A prospective phase II study of combined androgen blockade in patients with androgen receptor-positive metastatic or locally advanced unresectable salivary gland carcinoma.

Background: There is no standard first-line chemotherapy for recurrent/metastatic (RM) or unresectable locally advanced (LA) salivary gland carcinoma (SGC). Patients and methods: We conducted a single institution, open-label, single arm, phase II trial of combined androgen blockade (CAB) for androgen receptor (AR)-positive SGC. Leuprorelin acetate was administered subcutaneously at a dose of 3.75 mg every 4 weeks. Bicalutamide was administered orally at a daily dose of 80 mg. Patients were treated until progressive disease or unacceptable toxicities. Results: Thirty-six eligible patients were enrolled. Thirty-three patients had RM disease and three patients had LA disease. The pathological diagnoses were salivary duct carcinoma (34 patients, 94%) and adenocarcinoma, NOS (two patients, 6%). The best overall response rate was 41.7% [n = 15, 95% confidence interval (CI), 25.5%-59.2%], the clinical benefit rate was 75.0% (n = 27, 95% CI, 57.8%-87.9%). The median progression-free survival was 8.8 months (95% CI, 6.3-12.3 months) and the median overall survival was 30.5 months (95% CI, 16.8 months to not reached). Additional analyses between treatment outcomes and clinicopathological factors or biomarkers including AR positivity, human epidermal growth factor receptor 2 status, and its complex downstream signaling pathway gene mutations showed no statistically significant differences. Elevated grade 3 liver transaminases and increased serum creatinine were reported in two patients, respectively. Discontinuation of leuprorelin acetate or bicalutamide due to adverse event occurred in one patient. Conclusion: This study suggests that CAB has equivalent efficacy and less toxicity for patients with AR-positive RM or unresectable LA SGC compared with conventional chemotherapy, which warrants further study. Clinical Trial Registration: UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703.

Constitutively active ABL family kinases, TEL/ABL and TEL/ARG, harbor distinct leukemogenic activities in vivo.

ABL (ABL1) and ARG (ABL2) are highly homologous to each other in overall domain structure and amino-acid sequence, with the exception of their C termini. As with ABL, translocations that fuse ARG to ETV6/TEL have been identified in patients with leukemia. To assess the in vivo leukemogenic activity of constitutively active ABL and ARG, we generated a bone marrow (BM) transplantation model using the chimeric forms TEL/ABL and TEL/ARG, which have comparable kinase activities. TEL/ABL rapidly induced fatal myeloid leukemia in recipient mice, whereas recipients of TEL/ARG-transduced cells did not develop myeloid leukemia, instead, they succumbed to a long-latency infiltrative mastocytosis that could be adoptively transferred to secondary recipients. Swapping of the C termini of ABL and ARG altered disease latency and phenotypes. In a detailed in vitro study, TEL/ARG strongly promoted mast cell differentiation in response to stem cell factor or interleukin-3, whereas TEL/ABL preferentially induced myeloid differentiation of hematopoietic stem/progenitor cells. These results indicate that ABL and ARG kinase activate distinct differentiation pathways to induce specific diseases in vivo, that is, myeloid leukemia and mastocytosis, respectively. Further elucidation of the differences in their properties should provide important insight into the pathogenic mechanisms of oncogenes of the ABL kinase family.

Systematic review with meta-analysis: faecal occult blood tests show lower colorectal cancer detection rates in the proximal colon in colonoscopy-verified diagnostic studies.

BACKGROUND: The performance of faecal occult blood tests (FOBTs) to screen proximally located colorectal cancer (CRC) has produced inconsistent results. AIM: To assess in a meta-analysis, the diagnostic accuracy of FOBTs for relative detection of CRC according to anatomical location of CRC. METHODS: Diagnostic studies including both symptomatic and asymptomatic cohorts assessing performance of FOBTs for CRC were searched from MEDINE and EMBASE. Primary outcome was accuracy of FOBTs according to the anatomical location of CRC. Bivariate random-effects model was used. Subgroup analyses were performed to evaluate test performance of guaiac-based FOBT (gFOBT) and immunochemical-based FOBT (iFOBT). RESULTS: Thirteen studies, with 17 cohorts, reporting performance of FOBT were included; a total of 26 342 patients (mean age 58.9 years; 58.1% male) underwent both colonoscopy and FOBT. Pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of FOBTs for CRC detection in the proximal colon were 71.2% (95% CI 61.3-79.4%), 93.6% (95% CI 90.7-95.7%), 11.1 (95% CI 7.8-15.8) and 0.3 (95% CI 0.2-0.4) respectively. Corresponding findings for CRC detection in distal colon were 80.1% (95% CI 70.9-87.0%), 93.6% (95% CI 90.7-95.7%), 12.6 (95% CI 8.8-18.1) and 0.2 (95% CI 0.1-0.3). The area-under-curve for FOBT detection for proximal and distal CRC were 90% vs. 94% (P = 0.0143). Both gFOBT and iFOBT showed significantly lower sensitivity but comparable specificity for the detection of proximally located CRC compared with distal CRC. CONCLUSION: Faecal occult blood tests, both guaiac- and immunochemical-based, show better diagnostic performance for the relative detection of colorectal cancer in the distal colon than in the proximal bowel.

Role of macrophage migration inhibitory factor in age-related hearing loss.

Hearing loss related to aging is the most common sensory disorder among elderly individuals. Macrophage migration inhibitory factor (MIF) is a multi-functional molecule. The aim of this study was to identify the role of MIF in the inner ear. MIF-deficient mice (MIF(-/-) mice) of BALB/c background and wild-type BALB/c mice were used in this study. Expression of MIF protein in the inner ear was examined by immunohistochemistry in wild-type mice (WT). The hearing function was assessed by the click-evoked auditory brainstem response in both MIF(-/-) mice and WT at 1, 3, 6, 9, 12, and 18months of age. Morphological examination of the cochlea was also performed using scanning electron microscopy and light microscopy. MIF was observed in the spiral ligament, stria vascularis, Reissner's membrane, spiral ganglion cells (SGCs), saccular macula, and membranous labyrinth. The MIF(-/-) mice had a significant hearing loss as compared with the WT at 9, 12, and 18months of age. In the MIF(-/-) mice, scanning electron microscopy showed that the outer cochlear hair cells were affected, but that the inner cochlear hair cells were relatively well preserved. The number of SGCs was lower in the MIF(-/-) mice. MIF was strongly expressed in the mouse inner ear. Older MIF(-/-) mice showed accelerated age-related hearing loss and morphological inner ear abnormalities. These findings suggest that MIF plays an important role in the inner ear of mice.

One-year follow-up of transgene expression by integrase-defective lentiviral vectors and their therapeutic potential in spinocerebellar ataxia model mice.

We examined integrase-defective lentiviral vectors (IDLVs) with a mutant (D64V) integrase in terms of their residual integration capability, the levels and duration of transgene expression and their therapeutic potential in comparison to wild-type lentiviral vectors (WTLVs) with a wild-type integrase gene. Compared with WTLVs, the IDLV-mediated proviral integration into host-cell chromosomes was approximately 1/3850 in HeLa cells and approximately 1/111 in mouse cerebellar neurons in vivo. At 2 months, transgene expression by IDLVs in the mouse cerebellum was comparable to that by WTLVs, but then significantly decreased. The mRNA levels at 6 and 12 months after injection in IDLV-infected cerebella were approximately 26% and 5%, respectively, of the mRNA levels in WTLV-injected cerebella. To examine the therapeutic potential, IDLVs or WTLVs expressing a molecule that enhances the ubiquitin-proteasome pathway were injected into the cerebella of spinocerebellar ataxia type 3 model mice (SCA3 mice). IDLV-injected SCA3 mice showed a significantly improved rotarod performance even at 1 year after-injection. Immunohistochemistry at 1 year after injection showed a drastic reduction of mutant aggregates in Purkinje cellsfrom IDLV-injected, as well as WTLV-injected, SCA3 mice. Our results suggest that because of the substantially reduced risk of insertional mutagenesis, IDLVs are safer and potentially effective as gene therapy vectors.

Utility of glucagon stimulation test in type 1 diabetes after pancreas transplantation.

BACKGROUND: Despite recent progress of immunosuppressive therapy with newly developed agents, long-term pancreatic graft survival after pancreas transplantation still remains low. Therefore, precise assessment of ß-cell function after pancreas transplantation is necessary. METHODS: Pancreatic ß-cell secretory activity was measured by means of the peripheral plasma fasting serum C-peptide (CPR) response to 1 mg of glucagon intravenously in 23 patients after pancreas transplantation. The utility of ΔCPR after injection was compared with other indices that reflect insulin secretion. RESULTS: When we performed the test, 6 patients still needed insulin injection after the transplantation. Mean CPR before and after glucagon intravenously were 1.9 ± 0.98 ng/mL and 4.6 ± 2.29 ng/mL, respectively. Fasting serum CPR, secretory unit of islet in transplantation (SUIT) index, and ΔCPR after glucagon injection were significantly different between insulin users and nonusers. During follow-up (501 ± 228 days), 3 patients could stop using insulin, and their increase of CPR (1.8 ± 0.5 ng/mL) was significantly higher than that in continuous insulin users (0.3 ± 0.3 ng/mL). CONCLUSION: Fasting CPR, SUIT index, and ΔCPR after glucagon injection could reflect ß-cell function for post-pancreas transplant patients, and glucagon stimulation test could give us additional information to predict insulin-free treatment.

Diagnostic accuracy of faecal immunochemical test for screening individuals with a family history of colorectal cancer.

BACKGROUND: The role of a faecal immunochemical test (FIT) in screening individuals with a positive family history of colorectal cancer (CRC) is not clear. AIM: To assess the diagnostic accuracy of FIT using colonoscopy findings as the gold standard in identifying colorectal neoplasms. METHODS: We analysed data from 4539 asymptomatic subjects aged 50-70 years who had both colonoscopy and FIT (Hemosure; W.H.P.M., Inc, El Monte, CA, USA) at our bowel cancer screening centre between 2008 and 2012. A total of 572 subjects (12.6%) had a family history of CRC. Our primary outcome was the sensitivity of FIT in detecting advanced neoplasms and cancers in subjects with a family history of CRC. A family history of CRC was defined as any first-degree relative with a history of CRC. RESULTS: Among 572 subjects with a family history of CRC, adenoma, advanced neoplasm and cancer were found at screening colonoscopy in 29.4%, 6.5% and 0.7% individuals, respectively. The sensitivity of FIT in detecting adenoma, advanced neoplasm and cancer was 9.5% [95% confidence interval (CI), 5.7-15.3], 35.1% (95% CI, 20.7-52.6) and 25.0% (95% CI, 1.3-78.1), respectively. Among FIT-negative subjects who have a family history of CRC, adenoma was found in 152 (29.6%), advanced neoplasm in 24 (4.7%) and cancer in 3 (0.6%) individuals. CONCLUSION: Compared with colonoscopy, FIT is more likely to miss advanced neoplasms or cancers in individuals with a family history of CRC.

Meta-analysis: comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding.

BACKGROUND: The efficacy of adjuvant use of intravenous proton pump inhibitors (PPIs) after endoscopic therapy has been proved in peptic ulcer bleeding patients, but the efficacy of oral PPIs is uncertain. AIM: To compare the clinical outcomes of oral PPIs vs. intravenous PPIs in patients with peptic ulcer bleeding. METHODS: Prospective randomised controlled trials were systematically searched from OVID databases until June 2012. Trials comparing oral and intravenous PPIs among patients with peptic ulcer bleeding were included. Recurrent bleeding, length of hospitalisation, blood transfusion, requirement of surgery and mortality were measured. The risk of bias, study quality and heterogeneity were also evaluated. RESULTS: Six randomised trials from 2006 to 2011 were included. A total of 615 patients were randomly assigned to receive oral PPIs (n = 302) or intravenous PPIs (n = 313). The mean age was 60 years and 71.1% was male. No significant difference between oral and intravenous PPIs was observed regarding recurrent bleeding (RR: 0.92, 95% CI: 0.56-1.50), mean volume of blood transfused (-0.02 unit, 95% CI: -0.29-0.24 unit), requirement of surgery (RR: 0.82, 95% CI: 0.19-3.61) and all-cause mortality (RR: 0.88, 95% CI: 0.29-2.71). The duration of hospital stay in days was significantly shortened in those using oral PPIs (-0.74 day, 95% CI: -1.10 day to -0.39 day). CONCLUSION: Oral PPIs demonstrate a similar effectiveness to intravenous PPIs among patients with peptic ulcer bleeding, but the results were combined from open-labelled trials with limited sample size. A large double-blind non-inferiority trial is required to better assess the role of oral PPIs.

Postural dysfunction in a transgenic mouse model of spinocerebellar ataxia type 3.

During voluntary limb movements, humans exert anticipatory postural adjustments (APAs) to prevent any upcoming equilibrium disturbance that might be provoked by limb movements. Dysfunction in generation or control of APAs is associated with postural deficits in some human patients with cerebellar damage. To examine the role of the cerebellum in APAs, we investigated a conditional transgenic mouse of spinocerebellar ataxia type 3 (SCA3Tg) that has defective cerebellar Purkinje cells. Kinematic analyses and monitoring of electromyographic activities during quadrupedal standing showed that SCA3Tg mice exhibited greater hindlimb instability than wild-type (WT) mice. This instability increased during a reaching task that required postural adjustments associated with voluntary neck movements. Normally, the activities of the hindlimb muscles are synchronized with those in the neck that are the agonists for movement of the head in this reaching task; however, in SCA3Tg mice, activities in the hindlimbs were markedly delayed compared to the neck. These observations cannot simply be explained as a secondary outcome of the muscle atrophy that occurs in SCA3Tg mice. In WT mice with muscle atrophy induced by immobilization of the hindlimbs, we did not find impairment of APAs. These findings suggest that the deficits in APAs during the reaching task in SCA3Tg mice were not due to muscle atrophy in the hindlimbs, but were mainly caused by cerebellar degeneration. Therefore, we conclude that the cerebellum is critically involved in APAs.

C/EBPß promotes BCR-ABL-mediated myeloid expansion and leukemic stem cell exhaustion.

The BCR-ABL fusion oncoprotein accelerates differentiation and proliferation of myeloid cells during the chronic phase of chronic myeloid leukemia (CP-CML). Here, the role of CCAAT/enhancer binding protein ß (C/EBPß), a regulator for 'emergency granulopoiesis,' in the pathogenesis of CP-CML was examined. C/EBPß expression was upregulated in Lineage(-) CD34(+) CD38(-) hematopoietic stem cells (HSCs) and myeloid progenitors isolated from bone marrow of patients with CP-CML. In EML cells, a mouse HSC line, BCR-ABL upregulated C/EBPß, at least in part, through the activation of STAT5. Myeloid differentiation and proliferation induced by BCR-ABL was significantly impaired in C/EBPß-deficient bone marrow cells in vitro. Mice that were transplanted with BCR-ABL-transduced C/EBPß knockout bone marrow cells survived longer than mice that received BCR-ABL-transduced wild-type (WT) bone marrow cells. Significantly higher levels of leukemic stem cells were maintained in BCR-ABL-transduced C/EBPß-deficient cells than in BCR-ABL-transduced WT cells. These results suggest that C/EBPß is involved in BCR-ABL-mediated myeloid expansion. Further elucidation of the molecular mechanisms underlying the C/EBPß-mediated stem cell loss might reveal a novel therapeutic strategy for eradication of CML stem cells.

Repetitive sequences originating from the centromere constitute large-scale heterochromatin in the telomere region in the siamang, a small ape.

Chromosomes of the siamang Symphalangus syndactylus (a small ape) carry large-scale heterochromatic structures at their ends. These structures look similar, by chromosome C-banding, to chromosome-end heterochromatin found in chimpanzee, bonobo and gorilla (African great apes), of which a major component is tandem repeats of 32-bp-long, AT-rich units. In the present study, we identified repetitive sequences that are a major component of the siamang heterochromatin. Their repeat units are 171 bp in length, and exhibit sequence similarity to alpha satellite DNA, a major component of the centromeres in primates. Thus, the large-scale heterochromatic structures have different origins between the great apes and the small ape. The presence of alpha satellite DNA in the telomere region has previously been reported in the white-cheeked gibbon Nomascus leucogenys, another small ape species. There is, however, a difference in the size of the telomere-region alpha satellite DNA, which is far larger in the siamang. It is not known whether the sequences of these two species (of different genera) have a common origin because the phylogenetic relationship of genera within the small ape family is still not clear. Possible evolutionary scenarios are discussed.

Deletion of Ia-2 and/or Ia-2ß in mice decreases insulin secretion by reducing the number of dense core vesicles.

AIMS/HYPOTHESIS: Islet antigen 2 (IA-2) and IA-2ß are dense core vesicle (DCV) transmembrane proteins and major autoantigens in type 1 diabetes. The present experiments were initiated to test the hypothesis that the knockout of the genes encoding these proteins impairs the secretion of insulin by reducing the number of DCV. METHODS: Insulin secretion, content and DCV number were evaluated in islets from single knockout (Ia-2 [also known as Ptprn] KO, Ia-2ß [also known as Ptprn2] KO) and double knockout (DKO) mice by a variety of techniques including electron and two-photon microscopy, membrane capacitance, Ca(2+) currents, DCV half-life, lysosome number and size and autophagy. RESULTS: Islets from single and DKO mice all showed a significant decrease in insulin content, insulin secretion and the number and half-life of DCV (p < 0.05 to 0.001). Exocytosis as evaluated by two-photon microscopy, membrane capacitance and Ca(2+) currents supports these findings. Electron microscopy of islets from KO mice revealed a marked increase (p < 0.05 to 0.001) in the number and size of lysosomes and enzymatic studies showed an increase in cathepsin D activity (p < 0.01). LC3 protein, an indicator of autophagy, also was increased in islets of KO compared with wild-type mice (p < 0.05 to 0.01) suggesting that autophagy might be involved in the deletion of DCV. CONCLUSIONS/INTERPRETATION: We conclude that the decrease in insulin content and secretion, resulting from the deletion of Ia-2 and/or Ia-2ß, is due to a decrease in the number of DCV.

Oral health and cancer, cardiovascular, and respiratory mortality of Japanese.

Cardiovascular diseases, cancer, and respiratory disease are major causes of death in developed countries. No study has simultaneously compared the contribution of oral health with these major causes of death. This study examined the association between oral health and cardiovascular diseases, cancer, and respiratory mortality among older Japanese. Self-administered questionnaires were mailed to participants in the Aichi Gerontological Evaluation Study (AGES) Project in 2003. Mortality data were analyzed for 4425 respondents. Three categories of oral health were used: 20 or more teeth, 19 or fewer teeth and eat everything, 19 or fewer teeth and eating difficulty. Sex, age, body mass index (BMI), self-rated health, present illness, exercise, smoking, alcohol, education, and income were used as covariates. During 4.28 years' follow-up, 410 people died, 159 from cancer, 108 of cardiovascular diseases, and 58 of respiratory disease. Multivariate adjusted Cox proportional hazard models showed that, compared with the respondents with 20 or more teeth, respondents with 19 or fewer teeth and with eating difficulty had a 1.83 and 1.85 times higher hazard ratio for cardiovascular disease mortality and respiratory disease mortality, respectively. There was no significant association with cancer mortality. Oral health predicted cardiovascular and respiratory disease mortality but not cancer mortality in older Japanese.

Geographical accessibility to dental care in the Japanese elderly.

OBJECTIVE: The current research aims to clarify the factors relevant to elderly people's access to dental care in Japan, particularly focusing on geographical accessibility. METHODS: The sample was taken from among the Japanese elderly, aged 65 and over, who responded to a postal survey conducted in 2003 (n = 2,192). Six types of geographical accessibility to the dental clinics were calculated using Geographic Information Systems. Logistic regression analysis was conducted using 'having a regular dentist' as a dependent variable and geographical accessibility as an explanatory variable. RESULTS: The results showed an association between having a regular dentist and geographical accessibility only for females. In the univariate model, distance to the closest dental clinics (OR = 0.62 (95% CI: 0.43-0.90)), number of dental clinics at the school district level (OR = 1.14 (95% CI: 1.03-1.26)), number of dental clinics at the municipality level (OR = 1.02 (95% CI: 1.00-1.05)), and density distribution of dental clinics (OR = 1.56 (95% CI: 1.11-2.19)) showed significant relations with having a regular dentist. After controlling for demographic, socioeconomic, and health related variables, only the density distribution of dental clinics showed significant relations at the 5% level, although distance and number of dental clinics kept a marginal significance. CONCLUSION: The current study verifies that geographical accessibility correlates with access to dental care among women, and that there were large gender differences concerning the issue of geographical access.

[Intermittent opening of a mechanical mitral valve prosthesis due to pannus formation; report of a case].

A 76-year-old woman with a history of severe mitral valve stenosis had undergone mitral valve replacement with a 27 mm St. Jude Medical (SJM) valve in 1991. Follow-up transthoracic echocardiography revealed an increase in the pressure gradient across the mitral prosthesis 16 years after the surgery. Prosthetic valve dysfunction was suspected, but transesophageal echocardiography and cineradiography failed to show mechanical valve dysfunction. Two years later, she presented with dyspnea on exertion and leg edema. Cineradiography revealed intermittent restriction of the opening of the mechanical valve leaflet approximately every 10 beats. Thus, we diagnosed intermittent prosthetic valve dysfunction and performed a reoperation. On inspection of the prosthesis, we observed semicircular pannus formation around the posterior leaflet in the ventricular side. It was considered that the pannus tissue had interfered with 1 leaflet opening of the mitral valve prosthesis, resulting in intermittent valve dysfunction. We replaced the prosthesis with a new 25 mm SJM valve. The patient was discharged after confirmation of normal prosthetic function.

Lipopolysaccharide induces proinflammatory cytokines and chemokines in experimental otitis media through the prostaglandin D2 receptor (DP)-dependent pathway.

Otitis media is one of the most common and intractable ear diseases, and is the major cause of hearing loss, especially in children. Multiple factors affect the onset or development of otitis media. Prostaglandin D2 is the major prostanoid involved in infection and allergy. However, the role of prostaglandin D2 and prostaglandin D2 receptors on the pathogenesis of otitis media remains to be determined. Recent studies show that D prostanoid receptor (DP) and chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cells (CRTH2) are major prostaglandin D2 receptors. In this study, homozygous DP single gene-deficient (DP⁻(/)⁻) mice, CRTH2 single gene-deficient (CRTH2⁻(/)⁻) mice and DP/CRTH2 double gene-deficient (DP⁻(/)⁻ CRTH2⁻(/)⁻) mice were used to investigate the role of prostaglandin D2 and its receptors in otitis media. We demonstrate that prostaglandin D2 is induced by lipopolysaccharide (LPS), a major component of Gram-negative bacteria, and that transtympanic injection of prostaglandin D2 up-regulates macrophage inflammatory protein 2 (MIP-2), interleukin (IL)-1ß and IL-6 in the middle ear. We also show that middle ear inflammatory reactions, including infiltration of inflammatory cells and expression of MIP-2, IL-1ß and IL-6 induced by LPS, are reduced significantly in DP⁻(/)⁻ mice and DP⁻(/)⁻ CRTH2⁻(/)⁻ mice. CRTH2⁻(/)⁻ mice display inflammatory reactions similar to wild-type mice. These findings indicate that prostaglandin D2 may play significant roles in LPS-induced experimental otitis media via DP.

AV-65, a novel Wnt/ß-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model.

Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that ß-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/ß-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished ß-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.

Prospective randomized trial of short-term neoadjuvant chemotherapy for advanced gastric cancer.

BACKGROUND: We performed short-term neoadjuvant chemotherapy (s-NAC) to examine whether anticancer drugs can change the proliferative ability of cancer cells in gastric cancer patients. METHODS: Chemotherapy was performed for 72 h before gastrectomy in 63 gastric cancer patients. Patients were classed into four groups: Group F, 16 cases who received a single administration of 5-fluorouracil (5-FU); Group C, 15 cases who received a single administration of cis-diamminedichloroplatinum (CDDP; cisplatin); Group FC, 16 cases who received both 5-FU+CDDP; and a Control group, 16 cases who did not receive chemotherapy. We reviewed neoadjuvant biopsy tissue and gastric cancer tissue delivered by operation in these cases. The TUNEL method and immunohistochemistry with an anti-MIB-1 antibody were used to evaluate cellular apoptosis and proliferative ability, respectively. The apoptotic index (AI) and an MIB-1 index (MI) were also calculated. RESULTS: There were no differences in AI or MI in biopsy tissue between the groups. The AI of gastric cancer tissue in Group FC was significantly higher than in the other groups (P < 0.01). The MI of Group FC was significantly lower than in the other groups (P < 0.05). In addition, after s-NAC operation there was a significant inhibition of proliferative potency and an induction of apoptosis in Group FC. CONCLUSION: Combination of CDDP and 5-FU reduced proliferative potency and increased cellular apoptosis in gastric cancer cells.

Eradication of the commensal intestinal microflora by oral antimicrobials interferes with the host response to lipopolysaccharide.

The host components and commensal microorganisms of the intestinal microenvironment play roles in the development and maintenance of the host defence. Recent observations have suggested that toll-like receptors (TLRs) are involved in the recognition of innate immunity against intestinal microbes. However, little is known regarding the role of TLR in the maintenance of systemic host defence by intestinal microorganisms. We studied the expression and function of TLR4 and TLR2 on alveolar and peritoneal macrophages in mice after 3 weeks of oral administration of streptomycin and cefotaxime. After active treatment, the intestinal microorganisms were nearly completely eradicated, and the surface expression of TLR4 and TLR2 on the peritoneal macrophages was prominently downregulated. When the actively treated mice were challenged with lipopolysaccharide (LPS), a TLR4 ligand, the host response was markedly impaired. Our results suggest that the oral administration of antimicrobials downregulates the expression of surface TLR on the peritoneal macrophages and modulates the host immune responses against LPS by modifying the intestinal environment.