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Francisella tularensis , the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII pathway is a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. These compounds display an improved low nanomolar enzymatic activity as well as promising low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). The improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity. [ABSTRACT FROM AUTHOR]

This paper provides an analytical subthreshold model for trigate MOSFETs with thin buried oxide (BOX) for multithreshold (multi- Vth ) applications. This model shows a fairly good scalability in substrate bias and BOX thickness, which is crucial to the prediction of multi- Vth modulation through BOX. In addition, we demonstrate the application of our model in multi- Vth device design for trigate GeOI p-MOSFETs with the body-effect coefficient ( $\gamma $ ) over a wide range of design space efficiently examined. We have shown an enhanced multi- Vth modulation behavior in trigate GeOI p-MOSFETs. Our study indicates that, for a given subthreshold swing and $\gamma $ , the GeOI trigate p-MOSFET can possess a higher fin aspect ratio than the SOI counterpart. [ABSTRACT FROM PUBLISHER]

This paper investigates the impact of backgate biasing ( VBS ) on the drain current ( ID ) of ultrathin-body III-V heterojunction tunnel FET (HTFET). Compared with homojunction TFET and III-V/Ge MOSFET, this paper indicates that HTFET exhibits significantly higher I\mathrm{{\scriptstyle OFF}} ( ID at VGS = 0 V and VDS=0.5 V) modulation efficiency and the influence of VBS rapidly decreases with increasing VGS . In addition, it is observed that the change of source available states with VBS determines the ID modulation efficiency of p-type HTFET (pHTFET). Depending on the source doping concentration and operating VGS , the ID of HTFET under forward VBS can be anomalously smaller than that at VBS=0 V. Furthermore, the impacts of source/drain doping concentrations and junction properties are discussed and shown to be critical in determining the ID modulation efficiency of HTFET. We find that, under controlled ambipolar current, reverse backgate biasing can be utilized to suppress the I\mathrm{{\scriptstyle OFF}} of HTFET, and the modulation efficiency increases with decreasing source doping concentration. Our study may provide insights for device/circuit designs with advanced TFET technologies. [ABSTRACT FROM PUBLISHER]

5-Fluorouracil (5-FU) and its pro-drug Capecitabine have been widely used in treating colorectal cancer. However, not all patients will respond to the drug, hence there is a need to develop reliable early predictive biomarkers for 5-FU response. Here, we report a novel potentially functional Single Nucleotide Polymorphism (pfSNP) approach to identify SNPs that may serve as predictive biomarkers of response to 5-FU in Chinese metastatic colorectal cancer (CRC) patients. 1547 pfSNPs and one variable number tandem repeat (VNTR) in 139 genes in 5-FU drug (both PK and PD pathway) and colorectal cancer disease pathways were examined in 2 groups of CRC patients. Shrinkage of liver metastasis measured by RECIST criteria was used as the clinical end point. Four non-responder-specific pfSNPs were found to account for 37.5% of all non-responders (P<0.0003). Five additional pfSNPs were identified from a multivariate model (AUC under ROC = 0.875) that was applied for all other pfSNPs, excluding the non-responder-specific pfSNPs. These pfSNPs, which can differentiate the other non-responders from responders, mainly reside in tumor suppressor genes or genes implicated in colorectal cancer risk. Hence, a total of 9 novel SNPs with potential functional significance may be able to distinguish non-responders from responders to 5-FU. These pfSNPs may be useful biomarkers for predicting response to 5-FU. [ABSTRACT FROM AUTHOR]

This paper extensively evaluates the stability and performance of heterochannel 6T/8T SRAM cells integrated in monolithic 3-D scheme with interlayer coupling. Various bitcell layouts with different gate alignments of transistors from distinct layers are investigated. This paper indicates that stacking the NFET tier over the PFET tier results in larger design margins for cell robustness and performance. Furthermore, the partition of 3-D layout design among distinct layers shows profound impacts on the stability, standby leakage, and performance of monolithic 3-D SRAM cells. Compared with the Si-based cells, the use of heterochannel devices increases the improvements of monolithic 3-D design over the 2-D counterparts and emerges as a suitable candidate for future monolithic 3-D IC applications. [ABSTRACT FROM PUBLISHER]

Highlights: [•] We review the impacts of random telegraph noise on FinFET, Ge/Si Nanowire FET, Tunnel FET (TFET) and related circuits. [•] For FinFET, trap in the middle between source/drain and bottom of sidewall interface shows larger impact. [•] The RTN in Ge Nanowire FET exhibits stronger drain bias dependence and may yield current increase. [•] TFET exhibits drastically higher sensitivity to RTN and significant I OFF degradation. [•] The possible RTN combinations due to trapping/detrapping in each device are discussed for SRAM and logic circuits. [ABSTRACT FROM AUTHOR]

Background: The safety and tolerability of sequential radioembolization-sorafenib therapy is unknown. An open-label, single arm, investigator-initiated Phase II study (NCT0071279) was conducted at four Asia-Pacific centers to evaluate the safety and efficacy of sequential radioembolization-sorafenib in patients with hepatocellular carcinoma (HCC) not amenable to curative therapies. Methods: Sorafenib (400 mg twice-daily) was initiated 14 days post-radioembolization with yttrium-90 (90Y) resin microspheres given as a single procedure. The primary endpoints were safety and tolerability and best overall response rate (ORR) using RECIST v1.0.Secondary endpoints included: disease control rate (complete [CR] plus partial responses [PR] and stable disease [SD]) and overall survival (OS). Results: Twenty-nine patients with Barcelona Clinic Liver Cancer (BCLC) stage B (38%) or C (62%) HCC received a median of 3.0 GBq (interquartile range, 1.0) 90Y-microspheres followed by sorafenib (median dose/day, 600.0 mg; median duration, 4.1 months). Twenty eight patients experienced ≥1 toxicity; 15 (52%) grade ≥3. Best ORR was 25%, including 2 (7%) CR and 5 (18%) PR, and 15 (54%) SD. Disease control was 100% and 65% in BCLC stage B and C, respectively. Two patients (7%) had sufficient response to enable radical therapy. Median survivals for BCLC stage B and C were 20.3 and 8.6 months, respectively. Conclusions: This study shows the potential efficacy and manageable toxicity of sequential radioembolization-sorafenib. Trial Registration: ClinicalTrials.gov NCT00712790. [ABSTRACT FROM AUTHOR]

The impact of different carcinogenic exposures on the specific patterns of somatic mutation in human tumors remains unclear. To address this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non-O. viverrini-related etiologies. Whole-exome sequencing (n = 15) and prevalence screening (n = 194) identified recurrent somatic mutations in BAP1 and ARID1A, neither of which, to our knowledge, has previously been reported to be mutated in CCA. Comparisons between intrahepatic O. viverrini-related and non-O. viverrini-related CCAs demonstrated statistically significant differences in mutation patterns: BAP1, IDH1 and IDH2 were more frequently mutated in non-O. viverrini CCAs, whereas TP53 mutations showed the reciprocal pattern. Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations, even within the same tumor type. [ABSTRACT FROM AUTHOR]

Early diagnosis of hepatocellullar carcinoma (HCC) remains a challenge. The current practice of serum alpha-fetoprotein (AFP) measurement is inadequate. Here we utilized a proteomic approach to identify novel serum biomarkers for distinguishing HCC patients from non-cancer controls. We profiled the serum proteins in a group of 58 resectable HCC patients and 11 non-HCC chronic hepatitis B (HBV) carrier samples from the Singapore General Hospital (SGH) using the RayBio® L-Series 507 Antibody Array and found 113 serum markers that were significantly modulated between HCC and control groups. Selected potential biomarkers from this list were quantified using a multiplex sandwich enzyme-linked immunosorbent assay (ELISA) array in an expanded SGH cohort (126 resectable HCC patients and 115 non-HCC chronic HBV carriers (NC group)), confirming that serum prolactin and monocyte chemoattractant protein-1 (MCP-1) were significantly upregulated in HCC patients. This finding of serum MCP-1 elevation in HCC patients was validated in a separate cohort of serum samples from the Mochtar Riady Institute for Nanotechnology, Indonesia (98 resectable HCC, 101 chronic hepatitis B patients and 100 asymptomatic HBV/HCV carriers) by sandwich ELISA. MCP-1 and prolactin levels were found to correlate with AFP, while MCP-1 also correlated with disease stage. Subsequent receiver operating characteristic (ROC) analysis of AFP, prolactin and MCP-1 in the SGH cohort and comparing their area under the ROC curve (AUC) indicated that neither prolactin nor MCP-1 on their own performed better than AFP. However, the combination of AFP+MCP-1 (AUC, 0.974) had significantly superior discriminative ability than AFP alone (AUC, 0.942; p<0.001). In conclusion, prolactin and MCP-1 are overexpressed in HCC and are conveniently quantifiable in patients’ sera by ELISA. MCP-1 appears to be a promising complementary biomarker for HCC diagnosis and this MCP-1+AFP model should be further evaluated as potential biomarker on a larger scale in patients at-risk of HCC. [ABSTRACT FROM AUTHOR]

This paper analyzes the impacts of a single acceptor-type and donor-type interface trap induced random telegraph noise (RTN) on tunnel FET (TFET) devices and its interaction with work function variation (WFV) using atomistic 3-D TCAD simulations. Significant RTN amplitude (\Delta ID/ID) is observed for a single acceptor trap near the tunneling junction, whereas a donor trap is found to cause more severe impact over a broader region across the channel region. In addition, several device design parameters that can be used to improve TFET subthreshold characteristics (thinner equivalent oxide thickness or longer Leff) are found to increase the susceptibility to RTN. Our results indicate that under WFV, TFET exhibits weaker correlation between ION and IOFF than that in the conventional MOSFET counterpart. In the presence of WFV, the RTN amplitude can be enhanced or reduced depending on the type of the trap and the composition/orientation of metal-gate grain. [ABSTRACT FROM PUBLISHER]

With a steep subthreshold slope, tunneling FETs (TFETs) are promising candidates for ultralow-voltage operation compared with conventional MOSFETs. However, the delayed saturation characteristic and the broad soft transition region result in a large crossover region/current in an inverter, thus degrading the hold/read static noise margin (H/RSNM) of TFET SRAM cells. The write-ability and write static noise margin (WSNM) of TFET SRAM cells are constrained by the unidirectional conduction characteristics and large crossover contention of the write access transistor and the holding transistor. In this paper, we present a detailed analysis of TFET circuit switching/output characteristics/performance and the underlying physics. The stability/performance of several TFET SRAM cells are then analyzed/compared using atomistic technology computer-aided design mixed-mode simulations. Finally, a robust 7T driverless (DL) TFET SRAM cell is proposed. The proposed 7T DL TFET SRAM cell, with better output characteristics in single-gate mode, and decoupled read current path from cell storage node and push–pull write action with asymmetrical raised-cell-virtual-ground write-assist, provides a significant improvement in hold, read, and write stability and performance. [ABSTRACT FROM AUTHOR]

Purpose: The highest rates of gastric cancer occur in Eastern Asia. Fluoropyrimidine-based therapy is used initially in unresectable and metastatic disease, but no single standard of care exists following disease progression. Ixabepilone, an epothilone B analog, is a non-taxane microtubule-stabilizing agent with clinical activity across multiple tumor types approved by the United States Food and Drug Administration for treatment of metastatic breast cancer. Methods: Asian patients with unresectable or metastatic gastric adenocarcinoma who had failed fluoropyrimidine-based chemotherapy received ixabepilone 40 mg/m by 3-h intravenous infusion every 3 weeks. The primary endpoint was objective response rate (ORR). Results: Fifty-two patients were treated (65.4 % men; median age: 56.5 years). The ORR was 15.4 % (95 % confidence interval [CI] 6.9-28.1); 8 patients achieved partial responses for a median duration of 3.1 months (95 % CI 2.6-4.1 months) and 26 patients (50.0 %) had stable disease. Median progression-free survival was 2.8 months (95 % CI 2.1-3.5 months). The most common grade 3 non-hematological toxicities were fatigue (9.6 %), decreased appetite (7.7 %), sensory neuropathy (5.8 %), and diarrhea (5.8 %). Grade 3/4 neutropenia occurred in 46.2 % of patients. Conclusions: Ixabepilone is active in Asian patients with advanced gastric cancer and shows a toxicity profile similar to those previously reported in other tumor types. [ABSTRACT FROM AUTHOR]

This paper investigates the impact of quantum confinement (QC) on the backgate-bias (Vbg) modulated subthreshold and threshold-voltage (Vth) characteristics of ultra-thin-body germanium-on-insulator (UTB GeOI) MOSFETs using an analytical solution of the Schrödinger equation verified with TCAD numerical simulation. Our study indicates that the QC effect reduces the sensitivity of the subthreshold swing to Vbg. In addition, the sensitivity of Vth to Vbg can be enhanced by the QC effect particularly for electrostatically well-behaved UTB MOSFETs with triangular potential well. Aside from that, the sensitivity of Vth roll-off to Vbg is reduced by the QC effect. Since Ge and Si channels exhibit different degrees of QC due to different quantization effective mass, the impact of QC has to be considered when one-to-one comparisons between GeOI and SOI MOSFETs regarding the backgate-bias modulated threshold-voltage and subthreshold characteristics are made. Our study may provide insights for multi- Vth device/circuit designs using advanced UTB GeOI technologies. [ABSTRACT FROM PUBLISHER]

Background & Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death. Although sorafenib has been shown to improve survival of patients with advanced HCC, this improvement is modest and patients eventually have refractory disease. This study aims at investigating the antitumor, antiangiogenesis and antimetastatic activities of dovitinib in preclinical models of HCC. Methods: 21-0208 and SK-HEP1 cells as well as patient-derived HCC models were employed to study the antitumor effect of dovitinib. Changes of biomarkers relevant to FGFR/VEGFR/PDGFR pathways were determined by Western blotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry. Results: Treatment of SK-HEP1 cells with dovitinib resulted in G2/M cell cycle arrest, inhibition of colony formation in soft agar and blockade of bFGF-induced cell migration. Dovitinib inhibited basal expression and FGF-induced phosphorylation of FGFR-1, FRS2-α and ERK1/2. In vivo, dovitinib potently inhibited tumor growth of six HCC lines. Inhibition of angiogenesis correlated with inactivation of FGFR/PDGFR-β/VEGFR-2 signaling pathways. Dovitinib also caused dephosphorylation of retinoblastoma, upregulation of p-histone H2A-X and p27, and downregulation of p-cdk-2 and cyclin B1, which resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. In an orthotopic model, dovitinib potently inhibited primary tumor growth and lung metastasis and significantly prolonged mouse survival. Conclusions: Dovitinib demonstrated significant antitumor and antimetastatic activities in HCC xenograft models. This study provides a compelling rationale for clinical investigation in patients with advanced HCC. [Copyright &y& Elsevier]

This paper investigates the cell stability of recently introduced four-transistor (4T) and conventional six-transistor (6T) fin-shaped field-effect transistor static random access memory (SRAM) cells operating in a subthreshold region using an efficient model-based approach to consider the impact of device variations. Compared with the 6T cell, this paper indicates that 4T SRAM cells exhibit a better nominal read static noise margin (RSNM) because of the reduced read disturb. For 4T cells, the nearly ideal values of Vwrite, 0 and Vwrite, 1 guarantee the positive nominal write static noise margin (WSNM) for selected cells. For half-selected cells on the selected bit line, a sufficient margin is observed between write time (for selected cells) and write disturb (for half-selected cells). Using the established model-based approach, the variability of subthreshold 6T and 4T SRAM cells is assessed with 1000 samples. Our results indicate that the 4T driverless cell with a larger \mu\RSNM and a slightly worse \sigma\RSNM shows a comparable \mu/\sigma ratio in RSNM with the 6T cell. Furthermore, for a given cell area, 4T SRAM cells using relaxed device dimensions with reduced \sigma\RSNM can outperform the 6T cell. For write operation, 4T SRAM cells exhibit a superior WSNM, whereas the design margin between write time and write disturb needs to be carefully examined to ensure an adequate margin considering device variability. [ABSTRACT FROM PUBLISHER]

This paper analyzes the impacts of intrinsic process variations and negative bias temperature instability (NBTI)/positive BTI (PBTI)-induced time-dependent variations on the stability/variability of 6T FinFET static random access memory (SRAM) cells with various surface orientations and gate dielectrics. Due to quantum confinement, (110)-oriented pull-down n-channel FETs with fin line-edge roughness (LER) show larger Vread,0 and Vtrip variations, thus degrading read static noise margin (RSNM) and its variability. Pull-up p-channel FETs with fin LER that are (100)-oriented show larger Vwrite,0 and Vtrip variations, hence degrade the variability of write SNM. The combined effects of intrinsic process variations and NBTI/PBTI-induced statistical variations have been examined to optimize the FinFET SRAM cells. Worst-case stress scenario for SNM stability/variability is analyzed. With the presence of both NBTI and PBTI in high-k metal-gate FinFET SRAM, the RSNM suffers significant degradation as Vread,0 increases, whereas Vtrip simultaneously decreases. Variability comparisons for FinFET SRAM cells with different gate stacks (\SiO2 and \SiO2/\HfO2) are also examined. Our paper indicates that the consideration of NBTI/PBTI-induced temporal variation changes the optimal choice of FinFET SRAM cell surface orientations in terms of the \mu/\sigma ratio in RSNM. [ABSTRACT FROM PUBLISHER]

Oxaliplatin-related neurotoxicity is frequently dose-limiting. Following retrospective studies suggesting neuroprotective effects of calcium and magnesium (Ca and Mg), we conducted a prospective study using nerve conduction studies (NCS) to evaluate the effectiveness of such infusions in oxaliplatin-related neuropathy. Colorectal cancer patients receiving FOLFOX-4 or capecitabine plus oxaliplatin were randomized to (Arm A) calcium gluconate 1g +15% magnesium sulphate 1g diluted in 100 mL of dextrose 5% or (Arm B) placebo. Neuropathy was assessed using the National Cancer Center common toxicity criteria, oxaliplatin-specific scale and NCS. This study was terminated prematurely based on the initial negative results of the CONcePT trial. Median follow up was 8.7 months. Overall 22 out of 27 patients experienced neuropathy. The subjective neuropathy rate was 77% in Arm A and 86% in Arm B, ( P = 0.6). At the end of treatment, three patients in Arm A and 0 in Arm B had grade 3 numbness ( P = 0.09). There was no significant difference in neuropathy between arms, whether during or at the end of treatment. Median objective neuropathy score was 6 in Arm A and 0 in Arm B, ( P = 0.02). Premature closure of this study limits the interpretation of results. While there was a trend towards reduced subjective acute sensory neuropathy with Ca and Mg, this was not significant. Ca and Mg failed to reduce the rate of cumulative sensory neuropathy and instead increased the rate of abnormal NCS, suggesting a significant difference in perceived sensory and objective neuropathy. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular carcinoma (HCC) is a particularly vascularized solid tumor where the Raf/MEK/ERK pathway is activated; suggesting that inhibition of this pathway may have therapeutic potential. Methods: We treated patient-derived HCC xenografts with (i) sorafenib, (ii) AZD6244 (ARRY-142886), and (iii) sorafenib plus AZD6244. Western blotting was employed to determine pharmacodynamic changes in biomarkers relevant to both angiogenesis and MEK signaling. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry. Results: We report here that sorafenib treatment resulted in suppression of tumor growth, reduction in cell proliferation, induction of apoptosis and inhibition of mTOR targets. Sorafenib-induced elevation of the insulin-like growth factor receptor 1 (IGF-1R), phospho-c-Raf Ser338, phospho-MEK Ser217/221 and phospho-ERK Thr202/Tyr204 was attenuated by co-treating cells with anti-human IGF-1R antibody or over-expression of activated mutant p70S6K. Pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect of sorafenib in both orthotopic and ectopic models of HCC. Such inhibition led to a further increase in pro-apoptotic Bim, apoptosis and a profound inhibition of cell proliferation. Conclusion: Our findings underscore the potential of a combined therapeutic approach with sorafenib and MEK inhibitors in the treatment of HCC. [Copyright &y& Elsevier]

Abstract: Aim: To analyze the outcome of elderly patients compared with the younger age group patients who were diagnosed with gastrointestinal stromal tumours (GIST) at our institution. Methods: Patients diagnosed with GISTs were analyzed according to two age groups, those who were at least age 65 and less than age 65. Results: A total of 49 patients were reviewed. Median age at diagnosis was 59. 18 patients (36.7%) were of age at least 65 or above. Of these 11 patients presented with localized disease. Five patients subsequently developed recurrence with metastatic disease. The median recurrence free survival was 18.5 months. This was not significantly different compared to the younger age group patient (P =0.598). On univariate analysis, the presence of co-morbidities was found to be significantly associated with decrease recurrence-free survival (P =0.046). 13 patients (72.2.%) of the elderly age group had metastatic disease. 8 of these patients had metastasis at diagnosis and 5 developed metastasis at recurrence. The median progression-free survival for these patients was 33 months and there was no significant difference compared to the younger age group patient (P =0.887). On univariate analysis, low albumin was associated with low progression survival (P =0.047). The median overall survival for the elderly patients was 37.6 months. There was no significant difference compared to the younger age group patient (P =0.119). Presence of co-morbidity was associated with lower overall survival in the elderly age group in the multivariate analysis (P =0.037). Conclusion: The elderly with GIST can achieve a similar outcome as younger patients. Presence of co-morbidity was found to affect the survival of elderly patients with GIST. [Copyright &y& Elsevier]

Dynamic contrast-enhanced (DCE) CT imaging of four patients with hepatocellular carcinoma (HCC) was performed using a dual-phase imaging protocol designed with initial rapid dynamic imaging to capture the initial increase in contrast medium enhancement in order to assess perfusion, followed by a delayed imaging phase with progressively longer intervals to monitor subsequent tissue enhancement behaviour in order to assess tissue permeability. The DCE CT images were analysed using a dual-input two-compartment distributed parameter model to yield separate estimates for blood flow and permeability, as well as fractional intravascular and extravascular volumes. The HCCs and surrounding cirrhotic liver tissues were found to exhibit enhancement curves that can be appropriately described by two distinct compartments separated by a semipermeable barrier. Early contrast arrival was also found for HCC as compared with background liver. These findings are consistent with the current understanding of sinusoidal capillarization and hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

The article discusses a case of capecitabine-induced oromandibular dystonia and included a summary of other cases reported in the medical literature. According to the article, a patient diagnosed with stenosing adenocarcinoma of the rectum with a solitary live metastasis was treated with one cycle of capecitabine and nine days later he developed dystonia of tongue and pharyngeal muscles and involuntary jaw clenching.

Several letters to the editor related to medical care are presented, one responds to a survey sent to patients under specialist palliative care services, another discusses the impact of the European Union Directive regulations on medical studies in palliative care.

Abstract: We investigated the feasibility of two monitoring imaging methods to visualize and evaluate the high intensity focused ultrasound (HIFU) induced lesions in vitro during and after their formation, which were based on differential ultrasonic parameter estimation. Firstly, ultrasonic attenuation slope of tissue sample was estimated based on the spectral analysis of ultrasound RF backscattered signals. The differential attenuation slope maps were acquired, which were interpreted as the differences between the pretreatment image and those obtained in different stages during HIFU therapy. Secondly, ultrasonic integrated backscatter (IBS), defined as the frequency average of the backscatter transfer function over the useful bandwidth, was proposed quantitatively to evaluate the extent of lesions with the same RF signals as the first method. Differential IBS maps were also acquired to visualize temporal evolution of lesion formation. It was found in pig liver in vitro that more precise definition of the treated area was obtained from the differential IBS images than from differential attenuation slope images. Dramatic increase in both attenuation and IBS value was observed during the therapy, which may be related to dramatic enhancement of cavitation due to boiling and accompanying tissue damage. Two methods to obtain one differential image were compared and the cumulative differential image was found to be able to eliminate noises and artifacts to some extent, which was the cumulation of a series of differential images acquired from the differences between the temporally adjacent RF data frames. Moreover, we presented a bidirectional color code for identification of the artifacts due to tissue movements caused by HIFU radiation force. We conclude that cumulative differential IBS images have the potential to monitor the formation of HIFU-induced lesions.(E-mail: mxwan@mail.xjtu.edu.cn) [Copyright &y& Elsevier]

The objective of this study was to investigate the effects of ultrasound on the structure and function of human tumor necrosis factor–alpha (TNF-α) and to study whether TNF-alpha underwent a denaturation process and the molecular structure was damaged when it was irradiated by ultrasound. The samples of TNF-alpha were dissolved in aqueous solution and filled into polystyrene tubes. High intensity ultrasound processor (20 kHz frequency, burst mode, 0.5 duty factor, 100–500 W total electrical power, 0–20 min total treatment time) was used during the treatment. The biologic activity of TNF-alpha was determined by its toxic activity towards TNF-alpha sensitive cell line L929 in the presence of actinomycin D. The methods of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) were used to detect the integrity of TNF-alpha molecule after it was irradiated by ultrasound. The results showed TNF-alpha could keep its biological activity, instead of undergoing a denaturation process, when it is irradiated by ultrasound in the aqueous solution; at the same time, the aggregates of TNF-alpha formed by the recombinant DNA E. coli could be dissociated through the molecular vibration induced by ultrasound energy. The biologic activity of TNF-alpha was not reduced, but small quantities of TNF-alpha molecular structure were damaged during the process of sonication. These features of TNF-α molecule irradiated by ultrasound probably gave TNF-α the advantage in being used in the drug microencapsulation and provided a new drugs formulation for tumor therapy. (mxwan@mail.xjtu.edu.cn) [Copyright &y& Elsevier]

MicroRNAs (miRNAs) are small molecule RNAs widely involved in responses to plant abiotic stresses. We performed small RNA sequencing of cotton anthers at four developmental stages under normal and high temperature (NT and HT, respectively) conditions to investigate the stress response characteristics of miRNA to HT. A total of 77 miRNAs, including 33 known miRNAs and 44 novel miRNAs, were identified, and 41 and 28 miRNAs were differentially expressed under NT and HT stress conditions, respectively. The sporogenous cell proliferation (SCP), meiotic phase (MP), microspore release period (MRP), and pollen maturity (PM) stages had 10 (including 12 miRNAs), four (including six miRNAs), four (including five miRNAs), and seven (including 11 miRNAs) HT stress-responsive miRNA families, respectively, which were identified after removing the changes in genotype-specific miRNAs under NT condition. Seven miRNA families (miR2949, miR167, and miR160 at the SCP stage; miR156 and miR172 at the MP stage; miR156 at the MRP stage; and miR393 and miR3476 at the PM stage), which had expression abundance of more than 10% of the total expression abundance, served as the main regulators responding to HT stress with positive or negative regulation patterns. These miRNAs orchestrated the expression of the corresponding target genes and led to different responses in the HT-tolerant and the HT-sensitive lines. The results revealed that the HT stress response of miRNAs in cotton anthers were stage-specific and differed with the development of anthers. Our study may enhance the understanding of the response of miRNAs to HT stress in cotton anthers and may clarify the mechanism of plant tolerance to HT stress. [ABSTRACT FROM AUTHOR]

Corrigendum to "Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis" [J Hepatol 71 (2019) 543-552] It has come to our attention that there is an error in Table 4 of our manuscript. [Extracted from the article]

In recent years, the photosynthetic bacteria have been used widely in agriculture, but the effects of different agricultural applications on crop rhizosphere microorganism and crops are lack. In this study, we provide new insights into the structure and composition of the rice root-associated microbiomes as well as the effect on crop of the Rhodopseudomonas palustris(R. palustris) PSB06 and CGA009 at the rice seedling stage with seed immersion and root irrigation. Compare with CK group, the length of stem, the peroxidase (POD), and superoxide dismutase (SOD) activities in PSB06 treatment group was significantly higher, while the length of stem in CGA009 treatment group was significantly higher. The POD and SOD activities in CGA009 treatment groups only were higher slightly than the CK group. In the study, the dominant phyla were Proteobacteria (51.95–61.66%), Bacteroidetes (5.40–9.39%), Acidobacteria (4.50–10.52%), Actinobacteria (5.06–8.14%), Planctomycetes (2.90–4.48%), Chloroflexi (2.23–5.06%) and Firmicutes (2.38–7.30%), accounted for 87% bacterial sequences. The principal coordinate analysis (pCoA) and mantel results showed the two application actions of R. palustris CGA009 and PSB06 had significant effects on rice rhizosphere bacterial communities (p < 0.05). The PSB06 can significantly promote the rice growth and enhance stress resistance of rice at the seedling stage, while the R. palustris CGA009 has no significant effect on rice. Dissimilarity test and canonical correspondence analysis (CCA) results showed that the TN and pH were the key factors affecting rice rhizosphere bacterial community in the seedling stage. This study will provide some guidance advices for the study of the microecological regulation of photosynthetic bacteria on crops. [ABSTRACT FROM AUTHOR]

Development of a genetic tool for visualization of photosynthetic bacteria (PSB) is essential for understanding microbial function during their interaction with plant and microflora. In this study, Rhodopseudomonas palustris GJ-22-gfp harboring the vector pBBR1-pckAPT-gfp was constructed using an electroporation transformation method and was used for dynamic tracing of bacteria in plants. The results showed that strain GJ-22-gfp was stable and did not affect the biocontrol function, and the Confocal Laser Scanning Microscopy (CLSM) results indicated it could successfully colonised on the surface of leaf and root of tobacco and rice. In tobacco leaves, cells formed aggregates on the mesophyll epidermal cells. While in rice, no aggregate was found. Instead, the fluorescent cells colonise the longitudinal intercellular spaces between epidermal cells. In addition, the results of strain GJ-22 on the growth promotion and disease resistance of tobacco and rice indicated that the different colonization patterns might be related to the bacteria could induce systemic resistance in tobacco. [ABSTRACT FROM AUTHOR]

Background: Many patients with advanced HCC progress on standard-of-care therapy. Nivolumab is a fully human anti-programmed death-1 (PD-1) IgG4 monoclonal antibody that demonstrated durable responses (objective response rate [ORR], 20%; median duration of response [DOR], 9.9 mo; 9-mo overall survival [OS] rate, 74%) in patients with advanced HCC in the dose-expansion (EXP) phase of the CheckMate 040 study (NCT01658878; El-Khoueiry, Sangro et al. 2017). Here we present survival and durability of response data in both sorafenibnaive and -experienced patients with advanced HCC in CheckMate 040. Methods: Patients naive to or previously treated with sorafenib received nivolumab in phase 1/2 dose-escalation (ESC; 0.1-10 mg/kg) and -EXP (3 mg/kg) cohorts every 2 weeks regardless of PD-1 ligand 1 (PD-L1) status. Primary endpoints were safety/ tolerability (ESC) and ORR (EXP; ORR was reported by investigator [INV] and blinded independent central review) using RECIST v1.1. Secondary endpoints included DOR, disease control rate (DCR), and OS. Biomarkers were assessed using pretreatment tumor samples. Results: Patients (N=262) had median follow-up durations of 14-16 mo across the cohorts. Overall, 98% of patients (258/262) had Child-Pugh scores of 5-6. In sorafenib-naive patients (n=80), the ORR (INV) was 23%, with 39% of responses (7/18) ongoing. The DCR was 63%; 40% of patients had stable disease ?6 mo. In sorafenibexperienced patients (n=182; 91% progressed on sorafenib), the ORRs (INV) were 16%-19%. Overall, responses occurred regardless of etiology or tumor-cell PD-L1 expression. Nivolumab had a manageable safety profile consistent with that reported in other tumor types. Conclusion: Nivolumab demonstrated durable responses with long-term survival and favorable safety in both sorafenib-naive and -experienced patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Background: Effective management of rice blast, caused by the fungus Magnaporthe oryzae, requires an understanding of the genetic architecture of the resistance to the disease in rice. Rice resistance varies with M. oryzae strains, and many quantitative trait loci (QTLs) affecting rice blast resistance have been mapped using different strains of M. oryzae from different areas. However, little is known about the genetic architecture of rice resistance against the M. oryzae population in Hunan Province, which is a main rice production area in South China. Results: In this study, we used three isolates from Hunan Province and the rice diversity panel 1 to perform a genome-wide association study (GWAS) of blast resistance in rice. A total of 56 QTLs were identified. One of the QTLs is localized with the resistance gene Pik locus which confers resistance to all three isolates. Genomic sequence analysis of the resistant cultivars led to the identification of a new Pik allele, which we named Pikx. Yeast two-hybrid and co-immunoprecipitation assays between AvrPiks and Pikx confirmed that Pikx is a new allele at the Pik locus. Conclusions: Our GWAS has identified many new blast resistance QTLs. The identified new Pik allele Pikx will be useful for breeding cultivars with high resistance to blast in Hunan and other South China provinces. Further research on the relationship between AvrPiks and Pikx will provide new insights into the molecular mechanism of rice resistance to M. oryzae. [ABSTRACT FROM AUTHOR]

Background: In non-small cell lung cancer, response rates to chemotherapy given after immune checkpoint inhibitors has been reported to be higher compared to response rates to chemotherapy given before immune checkpoint inhibitors. However, this phenomenon has not been reported in patients with gastrointestinal cancers nor with the use of multi-targeted kinase inhibitors. Case presentation: We present a series of six patients who received multi-targeted kinase inhibitors or chemotherapy after progression on immune checkpoint inhibitors and showed unexpected response. Five of these patients had metastatic hepatocellular carcinoma and received salvage multi-targeted kinase inhibitors. Two of these five patients had no response to initial multi-targeted kinase inhibitors but had unexpected response to re-challenge with multi-targeted kinase inhibitors after immune checkpoint inhibitors exposure. The sixth patient had metastatic rectal cancer and showed response to salvage chemotherapy following immune checkpoint inhibitors. Conclusion: We postulate that the sequencing of immune checkpoint inhibitors prior to other forms of systemic therapy may potentially lead to an immunomodulatory effect in gastrointestinal cancers with potential improvement in response rates. [ABSTRACT FROM AUTHOR]

The phyllosphere is colonized by a wide variety of microorganisms including epiphytes, plant-pathogenic fungus, bacteria, as well as human or animal pathogens. However, little is known about how microbial community composition changes with the development of angular leaf-spot of cucumber. Here, 18 mixed samples were collected based on the lesion coverage rate (LCR) of angular leaf-spot of cucumber from three disease severity groups (DM1: symptomatic-mild, DM2: symptomatic-moderate, DM3: symptomatic-severe). In our study, the microbial community structure and diversity were examined by Illumina MiSeq sequencing. A significant differences was observed in α diversity and community structure among three disease severity groups. The phyllosphere microbiota was observed to be dominated by bacterial populations from Proteobacteria, Actinobacteria, and Firmicutes, as well as fungal species from Ascomycota and Basidiomycota. In addition, some plant-specific microbe such as Sphingomonas, Methylobacterium, Pseudomonas, and Alternaria showed significant changes in their relative abundance of population. The LCR was correlated negatively with Sphingomonas, Methylobacterium, Quadrisphaera, and Lactobacillus, whereas correlated positively with Pseudomonas and Kineococcus (p < 0.05). The LCR was negatively correlated with Alternaria and Arthrinium of the fungal communities (p < 0.05). Molecular ecological networks of the microbial communities were constructed to show the interactions among the OTUs. Our current results indicated that the competitive relationships among species were broken with the development of angular leaf-spot of cucumber. The microbial community composition changed over the development of angular leaf-spot of cucumber. The result of molecular ecological networks indicated that the overall bacterial community tends toward mutualism from the competition. The development of angular leaf-spot of cucumber affected the ecosystem functioning by disrupting the stability of the microbial community network. This work will help us to understand the host plant-specific microbial community structures and shows how these communities change throughout the development of angular leaf-spot of cucumber. [ABSTRACT FROM AUTHOR]

The complete mitochondrial genome of the shortfin mako ( Isurus oxyrinchus) was determined by using a PCR-based method. The total length of mitochondrial DNA is 16,701 bp and includes 13 protein-coding genes, 2 ribosomal RNA, 22 transfer RNA genes, 1 replication origin region, and 1 control region. The mitochondrial gene arrangement of the tiger tail seahorse is also matching the one observed in the most vertebrate creatures. Base composition of the genome is A (28.8%), T (28.0%), C (28.0%), and G (15.2%) with an A + T rich hallmark as that of other vertebrate mitochondrial genomes. [ABSTRACT FROM AUTHOR]

Circulating tumour DNA (ctDNA) has the potential to be a specific biomarker for the monitoring of tumours in patients with colorectal cancer (CRC). Here, our aim was to develop a personalised surveillance strategy to monitor the clinical course of CRC after surgery. We developed patient-specific ctDNA assays based on multiplexed detection of somatic mutations identified from patient primary tumours, and applied them to detect ctDNA in 44 CRC patients, analysing a total of 260 plasma samples. We found that ctDNA detection correlated with clinical events - it is detectable in pre-operative but not post-operative plasma, and also in patients with recurrent CRC. We also detected ctDNA in 11 out of 15 cases at or before clinical or radiological recurrence of CRC, indicating the potential of our assay for early detection of metastasis. We further present data from a patient with multiple primary cancers to demonstrate the specificity of our assays to distinguish between CRC recurrence and a second primary cancer. Our approach can complement current methods for surveillance of CRC by adding an individualised biological component, allowing us not only to point to the presence of residual or recurrent disease, but also attribute it to the original cancer. [ABSTRACT FROM AUTHOR]