Search

Abstract Background The randomized, dose-optimization, open-label ReDOS study in US patients with metastatic colorectal cancer (CRC) showed that, compared with a standard dosing approach, initiating regorafenib at 80 mg/day and escalating to 160 mg/day depending on tolerability increased the proportion of patients reaching their third treatment cycle and reduced the incidence of adverse events without compromising efficacy. Subsequently, the ReDOS dose-escalation strategy was included as an alternative regorafenib dosing option in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. A retrospective analysis was conducted using a US claims database to assess whether inclusion of this dose-escalation strategy in NCCN Guidelines has influenced the use of flexible dosing in routine US clinical practice, and to describe clinical outcomes pre- and post-inclusion in NCCN Guidelines. Methods Patients with CRC in the Optum’s de-identified Clinformatics® Data Mart database initiating regorafenib for the first time between January 2016 and June 2020 were stratified based on whether they initiated regorafenib pre- or post-inclusion of ReDOS in NCCN Guidelines, and in two groups: flexible dosing (

Abstract Accurate and efficient molecular recognition plays a crucial role in the fields of molecular detection and diagnostics. Conventional trial‐and‐error‐based molecular recognition approaches have always been challenged in distinguishing minimal differences between targets and non‐targets, such as single nucleotide polymorphisms (SNPs) of oligonucleotides. To address these challenges, here, a novel concept of dynamic addressing analysis is proposed. In this concept, by dissecting the regions of the target and creating a corresponding recognizer, it is possible to eliminate the inaccuracy and inefficiency of recognition. To achieve this concept, a Dynamic Addressing Molecular Robot (DAMR), a DNA‐based dynamic addressing device is developed which is capable of dynamically locating targets. DAMR is designed to first bind to the conserved region of the target while addressing the specific region dynamically until accurate recognition is achieved. DAMR has provided an approach for analyzing low‐resolution targets and has been used for analyzing SNP of miR‐196a2 in both cell and serum samples, which has opened new avenues for effective and efficient molecular recognition.

Although the tobacco industry is a significant contributor to energy consumption and carbon emissions its negative environmental impact has received inadequate attention globally. Cigarette factories are a key link in the tobacco industry’s production chain, and using data provided by a cigarette factory in China we conduct a life cycle assessment to account for the carbon footprint of cigar production in cigarette factories. The results of the assessment show that factory air conditioning is the most important contributor to the environmental load of the cigar manufacturing process, while electricity is the key factor that contributes the greatest environmental load across all of the processes in the product life cycle. In addition, packaging, including small boxes and cigarette cartons, have a significant impact on the industry’s environmental footprint due to its use of raw materials. We find the carbon footprint of the entire production process for cigar products to be 383.59 kg CO2 eq. Based on our findings, we suggest ways to optimize cigar/cigarette factory processes to reduce carbon emissions that can help to promote sustainable development in related industries.

Summary: The differentiation of embryonic stem cells (ESCs) begins with the transition from the naive to the primed state. The formative state was recently established as a critical intermediate between the two states. Here, we demonstrate the role of the histone chaperone FACT in regulating the naive-to-formative transition. We found that the Q265K mutation in the FACT subunit SSRP1 increased the binding of FACT to histone H3-H4, impaired nucleosome disassembly in vitro, and reduced the turnover of FACT on chromatin in vivo. Strikingly, mouse ESCs harboring this mutation showed elevated naive-to-formative transition. Mechanistically, the SSRP1-Q265K mutation enriched FACT at the enhancers of formative-specific genes to increase targeted gene expression. Together, these findings suggest that the turnover of FACT on chromatin is crucial for regulating the enhancers of formative-specific genes, thereby mediating the naive-to-formative transition. This study highlights the significance of FACT in fine-tuning cell fate transition during early development.

ABSTRACTObjective The prognosis of acute myeloid leukemia (AML) remains poor although the basic and translational research has been highly productive in understanding the genetics and pathopoiesis of AML and a plethora of targeted therapies have been developed. Consequently, it is crucial to deepen the knowledge of molecular pathogenesis underlying AML for the advancement of new treatment options.Method A RSK gene family-related signature was constructed to investigate whether RSK gene family members were useful in predicting the prognosis of AML patients. The relationship between the RSK gene family-related signature and the infiltration of immune cells was further assessed using the CIBERSORT algorithm. The ‘oncoPredict’ package was used to analyze relationships between the RSK gene family-related signature and the sensitivity to drugs or small molecules.Results Patients were classified into two groups using the RSK gene family-related signature following the median risk score. Overall survival (OS) was significantly longer in patients with low-risk scores than that in patients with high-risk scores as showed by both training and validation datasets. Moreover, the signature was helpful in predicting 1-year, 3-year, and 5-year OS in training and validation datasets. In addition, it was identified that low-risk patients exhibited greater sensitivity to 20 drugs or small molecules and that high-risk patients had higher sensitivity to 38 drugs or small molecules.Conclusion RSK gene family members, particularly RPS6KA1 and RPS6KA4, may help to predict prognosis for AML patients. Furthermore, RPS6KA1 may serve as a novel drug target for AML.

Building occupation is common for pipelines in urban area, which likely leads to the subsidence of foundations and deformation of pipelines and induces accidents such as oil and gas leakage, even explosions. In this study, a pipeline reliability model based on stress-strength interference was established. Meanwhile, the distribution of three random parameters under building occupation, including the additional stress under building occupation, the maximum reduced stress of dangerous pipeline sections and the pipe yield strength, were analyzed based on the theory of structural reliability. In order to achieve equivalent normalization, the variables in abnormal distribution were processed according to the classic JC algorithm, and the iterative initial value of the unknown was set based on the structural linearity performance functions to improve the convergence speed and precision of the algorithm. In addition, a reliability model of gas pipeline under the occupation of framed and brick-concrete buildings based on M-JC algorithm was established, and the reliability of the occupied pipeline was analyzed by implementing the M-JC algorithm in combination with Matlab programming. As shown by the results, the reliability of pipeline sections under the occupation of the framed and brick-concrete buildings is 0.985 2 and 0.999 8, respectively, indicating that the surface overburden load has little effect on the undamaged pipeline. In addition, the error between the results of M-JC algorithm and JC algorithm is very small, with a relative error less than 1%. Generally, the research results are applicable to the analysis on reliability of pipeline under building occupation and have reference value to the safe operation of pipelines and the urban construction planning.

Bio-nanomicelles based on biomaterials such as nucleic acids, peptides, glycans, and lipids have developed rapidly in the field of bioanalysis. Although DNA and peptides have unique advantages, unfortunately, there are few bio-nanomicelles integrating DNA with peptides. Here, we designed a peptide-DNA hybrid bio-nanomicelle for the activity detection of caspase-3. The detection mechanism is based on caspase-3 specific recognition and cleavage of peptide substrates, which owns high sensitivity and selectivity. Under optimal conditions, the detection of caspase-3 activity can be achieved using our designed bio-nanomicelles and the detection limit is 0.72 nM. Furthermore, the proposed method was also successfully applied for the detection of caspase-3 in cell lysate samples after apoptosis-inducing.

Bipolar disorder (BD) is a recurrent chronic mental disorder with a broad profile of functional deficits including disturbed emotional processing and cognitive impairments. The goal of the current study was to further explore the underlying neural mechanism of dysfunction in patients with BD from a comprehensive perspective of both cognition and emotion. Forty-six clinical patients with BD and forty-five healthy controls performed emotion induction task and verbal fluency task (VFT), with frontal activity measured by functional near-infrared spectroscopy (fNIRS). Our results show distinct hemodynamic activity in the prefrontal region during emotional and cognitive processing between patients with BD and healthy controls. Patients with BD exhibit valence-dependent prefrontal cortex (PFC) hemodynamic response to emotional stimuli, with bilateral frontal hypoactivity indicating decreased positive reactivity and left frontal hyperactivity indicating increased negative reactivity. On the other hand, patients with BD showed impaired performance with bilateral frontal hypoactivity during VFT. Taken together, frontal dysfunction of cognition and emotionality in patients with BD probed by fNIRS would be a potential biomarker in clinical assessment.

A dynamic phase demodulation algorithm for direct detection Φ-OTDR is proposed and experimentally demonstrated. It offers a way for single channel direct detection Φ-OTDR, which is the simplest and most cost-effective structure, to realize phase demodulation. Through making use of the redundant information between the sensing series from the vibration impacted region, the local extreme points(LEP) of the sensing series can be divided into two types. The second type LEP offers light phase quadrant information, and then the phase can be further reconstructed through anti-trigonometric function. Single frequency and amplitude-modulated waveforms have been correctly demodulated. The demodulated phase amplitude agrees well with theoretical value, which shows a potential application in strain measurement.

Wilms' tumor (WT) is the most common kidney tumor of children. The transformation suppressor gene RECK, which codes membrane-anchored glycoprotein, frequently downregulates multiple matrix metalloproteinases in tumors. And curcumin, which is a polyphenlic compound separated from turmeric, has antitumor effects on various cancers. However, the correlation of WT, RECK and curcumin is still unrevealed. In this study, we evaluated that the methylation degree of RECK was much higher in WT than in adjacent non-tumor tissues. And RECK methylation was closely associated with tumor metastasis in WT patients. After curcumin treatment, the level of RECK methylation was decreased significantly. And the expression of MMP2 and MMP9 was reduced consequently. Moreover, the proliferation, invasion and migration ability of WT cells were suppressed after curcumin treatment. Meanwhile, the apoptosis rate of WT cells was increased simultaneously. In nude mice model, curcumin restrained ability of tumorigenicity and promoted apoptosis of WT cells. Together, our results suggest that the RECK methylation can serve as a prognostic biomarker of WT. Moreover, curcumin could inhibit RECK methylation, thereby abates the expression of MMPs, and suppresses the tumor progression and metastasis of WT.

Due to the sudden outbreak of COVID-19 at the end of 2019, rapid detection has become an urgent need for community clinics and hospitals. The rapid development of isothermal amplification detection technology for nucleic acids in the field of molecular diagnostic point-of-care testing (POCT) has gained a great deal of attention in recent years. Thanks to intensive research on nicking enzymes, nicking enzyme-combined isothermal amplification has become a promising platform for rapid detection. This is a novel technique that uses nicking enzymes to improve ordinary isothermal amplification. It has garnered significant interest as it overcomes the complexity of traditional molecular diagnostics and is not subject to temperature limitations, relying on cleavage enzymes to efficiently amplify targets in a very short time to provide a high level of amplification efficiency. In recent years, several types of nicking enzyme-combined isothermal amplification have been developed and they have shown great potential in molecular diagnosis, immunodiagnosis, biochemical identification, and other fields. However, this kind of amplification has some disadvantages. In this review, the principles, advantages and disadvantages, and applications of several nicking enzyme-combined isothermal amplification techniques are reviewed and the prospects for the development of these techniques are also considered.

**Background:** Few studies have estimated the real-world economic burden such as all-cause and follicular lymphoma-related costs and health care resource utilization (HCRU) in patients with follicular lymphoma (FL). **Objectives:** This study evaluated outcomes in patients who were newly initiated with FL indicated regimens by line of therapy with real-world data. **Methods:** A retrospective study was conducted among patients with FL from MarketScan® databases between January 1, 2010 and December 31, 2013. Patients were selected if they were ≥18 years old when initiated on a FL indicated therapy, had at least 1 FL-related diagnosis, ≥1 FL commonly prescribed systemic anti-cancer therapy after diagnosis, and did not use any FL indicated regimen in the 24 months prior to the first agent. These patients were followed up at least 48 months and the outcomes, including the distribution of regimens by line of therapy, the treatment duration by line of therapy, all-cause and FL-related costs, and HCRU by line of therapy were evaluated. **Results:** This study identified 598 patients who initiated FL indicated treatment. The average follow-up time was approximately 5.7 years. Of these patients, 50.2% (n=300) were female, with a mean age of 60.7 years (SD=13.1 years) when initiating their treatment with FL indicated regimens. Overall, 598 (100%) patients received first-line therapy, 180 (43.6%) received second-line therapy, 51 received third-line therapy, 21 received fourth-line therapy, and 10 received fifth-line therapy. Duration of treatment by each line of therapy was 370 days, 392 days, 162 days, 148 days, and 88 days, respectively. The most common first-line regimens received by patients were rituximab (n=201, 33.6%), R-CHOP (combination of rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin]; n=143, 24.0%), BR (combination of bendamustine and rituximab; n=143, 24.0%), and R-CVP (combination of rituximab, cyclophosphamide, vincristine, and prednisone; n=71, 11.9%). The most common second-line treatment regimens were (N=180): rituximab (n=78, 43.3%) and BR (n=41, 22.8%). Annualized all-cause health care costs per patient ranged from US$97 141 (SD: US$144 730) for first-line to US$424 758 (SD: US$715 028) for fifth-line therapy. **Conclusions:** The primary regimens used across treatment lines conform to those recommended by the National Comprehensive Cancer Network clinical practice guidelines. The economic burden for patients with FL is high and grows with subsequent lines of therapy.

ABSTRACT Influenza A viruses cause an annual contagious respiratory disease in humans and are responsible for periodic high-mortality human pandemics. Pandemic influenza A viruses usually result from the reassortment of gene segments between human and avian influenza viruses. These avian influenza virus gene segments need to adapt to humans. Here we focus on the human adaptation of the synonymous codons of the avian influenza virus PB1 gene of the 1968 H3N2 pandemic virus. We generated recombinant H3N2 viruses differing only in codon usage of PB1 mRNA and demonstrated that codon usage of the PB1 mRNA of recent H3N2 virus isolates enhances replication in interferon (IFN)-treated human cells without affecting replication in untreated cells, thereby partially alleviating the interferon-induced antiviral state. High-throughput sequencing of tRNA pools explains the reduced inhibition of replication by interferon: the levels of some tRNAs differ between interferon-treated and untreated human cells, and evolution of the codon usage of H3N2 PB1 mRNA is skewed toward interferon-altered human tRNA pools. Consequently, the avian influenza virus-derived PB1 mRNAs of modern H3N2 viruses have acquired codon usages that better reflect tRNA availabilities in IFN-treated cells. Our results indicate that the change in tRNA availabilities resulting from interferon treatment is a previously unknown aspect of the antiviral action of interferon, which has been partially overcome by human-adapted H3N2 viruses. IMPORTANCE Pandemic influenza A viruses that cause high human mortality usually result from reassortment of gene segments between human and avian influenza viruses. These avian influenza virus gene segments need to adapt to humans. Here we focus on the human adaptation of the avian influenza virus PB1 gene that was incorporated into the 1968 H3N2 pandemic virus. We demonstrate that the coding sequence of the PB1 mRNA of modern H3N2 viruses enhances replication in human cells in which interferon has activated a potent antiviral state. Reduced interferon inhibition results from evolution of PB1 mRNA codons skewed toward the pools of tRNAs in interferon-treated human cells, which, as shown here, differ significantly from the tRNA pools in untreated human cells. Consequently, avian influenza virus-derived PB1 mRNAs of modern H3N2 viruses have acquired codon usages that better reflect tRNA availabilities in IFN-treated cells and are translated more efficiently.

Gamma glutamyl transpeptidase (GGT) is a transferase, which is of great importance in sustaining intracellular cysteine and glutathione levels. The abnormal expression of GGT is significantly associated with features of many metabolic syndromes (e.g., hepatocellular carcinoma). Therefore, it is essential to develop methods to detect GGT so as to monitor the physiological or pathological phenomena related to this species. In this work, by making use of a complex formed by Cu2+ and glutathione, which may exhibit excellent voltammetric response, we have proposed a novel potential electrochemical method for the detection of the enzyme. Results show that in the presence of GGT, the formation of Cu2+-glutathione complex on a working electrode will be disrupted, resulting in greatly depressed electrochemical signals. The primary method exhibits some advantages, such as it being fast, cost-efficient, and conveniently operated. It also has the potential to be further developed as an effective method in the quantitative detection of GGT in real samples.

In the title compound, [Cu(C7H7N2O)(C7H8N2O)(H2O)]ClO4·H2O, the CuII ion is five-coordinated by the N atoms from the 1-(pyridin-2-yl)ethanone oximate and 1-(pyridin-2-yl)ethanone oxime ligands and by the water O atom in a distorted square-pyramidal geometry. The two organic ligands are linked by an intramolecular O—H...O hydrogen bond. In the crystal, molecules and ions are linked by O—H...O hydrogen-bonding interactions, forming chains along the a axis. The perchlorate O atoms are disordered in a 0.58 (2):0.42 (2) ratio.

In the title compound, (C6H16N)[Ni(C9H4N2O3)(C9H5N2O3)], the NiIIion is four-coordinated by two N atoms and two O atoms from two indane-1,2,3-trione-1,2-dioxime ligands. The two organic ligands are linked by an intramolecular O—H...O hydrogen bond. In the crystal, molecules are linked by N—H...O hydrogen-bonds.

In the title compound, C16H13ClN2O2·C2H6O, the fused cyclohexene and pyran rings adopt envelope and flattened boat conformations, respectively. In the crystal, N—H...O and O—H...O hydrogen bonds link the chromene and ethanol solvent molecules into infinite chains along the c axis, and N—H...N hydrogen bonds link these chains into a three-dimensional framework. Weak C—H...π interactions are also present.

In the title molecule, C18H19N3O2, the fused cyclohexenone and pyran rings adopt sofa conformations. Intermolecular N—H...N and N—H...O hydrogen bonds link molecules into corrugated layers parallel to the bc plane.

In the filamentous fungus Aspergillus nidulans, both microtubules and actin filaments are important for polarized growth at the hyphal tip. Less clear is how different microtubule-based and actin-based motors work together to support this growth. Here we examined the role of myosin-V (MYOV) in hyphal growth. MYOV-depleted cells form elongated hyphae, but the rate of hyphal elongation is significantly reduced. In addition, although wild type cells without microtubules still undergo polarized growth, microtubule disassembly abolishes polarized growth in MYOV-depleted cells. Thus, MYOV is essential for polarized growth in the absence of microtubules. Moreover, while a triple kinesin null mutant lacking kinesin-1 (KINA) and two kinesin-3s (UNCA and UNCB) undergoes hyphal elongation and forms a colony, depleting MYOV in this triple mutant results in lethality due to a severe defect in polarized growth. These results argue that MYOV, through its ability to transport secretory cargo, can support a significant amount of polarized hyphal tip growth in the absence of any microtubule-based transport. Finally, our genetic analyses also indicate that KINA (kinesin-1) rather than UNCA (kinesin-3) is the major kinesin motor that supports polarized growth in the absence of MYOV.

Homologous recombination (HR) is essential for the maintenance of genome stability. During HR, Replication Protein A (RPA) rapidly coats the 3'-tailed single-strand DNA (ssDNA) generated by end resection. Then, the ssDNA-bound RPA must be timely replaced by Rad51 recombinase to form Rad51 nucleoprotein filaments that drive homology search and HR repair. How cells regulate Rad51 assembly dynamics and coordinate RPA and Rad51 actions to ensure proper HR remains poorly understood. Here, we identified that Rtt105, a Ty1 transposon regulator, acts to stimulate Rad51 assembly and orchestrate RPA and Rad51 actions during HR. We found that Rtt105 interacts with Rad51 in vitro and in vivo and restrains the adenosine 5' triphosphate (ATP) hydrolysis activity of Rad51. We showed that Rtt105 directly stimulates dynamic Rad51-ssDNA assembly, strand exchange, and D-loop formation in vitro. Notably, we found that Rtt105 physically regulates the binding of Rad51 and RPA to ssDNA via different motifs and that both regulations are necessary and epistatic in promoting Rad51 nucleation, strand exchange, and HR repair. Consequently, disrupting either of the interactions impaired HR and conferred DNA damage sensitivity, underscoring the importance of Rtt105 in orchestrating the actions of Rad51 and RPA. Our work reveals additional layers of mechanisms regulating Rad51 filament dynamics and the coordination of HR. [ABSTRACT FROM AUTHOR]

Micro-energy systems contribute significantly to environmental improvement by reducing dependence on power grids through the utilization of multiple renewable energy sources. This study quantified the environmental impact of a micro-energy network system in an industrial park through a life cycle assessment using the operation of the micro-energy network over a year as the functional unit and "cradle-to-gate" as the system boundary. Based on the baseline scenario, a natural gas generator set was added to replace central heating, and the light pipes were expanded to constitute the optimized scenario. The results showed that the key impact categories for both scenarios were global warming, fine particulate matter formation, human carcinogenic toxicity, and human non-carcinogenic toxicity. The overall environmental impact of the optimized scenario was reduced by 68% compared to the baseline scenario. A sensitivity analysis of the key factors showed that electricity from the power grid was the key impact factor in both scenarios, followed by central heating and natural gas. Therefore, to reduce the environmental impact of network systems, it is necessary to further optimize the grid power structure. The research approach can be used to optimize micro-energy networks and evaluate the environmental impact of different energy systems. [ABSTRACT FROM AUTHOR]

At the Taxus base of Pengshui Miao and Tujia Autonomous County, Chongqing, the comprehensive development and utilization of Taxus was carried out with seedling cultivation, understory economy, product processing, ecotourism and other aspects as the main line. The benefit linkage mechanism of the operation of the Taxus industrial chain was explored and analyzed, so as to extend and supplement the Taxus industrial chain. The two models of "company + farmer" and "company + village collective + farmer" are relatively close benefit linkage models, which indirectly promote the increase of farmers' income and smoothly guarantee the operation of the industrial chain, thereby playing a positive role during the development of the Taxus industry. This study provides reliable countermeasures and suggestions for the sustained and healthy development of the Taxus industry in Pengshui County. [ABSTRACT FROM AUTHOR]