Study on the sensitizing effect of SM-1 combined with irradiation on head and neck squamous cell carcinoma.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is globally prevalent with high recurrence, low survival rate, and poor quality of life for patients. Derived from PAC-1, SM-1 can activate procaspase-3 and induce apoptosis in cancer cells to exert anti-tumor effects. However, the inhibitory effect of SM-1 on HNSCC after combination with radiation are unclear. This study aims to investigate the radiosensitizing effect of SM-1 on HNSCC in vitro and in vivo. METHODS: MTT method was used to detect the effect of SM-1 on the viability of HNSCC cell lines (HONE1, HSC-2, and CAL27). The effects of SM-1 combined with radiation on the survival index of HONE1, HSC-2, and CAL27 cell lines were determined by colony formation assay. Flow cytometry was used to investigate the effects of SM-1 and radiation combination on cell apoptosis and cell cycle, and western blot experiments were performed to detect the expression of apoptosis and cell cycle-related proteins. Finally, a xenograft tumor model of CAL27 was established to evaluate the anti-tumor effect of SM-1 combined with radiation in vivo. RESULTS: In vitro, SM-1 effectively inhibited the activity of HNSCC cell lines HONE1, HSC-2, and CAL27 cells, and synergistically showed anti-proliferation activity during combined irradiation. Meanwhile, anti-tumor effect of SM-1 on HNSCC was higher than that of Debio1143, and the radiosensitivity of cells was greatly increased. Flow cytometry and western blot analysis showed that SM-1 induced G2/M phase arrest of head and neck squamous cell carcinoma cells via inhibiting the expression of CyclinB1 and CDC2. Moreover, SM-1 activated caspase-3 activity and up-regulated the cleaved form of PARP1 to induce cell apoptosis. In vivo, SM-1 combined irradiation showed a good anti-tumor effect. CONCLUSION: SM-1 enhances HNSCC cell radiation sensitivity in vitro and in vivo, supporting its potential as a radiosensitizer for clinical trials in combination with radiotherapy.

Evaluation of Smooth Muscle Myosin Heavy Chain Isoform Expressions in a Buried Penis.

BACKGROUND: A buried penis (BP) is rare in which the penile body is retracted into the prepubic adipose tissue. This research focuses on differences in smooth muscle myosin heavy chain (SMMHC) isoform expressions in the dartos fascia. METHODS: A total of 82 children, 41 of whom had BPs, who applied for circumcision between May and November 2021, were included in the study. The cases were divided into four groups aged ≥6 years (NP6, n = 18) and aged ≤3 years (NP3, n = 17) with normal penile appearance, aged ≥6 years (BP6, n = 23) and aged ≤3 years (BP,n = 24) with a BP. SMMHC isoforms mRNA gene expression analyses were performed by quantitative PCR technique in dartos fascia obtained from foreskin removed by circumcision. RESULTS: Compared to the NP3 group, the SM1 mRNA expressed in the BP6 group was statistically significantly higher (p < 0.005). SM2 mRNA levels expressed in dartos fascia were considerably higher in NP6 and NP3 groups compared to BP6 and BP3 groups (p < 0.001). The SM2/SM1 ratio was 0.85 in the BP6 group and 1.46 in the NP6 group, which was statistically significant (p = 0.006) and increased from 0.87 in the BP3 group to 2.21 in the NP3 group (p < 0.001). CONCLUSION: In a buried penis, there is a difference in the expression of SMMHC isoforms. SM1 is highly expressed, while SM2 decreases, increasing the SM2/SM1 ratio. This causes increased contractility in the smooth muscle, leading to retraction of the penile body. The dartos fascia surrounding it resembles aberrant muscle tissue in boys with a BP. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Case-control study.

Stronger proprioceptive BOLD-responses in the somatosensory cortices reflect worse sensorimotor function in adolescents with and without cerebral palsy.

Cerebral palsy (CP) is a motor disorder where the motor defects are partly due to impaired proprioception. We studied cortical proprioceptive responses and sensorimotor performance in adolescents with CP and their typically-developed (TD) peers. Passive joint movements were used to stimulate proprioceptors during functional magnetic resonance imaging (fMRI) session to quantify the proprioceptive responses whose associations to behavioral sensorimotor performance were also examined. Twenty-three TD (15 females, age: mean ± standard deviation 14.2 ± 2.4 years) and 18 CP (12 females, age: mean ± standard deviation, 13.8 ± 2.3 years; 12 hemiplegic, 6 diplegic) participants were included in this study. Participants' index fingers and ankles were separately stimulated at 3 Hz and 1 Hz respectively with pneumatic movement actuators. Regions-of-interest were used to quantify BOLD-responses from the primary sensorimotor (SM1) and secondary (SII) somatosensory cortices and were compared across the groups. Associations between responses strengths and sensorimotor performance measures were also examined. Proprioceptive responses were stronger for the individuals with CP compared to their TD peers in SM1 (p < 0.001) and SII (p < 0.05) cortices contralateral to their more affected index finger. The ankle responses yielded no significant differences between the groups. The CP group had worse sensorimotor performance for hands and feet (p < 0.001). Stronger responses to finger stimulation in the dominant SM1 (p < 0.001) and both dominant and non-dominant SII (p < 0.01, p < 0.001) cortices were associated with the worse hand sensorimotor performance across all participants. Worse hand function was associated with stronger cortical activation to the proprioceptive stimulation. This association was evident both in adolescents with CP and their typically-developed controls, thus it likely reflects both clinical factors and normal variation in the sensorimotor function. The specific mechanisms need to be clarified in future studies.

Validity of endoscopic resection for clinically diagnosed T1a-MM/T1b-SM1 N0 M0 esophageal squamous cell carcinoma.

BACKGROUND: Previous guidelines have not described clear recommendations for performing endoscopic resection (ER) of T1a-muscularis mucosa (MM)/T1b-submucosal (SM1) cancers that have invaded ≤ 200 µm because these are considered to have a non-negligible risk of metastasis based on previous analyses of pathologically diagnosed (p)MM/SM1 cancers. Considering that the indication for ER is determined based on a clinical diagnosis, the applicability of ER should be investigated in clinical (c)MM/SM1 but not pMM/SM1 cancers. This study aimed to evaluate validity of ER for cMM/SM1 cancers. METHODS: In total, 175 cMM/SM1 esophageal squamous cell carcinoma cases that were endoscopically or surgically resected between January 2008 and December 2018 were identified from a prospectively maintained database. We histologically evaluated resected specimens and divided them into low- (n = 92) and high-risk (n = 83) cancers for metastasis. RESULTS: Univariate analysis showed that longer tumor length and larger circumferential extent were significantly correlated with high-risk cancer (P < 0.001). Multivariate analysis showed that tumor circumference was an independent predictor of high-risk cancer (P = 0.036). The proportion of low-risk cancers among cases with ≤ 3/4, > 3/4 and < 1, and whole circumferential extent were 59, 17, and 14%, respectively, and the post-ER stricture rates of these groups were 12, 33, and 100%, respectively. CONCLUSION: ER is the first-line treatment for cMM/SM1 cancers with ≤ 3/4 circumferential extent considering that 59% of cMM/SM1 cancers were low-risk cancers for which ER is mostly curative. ER is not recommended for whole circumferential cMM/SM1 cancers given the low proportion of low-risk cancers and the high risk of stricture after ER.

Early Transcriptome Response of Trichoderma virens to Colonization of Maize Roots.

Trichoderma virens is a well-known mycoparasitic fungal symbiont that is valued for its biocontrol capabilities. T. virens initiates a symbiotic relationship with a plant host through the colonization of its roots. To achieve colonization, the fungus must communicate with the host and evade its innate defenses. In this study, we explored the genes involved with the host communication and colonization process through transcriptomic profiling of the wild-type fungus and selected deletion mutants as they colonized maize roots. Transcriptome profiles of the T. virens colonization of maize roots over time revealed that 24 h post inoculation appeared to be a key time for plant-microbe communication, with many key gene categories, including signal transduction mechanisms and carbohydrate transport and metabolism, peaking in expression at this early colonization time point. The transcriptomic profiles of Sm1 and Sir1 deletion mutants in the presence of plants demonstrated that Sir1, rather than Sm1, appears to be the key regulator of the fungal response to maize, with 64% more unique differentially expressed genes compared to Sm1. Additionally, we developed a novel algorithm utilizing gene clustering and coexpression network analyses to select potential colonization-related gene targets for characterization. About 40% of the genes identified by the algorithm would have been missed using previous methods for selecting gene targets.

The modern management of Barrett's oesophagus and related neoplasia: role of pathology.

Modern management of Barrett's oesophagus and related neoplasia essentially focuses upon surveillance to detect early low-risk neoplastic lesions and offering organ-preserving advanced endoscopic therapies, while traditional surgical treatments of oesophagectomy and lymph node clearance with or without chemoradiation are preserved only for high-risk and advanced carcinomas. With this evolution towards figless invasive therapy, the choice of therapy hinges upon the pathological assessment for risk stratifying patients into those with low risk for nodal metastasis who can continue with less invasive endoscopic therapies and others with high risk for nodal metastasis for which surgery or other forms of treatment are indicated. Detection and confirmation of neoplasia in the first instance depends upon endoscopic and pathological assessment. Endoscopic examination and biopsy sampling should be performed according to the recommended protocols, and endoscopic biopsy interpretation should be performed applying standard criteria using appropriate ancillary studies by histopathologists experienced in the pathology of Barrett's disease. Endoscopic resections (ERs) are both diagnostic and curative and should be performed by clinicians who are skilled with advanced endoscopic techniques. Proper preparation and handling of ERs are essential to assess histological parameters that dictate the curative nature of the procedure. Those parameters are adequacy of resection and risk of lymph node metastasis. The risk of lymph node metastasis is determined by depth invasion and presence of poor differentiation and lymphovascular invasion. Those adenocarcinomas with invasion up to muscularis mucosae (pT1a) and those with superficial submucosal invasion (pT1b) up to 500 µ with no poor differentiation and lymphovascular invasion and negative margins may be considered cured by endoscopic resections.

The Dielectric Constant of Ba6-3x(Sm1-yNdy)8+2xTi18O54 (x = 2/3) Ceramics for Microwave Communication by Linear Regression Analysis.

The electronics related to the fifth generation mobile communication technology (5G) are projected to possess significant market potential. High dielectric constant microwave ceramics used as filters and resonators in 5G have thus attracted great attention. The Ba6-3x(Sm1-yNdy)8+2xTi18O54 (x = 2/3) ceramic system has aroused people's interest due to its underlying excellent microwave dielectric properties. In this paper, the relationships between the dielectric constant, Nd-doped content, sintering temperature and the density of Ba6-3x(Sm1-yNdy)8+2xTi18O54 (x = 2/3) ceramics were studied. The linear regression equation was established by statistical product and service solution (SPSS) data analysis software, and the factors affecting the dielectric constant have been analyzed by using the enter and stepwise methods, respectively. It is found that the model established by the stepwise method is practically significant with Y = -71.168 + 6.946x1 + 25.799x3, where Y, x1 and x3 represent the dielectric constant, Nd content and the density, respectively. According to this model, the influence of density on the dielectric constant is greater than that of Nd doping concentration. We bring the linear regression analysis method into the research field of microwave dielectric ceramics, hoping to provide an instructive for the optimization of ceramic technology.

Pharmacodynamic and pharmacokinetic profile of SM-1, a triple-drug combination to increase total sleep time.

OBJECTIVE: The primary objective was to characterize the pharmacokinetics and pharmacodynamics of SM-1 after administration of a single oral dose to healthy volunteers in a placebo-controlled double-blind trial of daytime sedation. Secondary objectives were to determine the onset, duration, and offset of the sedative effects using subjective and objective measures of sedation. Safety and tolerability of SM-1 were also investigated. METHODS: Males and females 18-45 years of age received SM-1, a combination drug product comprised of diphenhydramine, zolpidem (delayed release), and lorazepam (delayed release). The pharmacokinetic profile of each drug was determined from blood samples. Sedative effects were assessed by visual analog scale, digit symbol substitution test, memory test, and quantitative electroencephalography. RESULTS: Similar number and severity of adverse events were observed following administration of SM-1 and placebo. Onset of sedation, as determined by subjective, performance, and electroencephalography measures, occurred 0.5-1 hr postdose, lasting about 7-7.5 hr. Plasma concentration curves for the two delayed-release components were altered compared with published data for unmodified drugs. Exposure values obtained with the combination product were in good agreement with published values of the drugs given individually. CONCLUSIONS: SM-1 was well tolerated and has pharmacologic activity starting within an hour of ingestion, lasting approximately 7-8 hr. Sedative activity was seen with subjective, psychomotor, and electroencephalography assays.

Pharmacokinetics, tissue distribution and plasma protein binding study of SM-1, a novel PAC-1 derivative.

As a PAC-1 derivative, SM-1 exhibts a promising antitumour property. To better understand the relationship between the drug concentrations and pharmacological effects, both liquid chromatography coupled with tandem mass spectrometry and high performance liquid chromatography methods were developed and validated in the work. Those methods were then applied to the pharmacokinetics (PK), tissue distribution and plasma protein binding (PPB) studies of SM-1. As a results, the proposed methods were demonstrated to be accurate, precise and stable for the analysis of the SM-1 in plasma and tissue samples. Meanwhile, the PK parameters of SM-1 showed that SM-1 had good PK properties. SM-1 had good absorption in the body, with 59.01% of the absolute bioavailability in rats and 55.63% of that in dogs. SM-1 rapidly distributed to all tissues, with the highest distribution in the lung and less in the brain and muscle. The PPB rates in rat plasma, dog plasma, and human plasma were 91.1%, 91.2%, and 90.7%, respectively. These good PK properties will contribute SM-1 to be a promising anti-tumour candidate. These results also provide insights into the further pharmacological investigation of SM-1.

Precise estimation of human corticospinal excitability associated with the levels of motor imagery-related EEG desynchronization extracted by a locked-in amplifier algorithm.

BACKGROUND: Physical motor exercise aided by an electroencephalogram (EEG)-based brain-computer interface (BCI) is known to improve motor recovery in patients with stroke. In such a BCI paradigm, event-related desynchronization (ERD) in the alpha and beta bands extracted from EEG recorded over the primary sensorimotor area (SM1) is often used, since ERD has been suggested to be associated with an increase of corticospinal excitability. Recently, we demonstrated a novel online lock-in amplifier (LIA) algorithm to estimate the amplitude modulation of motor-related SM1 ERD. With this algorithm, the delay time, accuracy, and stability to estimate motor-related SM1 ERD were significantly improved compared with the conventional fast Fourier transformation (FFT) algorithm. These technical improvements to extract an ERD trace imply a potential advantage for a better trace of the excitatory status of the SM1 in a BCI context. Therefore, the aim of this study was to assess the precision of LIA-based ERD tracking for estimation of corticospinal excitability using a transcranial magnetic stimulation (TMS) paradigm. METHODS: The motor evoked potentials (MEPs) induced by single-pulse TMS over the primary motor cortex depending on the magnitudes of SM1 ERD (i.e., 35% and 70%) extracted by the online LIA or FFT algorithm were monitored during a motor imagery task of wrist extension in 17 healthy participants. Then, the peak-to-peak amplitudes of MEPs and their variabilities were assessed to investigate the precision of the algorithms. RESULTS: We found greater MEP amplitude evoked by single-pulse TMS triggered by motor imagery-related alpha SM1 ERD than at rest. This enhancement was associated with the magnitude of ERD in both FFT and LIA algorithms. Moreover, we found that the variabilities of peak-to-peak MEP amplitudes at 35% and 70% ERDs calculated by the novel online LIA algorithm were smaller than those extracted using the conventional FFT algorithm. CONCLUSIONS: The present study demonstrated that the calculation of motor imagery-related SM1 ERDs using the novel online LIA algorithm led to a more precise estimation of corticospinal excitability than when the ordinary FFT-based algorithm was used.

Online detection of amplitude modulation of motor-related EEG desynchronization using a lock-in amplifier: Comparison with a fast Fourier transform, a continuous wavelet transform, and an autoregressive algorithm.

BACKGROUND: Neurofeedback of event-related desynchronization (ERD) in electroencephalograms (EEG) of the sensorimotor cortex (SM1) using a brain-computer interface (BCI) paradigm is a powerful tool to promote motor recovery from post-stroke hemiplegia. However, the feedback delay attenuates the degree of motor learning and neural plasticity. NEW METHOD: The present study aimed to shorten the delay time to estimate amplitude modulation of the motor-imagery-related alpha and beta SM1-ERD using a lock-in amplifier (LIA) algorithm. The delay time was evaluated by calculating the value of the maximal correlation coefficient (MCC) between the time-series trace of ERDs extracted by the online LIA algorithm and those identified by an offline algorithm with the Hilbert transform (HT). RESULTS: The MCC and delay values used to estimate the ERDs calculated by the LIA were 0.89±0.032 and 200±9.49ms, respectively. COMPARISON WITH EXISTING METHOD(S): The delay time and MCC values were significantly improved compared with those calculated by the conventional fast Fourier transformation (FFT), continuous Wavelet transformation (CWT), and autoregressive (AR) algorithms. Moreover, the coefficients of variance of the delay time and MCC values across trials were significantly lower in the LIA compared with the FFT, CWT, and AR algorithms. CONCLUSIONS: These results indicate that the LIA improved the detection delay, accuracy, and stability for estimating amplitude modulation of motor-related SM1-ERD. This would be beneficial for BCI paradigms to facilitate neurorehabilitation in patients with motor deficits.

Network-specific resting-state connectivity changes in the premotor-parietal axis in writer's cramp.

BACKGROUND: Writer's cramp is a task-specific dystonia impairing writing and sometimes other fine motor tasks. Neuroimaging studies using manifold designs have shown varying results regarding the nature of changes in the disease. OBJECTIVE: To clarify and extend the knowledge of underlying changes by investigating functional connectivity (FC) in intrinsic connectivity networks with putative sensorimotor function at rest in an increased number of study subjects. METHODS: Resting-state functional magnetic resonance imaging with independent component analysis was performed in 26/27 writer's cramp patients/healthy controls, and FC within and between resting state networks with putative sensorimotor function was compared. Additionally, voxel-based morphometry was carried out on the subjects' structural images. RESULTS: Patients displayed increased left- and reduced right-hemispheric primary sensorimotor FC in the premotor-parietal network. Mostly bilaterally altered dorsal/ventral premotor FC, as well as altered parietal FC were observed within multiple sensorimotor networks and showed differing network-dependent directionality. Beyond within-network FC changes and reduced right cerebellar grey matter volume in the structural analysis, the positive between-network FC of the cerebellar network and the basal ganglia network was reduced. CONCLUSIONS: Abnormal resting-state FC in multiple networks with putative sensorimotor function may act as basis of preexisting observations made during task-related neuroimaging. Further, altered connectivity between the cerebellar and basal ganglia network underlines the important role of these structures in the disease.

Novel proapoptotic agent SM-1 enhances the inhibitory effect of 5-fluorouracil on colorectal cancer cells in vitro and in vivo.

5-Fluorouracil (5-FU) is one of the most important agents used to treat colorectal cancer. However, the therapeutic effect of 5-FU on colon cancer is limited. SM-1 is a novel type of proapoptotic agent that directly activates procaspase-3 to caspase-3, leading to apoptosis in human cancer cells. The aim of the present study was to evaluate the antitumor effects of 5-FU in combination with SM-1. The human colorectal cancer cell lines HCT116 and LoVo were cultured in the presence of SM-1 and 5-FU. The combination of SM-1 and 5-FU treatment exhibited increased proliferation inhibitory effects compared with 5-FU treatment alone in HCT116 and LoVo cells, as determined using an MTT assay. SM-1 significantly decreased the half-maximal inhibitory concentration of 5-FU from 8.07±0.49 to 2.55±0.41 µmol/l in HCT116 cells, and from 7.90±0.98 to 3.14±0.81 µmol/l in LoVo cells. Similarly, the apoptotic activity was increased to 47.95 and 35.19% in HCT116 and LoVo cells, respectively, as determined using Annexin V/propidium iodide staining and flow cytometry. The combination of SM-1 and 5-FU treatment led to significantly increased caspase-3 activity compared with either compound alone. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis revealed the downregulation of B-cell lymphoma 2 and Survivin, and the upregulation of apoptosis regulator Bcl-2-associated X protein and cleaved poly (ADP-ribose) polymerase in HCT116 and LoVo cells. In addition, RT-qPCR identified downregulation of X-linked inhibitor of apoptosis protein mRNA. 5-FU and SM-1 treatment in combination increased tumor proliferation inhibition in HCT116 and LoVo xenograft mouse models of colorectal cancer, compared with SM-1 or 5-FU treatment alone. SM-1 significantly enhanced the antitumor activity of 5-FU in colorectal cancer. These improved effects were due to increased activity of the apoptotic signaling pathway.

Inhibitory effect of SM-1 on human liver microsomal cytochrome P450 enzyme / 中国药理学通报

Aim To investigate the effect of SM-1 on seven main cytochrome P450(CYP450)in human liver microsomes.Methods Substrate or SM-1 was incubated with human liver microsomes for 30 min in vitro,and divided into control group and experimental group.The effects of SM-1 on the main phase I metabolic enzymes in human liver microsomes was detected by HPLC.Phenacetin,bupropion,paclitaxel,tolbutamide,omeprazole,dextromethorphan,testosterone were investigated as probe drugs.Results Inhibition rate of SM-1 on the classical substrate of human liver microsomal CYP was 0.05％,3.37％,0.08％,2.07％,4.20％,-0.15％and 10.84％,respectively.Conclusions SM-1 may have inhibitory effect on CYP3A4.Attention should be paid to the interaction of clinical drug induced by CYP enzyme inhibition.

SM-1, a novel PAC-1 derivative, activates procaspase-3 and causes cancer cell apoptosis.

PURPOSE: To develop more potent procaspase-3 activator, 7 novel derivatives of PAC-1 were synthesized and evaluated. Among them, SM-1 stood out for its promising activity and good pharmacokinetics properties. The purpose of this study is to elucidate the pharmacological mechanism of SM-1 and evaluate its efficacy and toxicity in-depth. METHODS: To reveal the effects of SM-1 on caspase-3 activity, both in vitro activation assay and in cells fluorometric assay were tested. The protein levels and distributions of procaspase-3 and cleaved caspase-3 were also measured by western blot and immunostaining. MTT assay, apoptosis assay and mouse xenograft model were applied to evaluate the efficacy of SM-1. Preliminary safety assessments also tested the acute toxicity and tissue distribution of SM-1. RESULTS: Compared to PAC-1, SM-1 showed higher cytotoxicity in cancer cells. Further investigation demonstrated that SM-1 relieved zinc-mediated inhibition of procaspase-3 and activated the caspase-3 activity both in tube test and in cells. Efficacy evaluation showed SM-1-induced cell apoptosis mainly via activation of caspase-3 and reduced tumor size in mouse xenograft model. Its apoptosis induction efficacy was higher than PAC-1. The preliminary safety assessment demonstrated that the overall LD50 of SM-1 lied between 500 and 1000 mg/kg and the distribution of SM-1 in brain was low. CONCLUSIONS: We identified SM-1 as a promising antitumor candidate, which displayed enhanced procaspase-3 activating activity and potent cytotoxicity for cancer cells but low toxicity for normal cells.

SM-1 induces apoptosis of BGC-823 cells by activating procaspase-3 and exerts antitumor effect / 军事医学

Objective To investigate the antitumor activity of the procaspase-3 activator SM-1 in BGC-823 cells in vivo and in vitro and the mechanisms.Methods The inhibitory effects of SM-1 on proliferation of BGC-823 cells were evaluated using MTT method, the cell apoptosis rate was detected by flow cytometry, and the expression of caspase-3 protein and procaspase-3 mRNA was detected by Western blotting and RT-PCR, respectively.SM-1 Antitumor activity was evaluated using the xenograft of BGC-823 cells in nude mice.Results SM-1 effectively inhibited the proliferation in vitro and in-duced apoptosis of BGC-823 cells in a dose-dependent manner.After treatment with SM-1 for 48 h, the protein expression levels of caspase-3 and mRNA expression levels of procaspase-3 were increased.SM-1 significantly inhibited growth of BGC-823 xenograft tumor at the 300 mg/kg dose and the inhibition rate was 56.3%(P<0.05).Conclusion SM-1 can significantly inhibit the tumor growth of BGC-823 cells in vivo and in vitro.The mechanism is possibly related to the activation of procaspase-3 and induced apoptosis of tumor cells.

Submucosal invasion and risk of lymph node invasion in early Barrett's cancer: potential impact of different classification systems on patient management.

BACKGROUND: Due to the high mortality and morbidity rates of esophagectomy, endoscopic mucosal resection (EMR) is increasingly used for the curative treatment of early low risk Barrett's adenocarcinoma. OBJECTIVE: This retrospective cohort study aimed to assess the prevalence of lymph node metastases (LNM) in submucosal (T1b) esophageal adenocarcinomas (EAC) in relation to the absolute depth of submucosal tumor invasion and demonstrate the efficacy of EMR for low risk (well and moderately differentiated without lymphovascular invasion) EAC with sm1 invasion (submucosal invasion ≤500 µm) according to the Paris classification. METHODS: The pathology reports of patients undergoing endoscopic resection and surgery from January 1994 until December 2013 at one center were reviewed and 54 patients with submucosal invasion were included. LNM were evaluated in surgical specimens and by follow up examinations in case of EMR. RESULTS: No LNM were observed in 10 patients with sm1 adenocarcinomas that underwent endoscopic resection. Three of them underwent supplementary endoscopic eradication therapy with a median follow up of 27 months for patients with sm1 tumors. In the surgical series two patients (29%) with sm1 invasion according to the pragmatic classification (subdivision of the submucosa into three equal thirds), staged as sm2-3 in the Paris classification, had LNM. The rate of LNM for surgical patients with low risk sm1 tumors was 10% according to the pragmatic classification and 0% according to Paris classification. CONCLUSION: Different classifications of the tumor invasion depth lead to different LNM risks and treatment strategies for sm1 adenocarcinomas. Patients with low risk sm1 adenocarcinomas appear to be suitable candidates for EMR.

The Epl1 and Sm1 proteins from Trichoderma atroviride and Trichoderma virens differentially modulate systemic disease resistance against different life style pathogens in Solanum lycopersicum.

Fungi belonging to the genus Trichoderma, commonly found in soil or colonizing plant roots, exert beneficial effects on plants, including the promotion of growth and the induction of resistance to disease. T. virens and T. atroviride secrete the proteins Sm1 and Epl1, respectively, which elicit local and systemic disease resistance in plants. In this work, we show that these fungi promote growth in tomato (Solanum lycopersicum) plants. T. virens was more effective than T. atroviride in promoting biomass gain, and both fungi were capable of inducing systemic protection in tomato against Alternaria solani, Botrytis cinerea, and Pseudomonas syringae pv. tomato (Pst DC3000). Deletion (KO) of epl1 in T. atroviride resulted in diminished systemic protection against A. solani and B. cinerea, whereas the T. virens sm1 KO strain was less effective in protecting tomato against Pst DC3000 and B. cinerea. Importantly, overexpression (OE) of epl1 and sm1 led to an increase in disease resistance against all tested pathogens. Although the Trichoderma WT strains induced both systemic acquired resistance (SAR)- and induced systemic resistance (ISR)-related genes in tomato, inoculation of plants with OE and KO strains revealed that Epl1 and Sm1 play a minor role in the induction of these genes. However, we found that Epl1 and Sm1 induce the expression of a peroxidase and an α-dioxygenase encoding genes, respectively, which could be important for tomato protection by Trichoderma spp. Altogether, these observations indicate that colonization by beneficial and/or infection by pathogenic microorganisms dictates many of the outcomes in plants, which are more complex than previously thought.

Endoscopic submucosal dissection for gastric tube cancer after esophagectomy.

BACKGROUND: Recent improvements in the survival of patients after esophagectomy have led to an increasing occurrence of gastric tube cancer (GTC). Removal of the reconstructed gastric tube, however, can lead to high morbidity and mortality. OBJECTIVE: To assess the feasibility and effectiveness of endoscopic submucosal dissection (ESD) for GTC. DESIGN: Retrospective study. SETTING: National Cancer Center Hospital, Tokyo, Japan. PATIENTS: We investigated patients with GTC after esophagectomy undergoing ESD from 1998 to 2011. INTERVENTION ESD MAIN OUTCOME MEASUREMENTS: Patient characteristics, endoscopic findings, technical results, histopathology including curability and Helicobacter pylori gastritis, and long-term outcomes. RESULTS: There were 51 consecutive patients with 79 lesions including 38 lesions (48%) meeting the absolute indication, 31 (39%) satisfying the expanded indications, and 10 (13%) falling outside such indications. The median procedure time was 90 minutes. There were 73 en bloc resections (92%), 59 en bloc resections with tumor-free margins (R0 resections, 75%), and 51 curative resections (65%) based on the Japanese Gastric Cancer Association criteria. Fifty patients (98%) were assessed as H pylori gastritis positive. Adverse events included 3 perforations (3.8%) during ESD and 2 delayed perforations (2.5%) without any emergency surgery and 3 delayed bleeding (3.8%). Local recurrence was detected in 4 patients (7.8%), and metachronous GTCs were identified in 18 patients (35%). Five patients (10%) died of GTC including 3 metachronous lesions. The 5-year overall survival rate was 68.4%, and the disease-specific survival rate was 86.7% with 100% for curative and 72.7% for non-curative patients during a median follow-up period of 3.8 years (range, 0-12.1 years). LIMITATION: Single-center retrospective study. CONCLUSIONS: ESD for GTC was feasible and effective for curative patients; however, long-term outcomes for non-curative patients were less satisfactory.

Absorption mechanism of SM-1：a procaspase-3-activated anti-tumor agent / 中国药理学通报

Aim To study absorption characteristics of SM-1 , a novel anti-tumor agent , to provide a research basis for the druggability evaluation of SM-1 and formu-lation design. Methods Caco-2 cell monolayer model and in situ single-pass intestinal perfusion rat model were used to study the absorption characteristics of SM-1 , and the absorption of SM-1 in vivo was evaluated through absolute bioavailability study in rats. Results The results of cell monolayer model showed that cu-mulative absorption and efflux of SM-1 increased line-arly with concentration ( 10 ~40 mg · L-1 ) . There were no significant differences in Papp with different concentrations ( P>0. 05 ) . SM-1 was absorbed mainly through passive diffusion. The intestinal perfusion re-sults showed that Ka and Pef of SM-1 had no significant differences ( P > 0. 05 ) , when the concentrations ranged from 25 to 100 mg · L-1 . SM-1 entered the systemic circulation mainly via on passive diffusion, indicating it is a compound with high permeability. The absorption of SM-1 in duodenum was superior to other intestinal segments ( P 0. 05 ) . The absolute bioavailability of SM-1 in rats was 29. 3%. Conclusion The membrane perme-ability of SM-1 is high and it can be absorbed by intes-tine well. The absorption mechanism of SM-1 is pas-sive diffusion, and it possibly escapes from the efflux transporter protein. The absolute bioavailability of SM-1 in rats is low.