sided CDH (p < 0.025).
In this study, it was revealed that the left-sided CDH was more frequent than the right-sided CDH at C6–7 level.
Cervical disc herniation; C6–7 level; Handedness; Laterality
In the opportunistic fungal pathogen Candida albicans, up-regulation of MDR1, encoding an efflux transporter, leads to increased resistance to the antifungal drug fluconazole. Antifungal resistance has been linked to several types of genetic change in C. albicans, including changes in genome structure, genetic alteration of the drug target, and overexpression of transporters. High-level over-expression of MDR1 is commonly mediated by mutation in a trans-acting factor, Mrr1p. This report describes a second mechanism that contributes to up-regulation of MDR1 expression. By analyzing the sequence of the MDR1 promoter region in fluconazole-resistant and fluconazole-susceptible strains, we identified sequence polymorphisms that defined two linkage groups, corresponding to the two alleles in the diploid genome. One of the alleles conferred higher MDR1 expression compared with the other allele. Strains in which both alleles were of the higher activity type were common in collections of clinically isolated strains while strains carrying only the less active allele were rare. As increased expression of MDR1 confers higher resistance to drugs, strains with the more active MDR1 promoter allele may grow or survive longer when exposed to drugs or other selective pressures, providing greater opportunity for mutations that confer high-level drug resistance to arise. Through this mechanism, higher activity alleles of the MDR1 promoter could promote the development of drug resistance.
Candida albicans; Drug resistance; MDR1; Fluconazole; Polymorphism; Promoter
Nonalcoholic fatty liver disease (NAFLD) is a risk for hepatocellular carcinoma (HCC), but the association between a high-fructose diet and HCC is not fully understood. In this study, we investigated whether a high-fructose diet affects hepatocarcinogenesis induced by administration of diethylnitrosamine (DEN).
Seven-week-old male Sprague–Dawley rats were fed standard chow (controls), a high-fat diet (54% fat), or a high-fructose diet (66% fructose) for 8 weeks. All rats were given DEN at 50 μg/L in drinking water during the same period. Precancerous hepatocytes were detected by immunostaining of the placental form of glutathione-S-transferase (GST-P). The number of GST-P-positive hepatocytes was assessed in liver specimens.
Serum levels of total cholesterol were similar among the three groups, but serum triglyceride, fasting blood glucose, and insulin levels were higher in the high-fructose group compared to the high-fat group. In contrast, hepatic steatosis was more severe in the high-fat group compared with the high-fructose and control groups, but the incidence of GST-P-positive specimens was significantly higher in the high-fructose group compared to the other two groups. The average number of GST-P-positive hepatocytes in GST-P positive specimens in the high-fructose group was also higher than those in the other two groups. This high prevalence of GST-P-positive hepatocytes was accompanied by higher levels of 8-hydroxydeoxyguanosine in serum and liver tissue.
These results indicate that dietary fructose, rather than dietary fat, increases the incidence of precancerous hepatocytes induced by administration of DEN via insulin resistance and oxidative stress in rat. Thus, excessive fructose intake may be a potential risk factor for hepatocarcinogenesis.
Diethylnitrosamine; Fructose; Hepatocarcinogenesis; Nonalcoholic steatohepatitis; Placental form of glutathione-S-transferase
Lung adenocarcinoma (LADCA) patients with epidermal growth factor receptor (EGFR) mutations are in general associated with relatively high clinical response rate to EGFR-tyrosine kinase inhibitors (TKIs) but not all responded to TKI. It has therefore become important to identify the additional surrogate markers regarding EGFR-TKI sensitivity.
We first examined the effects of EGFR-TKIs, gefitinib and erlotinib, upon cell proliferation of lung adenocarcinoma cell lines. We then evaluated the gene profiles related to EGFR-TKI sensitivity using a microarray analysis. Results of microarray analysis led us to focus on carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, CEACAM 3, 5, 6, 7, and 19, as potential further surrogate markers of EGFR-TKI sensitivity. We then examined the correlation between the status of CEACAM 3, 5, 6, 7, and 19 immunoreactivity in LADCA and clinicopathological parameters of individual cases.
In the cases with EGFR mutations, the status of all CEACAMs examined was significantly higher than that in EGFR wild-type patients, but there were no significant differences in the status of CEACAMs between TKI responder and nonresponder among 22 patients who received gefitinib therapy. However, among 115 EGFR mutation-negative LADCA patients, both CEACAM6 and CEACAM3 were significantly associated with adverse clinical outcome (CEACAM6) and better clinical outcome (CEACAM3).
CEACAMs examined in this study could be related to the presence of EGFR mutation in adenocarcinoma cells but not represent the effective surrogate marker of EGFR-TKI in LADCA patients. However, immunohistochemical evaluation of CEACAM3/6 in LADCA patients could provide important information on their clinical outcome.
carcinoembryonic antigen-related cell adhesion molecule; lung adenocarcinoma; epidermal growth factor receptor (EGFR); EGFR inhibitor; immunohistochemistry
This study examines the effects of types of liver resection on the growth of liver and lung metastasis.
Materials and Methods
Experimental liver metastases were established by spleen injection of the Colon 26 murine adenocarcinoma cell line expressing GFP into transgenic nude mice expressing RFP. Experimental lung metastases were established by tail vein injection with Colon 26-GFP. Three days after cell injection, groups of mice underwent liver resection (35%+35% [repeated minor resection] vs. 70% [major resection]). Metastatic tumor growth was measured by color-coded fluorescence imaging of the GFP-expressing cancer cells and RFP-expressing stroma.
Although major and repeated minor resection removed the same volume of liver parenchyma, the two procedures had very different effects on metastatic tumor growth: major resection, stimulated liver and lung metastatic growth as well as recruitment of host-derived stroma compared to repeated minor resection. Repeated minor resection did not stimulate metastasis or stromal recruitment. There was no significant difference in liver regeneration between the two groups. Host-derived stroma density, which is stimulated by major resection compared to repeated minor resection, may stimulate growth in the liver-metastatic tumor. TGF-β is also preferentially stimulated by major resection and may play a role in stroma and metastasis stimulation.
The results of this study indicate that when liver resection is necessary, repeated minor liver resection is superior to major liver resection, since major resection, in contrast to repeated minor resection, stimulates metastasis, which should be taken into consideration in clinical situations indicating liver resection.
Nude mice; liver resection; lung metastasis; liver metastasis; stroma; green fluorescent protein; red fluorescent protein; color-coded imaging
Candida albicans, a dimorphic fungus, undergoes hyphal development in response to many different environmental cues, including growth in contact with a semi-solid matrix. C. albicans forms hyphae that invade agar when cells are embedded in or grown on the surface of agar, and the integral membrane protein Dfi1p is required for this activity. In addition, Dfi1p is required for full activation of mitogen activated protein kinase Cek1p during growth on agar. In this study, we identified a putative calmodulin binding motif in the C-terminal tail of Dfi1p. This region of Dfi1p bound to calmodulin in vitro, and mutations that affected this region affected both calmodulin binding in vitro and invasive filamentation when incorporated into the full length Dfi1p protein. Moreover, increasing intracellular calcium levels led to calcium-dependent, Dfi1p-dependent Cek1p activation. We propose that conformational changes in Dfi1p in response to environmental conditions encountered during growth allow the protein to bind calmodulin and initiate a signaling cascade that activates Cek1p.
The use of immunosuppressants after liver transplantation (LT) is associated with postoperative complications, including infections. A 49-year-old male underwent living-donor (LD) LT because of primary sclerosing cholangitis. He was treated with tacrolimus, mycophenolate mofetil, and steroids as immunosuppressants, discharged on postoperative day (POD) 40, and re-admitted because of severe acute cellular rejection on POD 48. Three courses of steroid pulse therapy were performed, and continuous peripheral intravenous drip infusion therapy via the left forearm was necessary for 20 days because of appetite loss. The patient was discharged on POD 83, but re-admitted on POD 87 with pyrexia. A subcutaneous abscess was present at a puncture wound on the left forearm formed by an intravenous drip during the last hospital stay. Furthermore, computed tomography showed five pieces of cavitary or wedge-shaped nodules in the bilateral lung. Because sputum revealed the presence of Gram-positive coccus, and subcutaneous abscess and blood cultures revealed Staphylococcus aureus, the pathogenesis was septic pulmonary embolism (SPE) secondary to S. aureus septicemia originating from a subcutaneous abscess formed by an intravenous drip. The patient was treated with drainage of the subcutaneous abscess and antibiotic therapy, and recovered immediately. Although there have been few reports of SPE after LDLT, SPE is fatal in up to 13.3 % of patients. Early diagnosis, drainage of the infectious source, and appropriate use of antimicrobial therapy should be necessary to overcome SPE. Furthermore, the identical intravenous catheters should be removed whenever possible to avoid infectious complications including SPE for patients who receive steroid pulse therapy after LDLT.
Septic pulmonary embolism; Living donor liver transplantation; Steroid pulse therapy
We report a case of necrosis of a reconstructed gastric tube in a 77-year-old male patient who had undergone esophagectomy. At the time of admission, the patient had active gastric ulcers, but these were resolved by treatment with a proton pump inhibitor. Subtotal esophagectomy with gastric tube reconstruction was performed. Visually, the reconstructed gastric tube appeared to be well perfused with blood. Using indocyanine green (ICG) fluorescence imaging the gastroepiploic vessels were well enhanced and no enhancement was visable 3 to 4 cm from the tip of the gastric tube. Four days after esophagectomy, gastric tube necrosis was confirmed, necessitating a second operation. The necrosis of the gastric tube matched the area that had been shown to lack blood perfusion by ICG angiography imaging. It seems that ICG angiography is useful for the evaluation of perfusion in a reconstructed gastric tube.
Ischemia; Necrosis; ICG angiography; Esophageal cancer; Gastric tube; Esophagectomy
To investigate the non-inferiority of postoperative single-dose intravenous antimicrobial prophylaxis to multiple-dose intravenous antimicrobial prophylaxis in terms of the incidence of surgical site infections (SSIs) in patients undergoing elective rectal cancer surgery by a prospective randomized study.
Patients undergoing elective surgery for rectal cancer were randomized to receive a single intravenous injection of flomoxef (group 1) or five additional doses (group 2) of flomoxef after the surgery. All the patients had received preoperative oral antibiotic prophylaxis (kanamycin and erythromycin) after mechanical cleansing within 24 h prior to surgery, and had received intravenous flomoxef during surgery.
A total of 279 patients (including 139 patients in group 1 and 140 in group 2) were enrolled in the study. The incidence of SSIs was 13.7 % in group 1 and 13.6 % in group 2 (difference [95 % confidence interval]: −0.2 % [−0.9 to 0.7 %]).
The incidence of SSIs was not significantly different in patients undergoing elective rectal surgery who were treated using a single dose of postoperative antibiotics compared to those treated using multiple-dose antibiotics when preoperative mechanical and chemical bowel preparations were employed.
Rectal cancer; Antimicrobial prophylaxis; Surgical site infection
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive neoplasms in humans and myeloid-derived suppressor cells (MDSCs) contribute to the negative regulation of immune responses in the context of cancer and inflammation. In order to investigate the pathophysiology of thyroid cancer, peripheral blood mononuclear cells (PBMCs) were obtained from 49 patients with thyroid cancer, 18 patients with non-cancerous thyroid diseases and 22 healthy volunteers. The MDSC levels were found to be higher in patients with any type of thyroid cancer (P<0.05), patients with ATC (P<0.001) and patients with medullary thyroid carcinoma (P<0.05), when compared to patients with non-cancerous thyroid diseases. The MDSC levels were also higher in patients with stage III–IV thyroid cancer compared to those in patients with non-cancerous thyroid diseases (P<0.05). The stimulation index (SI) of phytohemagglutinin (PHA)-induced lymphocyte blastogenesis was significantly lower, the C-reactive protein (CRP) levels were significantly higher and the serum albumin levels were significantly lower in patients with ATC compared to those in patients with non-cancerous thyroid diseases. The SI was significantly lower in stage III and IV thyroid cancer compared to that in non-cancerous thyroid disease (P<0.05). Furthermore, the CRP levels were higher and the concentration of albumin was lower in stage IV thyroid cancer compared to those in non-cancerous thyroid disease (P<0.05). Patients with thyroid carcinoma were then classified into one of two groups according to a %PBMC of MDSC cut-off level of 1.578, which was the average %PBMC of MDSC of patients with any type of thyroid carcinoma. In patients with higher MDSC levels, the production of CRP and interleukin (IL)-10 was significantly higher (P<0.05) and the albumin levels were significantly lower (P<0.05) compared to those in patients with lower MDSC levels. These data indicate that MDSCs are increased in patients with ATC. Furthermore, these patients exhibited suppression of cell-mediated immune responses, chronic inflammation and nutritional impairment.
myeloid-derived suppressor cells; C-reactive protein; hypoalbuminemia; anaplastic thyroid carcinoma
A vast majority of human vaccines rely on neutralizing antibodies for protection. With the exception of vaccines against human papillomavirus, despite a great amount of dedicated effort by the scientific community, development of vaccines against sexually transmitted viruses has generally been unsuccessful. Understanding the immunobiology of the genital tract is key to designing vaccines that prevent spreading of these viruses. Recent studies demonstrate that adaptive immunity in the vaginal mucosa is uniquely regulated compared to other mucosal organs. In particular, development of virus-specific CD4+ and CD8+ T cells is critically important for antiviral defense in vagina. In this review, we provide an overview of our current understanding of a wide spectrum of immune responses in vagina - from innate viral sensing to memory development.
Branched sugar nucleosides have attracted much attention due to their biological activities. We have demonstrated that epoxy-sugar nucleosides serve as versatile precursor for the stereo-defined synthesis of these nucleoside derivatives on the basis of its ring opening with organoaluminum or organosilicon reagents. In this review article, novel methods for the synthesis of nucleoside analogues branched at the 1′ and 4′-position will be described. During this study, we could discover an anti-HIV agent, 4′-ethynylstavudine (Festinavir).
Festinavir showed more potent anti-HIV activity than the parent compound stavudine (d4T). Other significant properties of Festinavir are as follows: 1) much less toxic to various cells and also to mitochondorial DNA synthesis than d4T, 2) better substrate for human thymidine kinase than d4T, 3) resistant not only to chemical glycosidic bond cleavage but also to catabolism by thymidine phosphorylase, 4) the activity improves in the presence of a major mutation, K103N, associated with resistance to non-nucleoside reverse transcriptase inhibitors. Detailed profile of the antiviral activities, biology and pharmacology of Festinavir are also described.
Epoxide; sugar; nucleoside; organoaluminum reagent; NRTIs; stavudine; anti-HIV-1 agent
The aim of the current study was to examine whether polymorphisms in drug metabolism genes have any clinical impact on patients treated with 5-fluorouracil (FU)/oxaliplatin for metastatic colorectal cancer (MCRC). In total, 63 patients with MCRC were recruited and treated with a modified FOLFOX6 (mFOLFOX6) treatment as a first-line chemotherapy. Polymorphisms in five drug metabolism genes and two DNA-repair genes were assessed in these patients using polymerase chain reaction (PCR), a PCR restriction fragment length polymorphism (PCR-RFLP) technique or invader techniques. These included a 28-bp tandem repeat in the 5′-untranslated region (UTR) and 6-bp deletions in the 3′-UTR of thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR; Ala677Val), glutathione S-transferase π (GSTP1; IIe105Val), GST θ1 (GSTT1; deletion) and GST μ1 (GSTM1; deletion) and the two DNA-repair genes, excision repair cross-complementing-1 (ERCC1; Asp118Asn) and ERCC2 (Lys751Gln). The correlation between these polymorphisms and the clinical outcome, including drug response, progression-free survival (PFS), overall survival (OS) and the incidence of peripheral neuropathy, were evaluated. Patients with the GSTP1-105 A/A genotype had poor responses to mFOLFOX6 treatment compared with those with the GSTP1-105 A/G and G/G genotypes (P=0.01). The median PFS of patients with the ERCC2-751 A/A genotype tended to be longer than that of patients with the ERCC2-751 A/C genotype (P=0.05). Patients with the TS-3′-UTR −6/−6 genotype had a significantly longer OS compared with patients with other genotypes (P=0.003). A statistically significant association between the incidence of peripheral neuropathy higher than grade 2 and the GSTP1-105 (P=0.03) and GSTM1 genotypes (P=0.02) was identified by multivariate logistic regression analyses. Results demonstrated that polymorphisms in GSTP1-105, ERCC2-751 and the 3′-UTR of TS may be a statistically significant predictors of clinical outcome. GSTP1-105 and GSTM1 genotypes may be useful markers of severe peripheral neuropathy in MCRC patients treated with 5-FU/oxaliplatin as first-line chemotherapy.
FOLFOX; colorectal cancer; polymorphism
Although gastrointestinal colonization by the opportunistic fungal pathogen Candida albicans is generally benign, severe systemic infections are thought to arise due to escape of commensal C. albicans from the gastrointestinal (GI) tract. The C. albicans transcription factor Efg1p is a major regulator of GI colonization, hyphal morphogenesis, and virulence. The goals of this study were to identify the Efg1p regulon during GI tract colonization and to compare C. albicans gene expression during colonization of different organs of the GI tract. Our results identified significant differences in gene expression between cells colonizing the cecum and ileum. During colonization, efg1− null mutant cells expressed higher levels of genes involved in lipid catabolism, carnitine biosynthesis, and carnitine utilization than did colonizing wild-type (WT) cells. In addition, during laboratory growth, efg1− null mutant cells grew to a higher density than WT cells. The efg1− null mutant grew in depleted medium, while WT cells could grow only if the depleted medium was supplemented with carnitine, a compound that promotes the metabolism of fatty acids. Altered gene expression and altered growth capability support the ability of efg1− cells to hypercolonize naïve mice. Also, Efg1p was shown to be important for transcriptional responses to the stresses present in the cecum environment. For example, during colonization, SOD5, encoding a superoxide dismutase, was highly upregulated in an Efg1p-dependent manner. Ectopic expression of SOD5 in an efg1− null mutant increased the fitness of the efg1− null mutant cells during colonization. These data show that EFG1 is an important regulator of GI colonization.
Candida albicans, an opportunistic fungal pathogen and a component of the gastrointestinal tract normal flora, is a frequent colonizer of humans. Is C. albicans capable of sensing the immune status of its host, a process we term immunosensing, and, if so, how? C. albicans causes serious disease only in immunocompromised hosts and therefore, the ability to immunosense would be advantageous to the organism. We propose a speculative model that, during colonization, C. albicans produces phenotypic variants that vary in relative concentration depending on host status. One variant is optimized for persistence as a commensal while the other variant has higher capacity to initiate pathogenic interactions. When the ratio of the two variants changes, the pathogenic potential of the population changes. The critical element of this model is that the C. albicans colonizing population is not uniform but is composed of subpopulations of phenotypic variants that are advantageous under different host conditions.