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Abstract Charge density waves (CDWs) are pervasive orders in solids that usually enhance the effective mass (m*) and reduce the Fermi velocity ( $${v}_{{{{\rm{F}}}}}$$ v F ) of carriers. Here, we report on the inverse — a reduced m* and an enhanced $${v}_{{{{\rm{F}}}}}$$ v F correlated with the growth of the CDW order in CuTe with gapped, practically linearly dispersing bands — reminiscent of emergent CDW-gapped topological semimetals. Using momentum-dependent electron energy-loss spectroscopy (q-EELS), we simultaneously capture m* and $${v}_{{{{\rm{F}}}}}$$ v F of the CDW-related, practically linearly dispersing electrons by plasmon dispersions across the transition (335 K, TCDW), with m* of 0.28 m0 (m0, the electron rest mass) and $${v}_{{{{\rm{F}}}}}$$ v F of ~ 0.005c (c, the speed of light) at 300 K. With the growth of the CDW order-parameter strength toward 100 K, the electrons become lighter and move faster by ~ 20%. Thorough inspection below TCDW unveils the essential role of the increasing opening of the CDW gap. CuTe is a rich platform for the exploration of CDW/correlation physics with q-EELS established as a useful probe for this type of physics.

Abstract Background Tangshenning (TSN) is a safe and effective formula to treat diabetic nephropathy (DN), and clinical studies have demonstrated that its therapeutic effects are related to oxidative stress improvements in patients. Herein, this study aims to explore the potential mechanism of how TSN alleviates diabetic renal tubular injury. Methods The ultrahigh pressure liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-QTOF/MS) was used to identify the chemical composition and serum components of TSN. KK-Ay mice served to investigate the protective effects and regulatory mechanisms of TSN on tubular damage in DN. Furthermore, inhibitors and inducers of ferroptosis were employed in high glucose-cultured tubular epithelial cells (TECs) to verify the potential mechanisms of TSN. The expressions of proteins related to renal tubular injury, ferroptosis and solute carrier family 7, member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis were analyzed by western blot and immunofluorescence. Mitochondrial ultrastructure was observed in kidney tissues and TECs by a transmission electron microscope. Pathological changes in the renal tissues were observed by HE, PAS, and Prussian blue staining. Ferroptosis-related reactive oxygen species (ROS), malondialdehyde (MDA), ferrous ion, the intake of cystine, GSH, and oxidized glutathione (GSSG) were evaluated and contrasted in vivo or in vitro. Results 51 compounds of TSN powder and 11 components in TSN-containing serum were identified by UPLC-QTOF/MS method. Administration of TSN ameliorated the elevated levels of proteinuria, serum creatinine, blood urea nitrogen, abnormal expression of renal tubular injury markers, and pathological damage to the renal tubules in DN mice model. Intriguingly, a strong inhibition of ferroptosis after TSN treatment occurred in both DN mice model and high glucose-cultured TECs. Notably, induction of ferroptosis by erastin attenuated the protective effect of TSN in high glucose-cultured TECs, while the ferroptosis inhibition by ferrostatin-1 treatment protected renal tubular, which was similar to TSN, suggesting the contribution of TSN-mediated by the inhibition of ferroptosis in DN progression. Mechanistically, TSN upregulated the SLC7A11/GSH/GPX4 axis to inhibit ferroptosis. Conclusion TSN may delay the DN progression and attenuate the renal tubular injury by inhibiting the ferroptosis regulated by the SLC7A11/GSH/GPX4 axis.

Abstract Soft-matter-based photonic crystals like blue-phase liquid crystals (BPLC) have potential applications in wide-ranging photonic and bio-chemical systems. To date, however, there are limitations in the fabrication of large monocrystalline BPLCs. Traditional crystal-growth process involves the transition from a high-temperature disordered phase to an ordered (blue) phase and is generally slow (takes hours) with limited achievable lattice structures, and efforts to improve molecular alignment through post-crystallization field application typically prove ineffective. Here we report a systematic study on the molecular self-assembly dynamics of BPLC starting from a highly ordered phase in which all molecules are unidirectionally aligned by a strong electric field. We have discovered that, near the high-temperature end of the blue phase, if the applied field strength is then switched to an intermediate level or simply turned off, large-area monocrystalline BPLCs of various symmetries (tetragonal, orthorhombic, cubic) can be formed in minutes. Subsequent temperature tuning of the single crystal at a fixed applied field allows access to different lattice parameters and the formation of never-before-seen monoclinic structures. The formed crystals remain stable upon field removal. The diversity of stable monocrystalline BPLCs with widely tunable crystalline symmetries, band structures, and optical dispersions will significantly improve and expand their application potentials.

Transverse Mode Instability (TMI) that results from dynamic nonlinear thermo-optical scattering is the primary limitation to power scaling in high-power fiber lasers and amplifiers. It has been proposed that TMI can be suppressed by exciting multiple modes in a highly multimode fiber. We derive a semi-analytic frequency-domain theory of the threshold for the onset of TMI in narrowband fiber amplifiers under arbitrary multimode input excitation for general fiber geometries. Our detailed model includes the effect of gain saturation, pump depletion, and mode-dependent gain. We show that TMI results from the exponential growth of noise in all the modes at downshifted frequencies due to the thermo-optical coupling. The noise growth rate in each mode is given by the sum of signal powers in various modes weighted by pairwise thermo-optical coupling coefficients. We calculate thermo-optical coupling coefficients for all ∼104 pairs of modes in a standard circular multimode fiber and show that modes with large transverse spatial frequency mismatch are weakly coupled, resulting in a banded coupling matrix. This short-range behavior is due to the diffusive nature of the heat propagation, which mediates the coupling and leads to a lower noise growth rate upon multimode excitation compared to a single mode, resulting in significant TMI suppression. We find that the TMI threshold scales linearly with the number of modes that are excited asymptotically, leading to roughly an order of magnitude increase in the TMI threshold in an 82-mode fiber amplifier.

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

Abstract Background While liver cancer stem cells (CSCs) play a crucial role in hepatocellular carcinoma (HCC) initiation, progression, recurrence, and treatment resistance, the mechanism underlying liver CSC self-renewal remains elusive. We aim to characterize the role of Methyltransferase 16 (METTL16), a recently identified RNA N 6-methyladenosine (m6A) methyltransferase, in HCC development/maintenance, CSC stemness, as well as normal hepatogenesis. Methods Liver-specific Mettl16 conditional KO (cKO) mice were generated to assess its role in HCC pathogenesis and normal hepatogenesis. Hydrodynamic tail-vein injection (HDTVi)-induced de novo hepatocarcinogenesis and xenograft models were utilized to determine the role of METTL16 in HCC initiation and progression. A limiting dilution assay was utilized to evaluate CSC frequency. Functionally essential targets were revealed via integrative analysis of multi-omics data, including RNA-seq, RNA immunoprecipitation (RIP)-seq, and ribosome profiling. Results METTL16 is highly expressed in liver CSCs and its depletion dramatically decreased CSC frequency in vitro and in vivo. Mettl16 KO significantly attenuated HCC initiation and progression, yet only slightly influenced normal hepatogenesis. Mechanistic studies, including high-throughput sequencing, unveiled METTL16 as a key regulator of ribosomal RNA (rRNA) maturation and mRNA translation and identified eukaryotic translation initiation factor 3 subunit a (eIF3a) transcript as a bona-fide target of METTL16 in HCC. In addition, the functionally essential regions of METTL16 were revealed by CRISPR gene tiling scan, which will pave the way for the development of potential inhibitor(s). Conclusions Our findings highlight the crucial oncogenic role of METTL16 in promoting HCC pathogenesis and enhancing liver CSC self-renewal through augmenting mRNA translation efficiency.

As the most common internal modification of mRNA, N6-methyladenosine (m6A) and its regulators modulate gene expression and play critical roles in various biological and pathological processes including tumorigenesis. It was reported previously that m6A methyltransferase (writer), methyltransferase-like 3 (METTL3) adds m6A in primary microRNAs (pri-miRNAs) and facilitates its processing into precursor miRNAs (pre-miRNAs). However, it is unknown whether m6A modification also plays a role in the maturation process of pre-miRNAs and (if so) whether such a function contributes to tumorigenesis. Here, we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia (AML) patients, especially in relapsed patients, and plays an oncogenic role in AML. Moreover, YTHDF2 promotes expression of miR-126-3p (also known as miR-126, as it is the main product of precursor miR-126 (pre-miR-126)), a miRNA that was reported as an oncomiRNA in AML, through facilitating the processing of pre-miR-126 into mature miR-126. Mechanistically, YTHDF2 recognizes m6A modification in pre-miR-126 and recruits AGO2, a regulator of pre-miRNA processing, to promote the maturation of pre-miR-126. YTHDF2 positively and negatively correlates with miR-126 and miR-126's downstream target genes, respectively, in AML patients, and forced expression of miR-126 could largely rescue YTHDF2/Ythdf2 depletion-mediated suppression on AML cell growth/proliferation and leukemogenesis, indicating that miR-126 is a functionally important target of YTHDF2 in AML. Overall, our studies not only reveal a previously unappreciated YTHDF2/miR-126 axis in AML and highlight the therapeutic potential of targeting this axis for AML treatment, but also suggest that m6A plays a role in pre-miRNA processing that contributes to tumorigenesis.

Stimulated Brillouin scattering (SBS) is often an unwanted loss mechanism in both active and passive fibers. Highly multimode excitation of fibers has been proposed as a novel route toward efficient SBS suppression. Here, we develop a detailed, quantitative theory which confirms this proposal and elucidates the physical mechanisms involved. Starting from the vector optical and scalar acoustic equations, we derive appropriate nonlinear coupled mode equations for the signal and Stokes modal amplitudes and an analytical formula for the SBS (Stokes) gain with applicable approximations, such as the neglect of shear effects. This allows us to calculate the exponential growth rate of the Stokes power as a function of the distribution of power in a highly multimode signal. The peak value of the gain spectrum across the excited modes determines the SBS threshold—the maximum SBS-limited power that can be sent through the fiber. The theory shows that the peak SBS gain is greatly reduced by highly multimode excitation due to gain broadening and relatively weaker intermodal SBS gain. The inclusion of exact vector optical modes in the calculation is crucial in order to capture the incomplete intermodal coupling due to mismatch of polarization patterns of higher-order modes. We demonstrate that equal excitation of the 160 modes of a commercially available, highly multimode circular step index fiber raises the SBS threshold by a factor of 6.5 and find comparable suppression of SBS in similar fibers with a D-shaped cross section.

Abstract The key challenge for high-power delivery through optical fibers is overcoming nonlinear optical effects. To keep a smooth output beam, most techniques for mitigating optical nonlinearities are restricted to single-mode fibers. Moving out of the single-mode paradigm, we show experimentally that wavefront-shaping of coherent input light to a highly multimode fiber can increase the power threshold for stimulated Brillouin scattering (SBS) by an order of magnitude, whilst simultaneously controlling the output beam profile. The SBS suppression results from an effective broadening of the Brillouin spectrum under multimode excitation, without broadening of transmitted light. Strongest suppression is achieved with selective mode excitation that gives the broadest Brillouin spectrum. Our method is efficient, robust, and applicable to continuous waves and pulses. This work points toward a promising route for mitigating detrimental nonlinear effects in optical fibers, enabling further power scaling of high-power fiber systems for applications to directed energy, remote sensing, and gravitational-wave detection.

Abstract The ERG (ETS-related gene) transcription factor is linked to various types of cancer, including leukemia. However, the specific ERG domains and co-factors contributing to leukemogenesis are poorly understood. Drug targeting a transcription factor such as ERG is challenging. Our study reveals the critical role of a conserved amino acid, proline, at position 199, located at the 3’ end of the PNT (pointed) domain, in ERG’s ability to induce leukemia. P199 is necessary for ERG to promote self-renewal, prevent myeloid differentiation in hematopoietic progenitor cells, and initiate leukemia in mouse models. Here we show that P199 facilitates ERG’s interaction with the NCoR-HDAC3 co-repressor complex. Inhibiting HDAC3 reduces the growth of ERG-dependent leukemic and prostate cancer cells, indicating that the interaction between ERG and the NCoR-HDAC3 co-repressor complex is crucial for its oncogenic activity. Thus, targeting this interaction may offer a potential therapeutic intervention.

Topological mechanical metamaterials have been considered effective for energy manipulation via edge states, but manipulating these states remains challenging. Here, a Kresling origami mechanical metamaterial hosts multiple topological edge states at finite frequencies, which can be manipulated and transferred across the boundaries of the system by adjusting the lattice torsion.

Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3, encoded by KMT2C) histone methyltransferase occur in a range of solid tumors, and heterozygous deletions encompassing KMT2C occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here, we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Kmt2c cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded tumor suppressors p16/Ink4a and p19/Arf. Conversely, elevated KMT2C expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Kmt2c restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in KMT2C and CDKN2A were associated with similar transcriptional profiles in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.

Abstract Epigenetic dysregulation is reported in multiple cancers including Ewing sarcoma (EwS). However, the epigenetic networks underlying the maintenance of oncogenic signaling and therapeutic response remain unclear. Using a series of epigenetics‐ and complex‐focused CRISPR screens, RUVBL1, the ATPase component of NuA4 histone acetyltransferase complex, is identified to be essential for EwS tumor progression. Suppression of RUVBL1 leads to attenuated tumor growth, loss of histone H4 acetylation, and ablated MYC signaling. Mechanistically, RUVBL1 controls MYC chromatin binding and modulates the MYC‐driven EEF1A1 expression and thus protein synthesis. High‐density CRISPR gene body scan pinpoints the critical MYC interacting residue in RUVBL1. Finally, this study reveals the synergism between RUVBL1 suppression and pharmacological inhibition of MYC in EwS xenografts and patient‐derived samples. These results indicate that the dynamic interplay between chromatin remodelers, oncogenic transcription factors, and protein translation machinery can provide novel opportunities for combination cancer therapy.

Background Type I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune responses in hematopoietic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) are unknown.Methods Using high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL.Results We find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYChigh human B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15.Conclusion We find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL.

Abstract Background Low-dose aspirin and clopidogrel have demonstrated potential chemoprevention for colorectal cancer (CRC). Proton-pump inhibitors (PPI) are commonly prescribed with anticoagulation drugs, but the relationship between PPI and CRC is unclear. Moreover, evidence of CRC risk under direct oral anticoagulant (DOAC) is limited. This study aimed to investigate the effects of anticoagulation drugs combined with or without PPI on the risks of CRC in Taiwan. Methods A retrospective case–control study of 1,024,227 cases based on the Chang Gung Research Database from 2010 to 2017 was performed. Clinical characteristics, indications, duration of anticoagulation and PPI use, and CRC occurrence data were collected. Logistic regression was employed to adjust for known confounders of CRC risk. Results Monotherapy of clopidogrel decreased the risk of CRC (AOR 0.70; 95% CI 0.60–0.83), while no protective effect was observed in aspirin alone or aspirin plus clopidogrel. DOAC did not affect CRC significantly. The risk of CRC increased in patients with PPI (AOR 1.38; 95% CI 1.28–1.49) and PPI plus DOAC (OR 3.91; 95% CI 1.49–10.27), while PPI plus aspirin decreased the risk of CRC (OR 0.48; 95% CI 0.32–0.73). PPI plus clopidogrel showed no significant effect on the CRC. Conclusion This study suggests clopidogrel alone and PPI plus aspirin offer a preventative benefit against CRC in the Taiwanese population studied. The same effect was not observed in DOAC. Moreover, a significant increase in CRC was observed in patients on PPI monotherapy and PPI plus DOAC, suggesting a possible risk.

Abstract RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights into the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival.

Abstract Both weather fluctuation and farming system influence the epidemiology of crop diseases. However, short-term experiments are difficult to mechanistically extrapolate into long-term ecological responses. Using a mechanistic model with Bayesian inference, long-term data spanning 10 years were used to construct relationships among weather fluctuation (temperature, relative humidity, wind, and rainfall), farming system (conventional and low-external-input farming), and crop disease in experimental rice fields in Taiwan. Conventional and low-external-input farming had similar influences on the disease incidence of rice blast. Temperature had a positive influence on the disease incidence only under high relative humidity. Rainfall positively affected the disease incidence until an optimum level of rainfall. Low-external-input farming, with a lower application of fertilizers and other sustainable nutrient management, achieved similar effects on the disease incidence to those achieved by conventional farming. This suggests that weather fluctuation may override the effect of the farming systems on fungal disease incidence in rice fields.

The reorientational dynamics of A-site cations in two-dimensional organic-inorganic hybrid perovskites play an important role in determining their physical properties. Here the authors use solid state NMR and isotope labelling to reveal multiple modes of reorientational motions of methylammonium cations and the role of structural rigidity of the organic spacers on their dynamics.

Protein S-palmitoylation, a type of post-translational modification, refers to the reversible process of attachment of a fatty acyl chain—a 16-carbon palmitate acid—to the specific cysteine residues on target proteins. By adding the lipid chain to proteins, it increases the hydrophobicity of proteins and modulates protein stability, interaction with effector proteins, subcellular localization, and membrane trafficking. Palmitoylation is catalyzed by a group of zinc finger DHHC-containing proteins (ZDHHCs), whereas depalmitoylation is catalyzed by a family of acyl-protein thioesterases. Increasing numbers of oncoproteins and tumor suppressors have been identified to be palmitoylated, and palmitoylation is essential for their functions. Understanding how palmitoylation influences the function of individual proteins, the physiological roles of palmitoylation, and how dysregulated palmitoylation leads to pathological consequences are important drivers of current research in this research field. Further, due to the critical roles in modifying functions of oncoproteins and tumor suppressors, targeting palmitoylation has been used as a candidate therapeutic strategy for cancer treatment. Here, based on recent literatures, we discuss the progress of investigating roles of palmitoylation in regulating cancer progression, immune responses against cancer, and cancer stem cell properties.

Activating mutations in Interleukin-7 receptor alpha (IL7Ra) have been reported in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) but its role in leukaemogenesis is not clear. Here, the authors show that activation of IL7Ra in primary human hematopoietic progenitors initiates preleukaemia and cooperates with CDKN2A silencing to develop BCP-ALL.

Abstract Rice blast, one of the most destructive epidemic diseases, annually causes severe losses in grain yield worldwide. To manage blast disease, breeding resistant varieties is considered a more economic and environment-friendly strategy than chemical control. For breeding new resistant varieties, natural germplasms with broad-spectrum resistance are valuable resistant donors, but the number is limited. Therefore, artificially induced mutants are an important resource for identifying new broad-spectrum resistant (R) genes/loci. To pursue this approach, we focused on a broad-spectrum blast resistant rice mutant line SA0169, which was previously selected from a sodium azide induced mutation pool of TNG67, an elite japonica variety. We found that SA0169 was completely resistant against the 187 recently collected blast isolates and displayed durable resistance for almost 20 years. Linkage mapping and QTL-seq analysis indicated that a 1.16-Mb region on chromosome 6 (Pi169-6(t)) and a 2.37-Mb region on chromosome 11 (Pi169-11(t)) conferred the blast resistance in SA0169. Sequence analysis and genomic editing study revealed 2 and 7 candidate R genes in Pi169-6(t) and Pi169-11(t), respectively. With the assistance of mapping results, six blast and bacterial blight double resistant lines, which carried Pi169-6(t) and/or Pi169-11(t), were established. The complementation of Pi169-6(t) and Pi169-11(t), like SA0169, showed complete resistance to all tested isolates, suggesting that the combined effects of these two genomic regions largely confer the broad-spectrum resistance of SA0169. The sodium azide induced mutant SA0169 showed broad-spectrum and durable blast resistance. The broad resistance spectrum of SA0169 is contributed by the combined effects of two R regions, Pi169-6(t) and Pi169-11(t). Our study increases the understanding of the genetic basis of the broad-spectrum blast resistance induced by sodium azide mutagenesis, and lays a foundation for breeding new rice varieties with durable resistance against the blast pathogen.

Identifying functional domains and genetic regulatory mechanisms is essential for developing new therapies. Here the authors present sc-Tiling, single-cell high-density CRISPR tiling screening for functional domain characterization.

Topological boundary modes in mechanical systems have recently attracted great attention due to their unique protection features. Here, tunable corner localization of mechanical waves is numerically and experimentally demonstrated in a continuous elastic plate with hexagonally arranged bolts.

Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early-phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR/Cas9 screens implicated decreased translation initiation as protective following GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to the effects of GSPT1 degradation. We defined 2 Crbn amino acids that prevent Gspt1 degradation in mice, generated a knockin mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant acute myeloid leukemia.

Camera pose estimation is crucial for 3D surface reconstruction and augmented reality applications. For systems equipped with RGB-D sensors, the corresponding transformation between frames can be effectively estimated using the iterative closest point (ICP) algorithms. Edge points, which cover most of the geometric structures in a frame, are good candidates for control points in ICP. However, the depth of object contour points is hard to accurately measure using commercial RGB-D sensors. Inspired by the model-agnostic meta-learning (MAML) algorithm, this work proposes a meta-ICP algorithm to jointly estimate the optimal transformation for multiple tasks, which are constructed by sampled datapoints. To increase task sampling efficiency, an edge-based task set partition algorithm is introduced for constructing complementary task sets. Moreover, to prevent ICP from being trapped in local minima, a dynamic model adaptation scheme is adopted to disturb the trapped tasks. Experimental results reveal that the probability of unstable estimations can be effectively reduced, indicating a much narrower error distribution of repeated experiments when adopting re-sampled points. With the proposed scheme, the overall absolute trajectory error can be improved by more than 30% as compared to the related edge-based methods using frame-to-frame pose estimation.

DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.

Abstract Background Delayed post-polypectomy bleeding (PPB) is a major complication of polypectomy. The effect of prophylactic hemoclipping on delayed PPB is uncertain. The aim of this study was to evaluate the effectiveness of prophylactic hemoclipping and identify the risk factors of delayed PPB. Methods Patients with polyps sized 6 to 20 mm underwent snare polypectomy from 2015 to 2017 were retrospectively reviewed. The patients with prophylactic hemoclipping for delayed PPB prevention were included in the clipping group, and those without prophylactic hemoclipping were included in the non-clipping group. The incidence of delayed PPB and time to bleeding were compared between the groups. Multivariate analysis was used to identify the risk factors of delayed PPB. Propensity score matching was used to minimize potential bias. Results After propensity score matching, 612 patients with 806 polyps were in the clipping group, and 576 patients with 806 polyps were in the non-clipping group. There were no significant differences in the incidence of delayed PPB and days to bleeding between two groups (0.8% vs 1.3%, p = 0.4; 3.4 ± 1.94 days vs 4.13 ± 3.39 days, p = 0.94). In the multivariate analysis, the polyp size [Odds ratio (OR):1.16, 95% confidence interval (CI):1.01–1.16, p = 0.03), multiple polypectomies (OR: 4.64, 95% CI:1.24–17.44, p = 0.02) and a history of anticoagulant use (OR:37.52, 95% CI:6.49–216.8, p

Here, the authors develop a self-capping vapour-liquid-solid reaction to fabricate large-grain continuous MoS2 films, whereby an intermediate liquid phase-Na2Mo2O7 is formed through a eutectic reaction of MoO3 and NaF, followed by sulphurisation into MoS2.

Abstract Background Frail older adults are predisposed to multiple comorbidities and adverse events. Recent interventional studies have shown that frailty can be improved and managed. In this study, effective individualized home-based exercise and nutrition interventions were developed for reducing frailty in older adults. Methods This study was a four-arm, single-blind, randomized controlled trial conducted between October 2015 and June 2017 at Miaoli General Hospital in Taiwan. Overall, 319 pre-frail or frail older adults were randomly assigned into one of the four study groups (control, exercise, nutrition, and exercise plus nutrition [combination]) and followed up during a 3-month intervention period and 3-month self-maintenance period. Improvement in frailty scores was the primary outcome. Secondary outcomes included improvements in physical performance and mental health. The measurements were performed at baseline, 1 month, 3 months, and 6 months. Results At the 6-month measurement, the exercise (difference in frailty score change from baseline: − 0.23; 95% confidence interval [CI]: − 0.41, − 0.05; p = 0.012), nutrition (− 0.28; 95% CI: − 0.46, − 0.11; p = 0.002), and combination (− 0.34; 95% CI: − 0.52, − 0.16; p

Summary: Cytotoxic natural killer cells kill tumors and infected cells. We carried out CRISPR-based gene editing and transcriptional regulation in hard-to-manipulate NK-92 cells. NK-92-based therapies were found to be safe and efficacious in preclinical studies of cancers. Here, we have pioneered the generation and validation of NK-92 cells constitutively expressing Cas9 or dCas9 for knockout (CRISPRko), transcriptional activation (CRISPRa), or transcriptional repression (CRISPRi) of genes. Our CRISPR-engineered NK-92 cell platforms can be modified for research and off-the-shelf therapeutic applications.

Gastric MALToma is an extra-nodal marginal-type B-cell lymphoma. MALToma may occur secondary to chronic inflammation and autoimmunity. The most common gastrointestinal (GI) site of MALToma is the stomach, with approximately 50% of lesions occurring there. Synchronous upper and lower GI MALTomas rarely occur, with few cases reported. We present the case of a 67-year-old patient who presented asymptomatic and was found to have synchronous multifocal upper and lower GI MALTomas in the stomach, duodenum, terminal ileum, and sigmoid, which did not respond to H. Pylori eradication therapy.

Background and Objectives: Endoscopic variceal ligation (EVL) is the primary and secondary treatment for acute esophageal variceal bleeding. Post-banding ulcer bleeding (PBUB) may lead to bleeding episodes following EVL, increasing mortality. The aim of this study was to evaluate the risk factors for PBUB and predict the 6-week mortality risk after PBUB. Materials and Methods: We retrospectively analyzed the data collected from cirrhotic patients with EVL from 2015 to 2017. The incidence of PBUB and the 6-week mortality rate were evaluated. Risk factors for PBUB and predictive factors for mortality after PBUB were analyzed. Results: A total of 713 patients were enrolled in this study. Among the studied subjects, the incidence of PBUB was 5.8% (N = 41). The 6-week mortality rate was 63.4% (26/41). In multivariate analysis, MELD score ≥20 (OR: 3.77, 95% CI: 1.94–7.33, p < 0.001), ALBI score of 3 (OR: 2.67, 95% CI: 1.34–5.3, p = 0.005) and the presence of gastric varices (OR: 2.1, 95% CI: 1.06–4.16, p = 0.03) were associated with the development of PBUB. Patients with ALBI grade 3 (OR: 4.8, 95% CI: 1.18–19.6, p = 0.029) and Child-Pugh scores B and C (OR: 16.67, 95% CI: 1.75–158.1, p = 0.014) were associated with 6-week mortality after PBUB. Conclusions: PBUB is a complication with low incidence but increased mortality following EVL. The ALBI grade is a useful score to predict not only the development of PBUB but also the 6-week mortality after PBUB.

In this study, the HIV-1 P18I10 CTL peptide derived from the V3 loop of HIV-1 gp120 and the T20 anti-fusion peptide of HIV-1 gp41 were inserted into the HPV16 L1 capsid protein to construct chimeric HPV:HIV (L1:P18I10 and L1:T20) VLPs by using the mammalian cell expression system. The HPV:HIV VLPs were purified by chromatography. We demonstrated that the insertion of P18I10 or T20 peptides into the DE loop of HPV16 L1 capsid proteins did not affect in vitro stability, self-assembly and morphology of chimeric HPV:HIV VLPs. Importantly, it did not interfere either with the HIV-1 antibody reactivity targeting sequential and conformational P18I10 and T20 peptides presented on chimeric HPV:HIV VLPs or with the induction of HPV16 L1-specific antibodies in vivo. We observed that chimeric L1:P18I10/L1:T20 VLPs vaccines could induce HPV16- but weak HIV-1-specific antibody responses and elicited HPV16- and HIV-1-specific T-cell responses in BALB/c mice. Moreover, could be a potential booster to increase HIV-specific cellular responses in the heterologous immunization after priming with rBCG.HIVA vaccine. This research work would contribute a step towards the development of the novel chimeric HPV:HIV VLP-based vaccine platform for controlling HPV16 and HIV-1 infection, which is urgently needed in developing and industrialized countries.

Abstract Organometallic two‐dimensional (2D) nanosheets with tailorable components have recently fascinated the optoelectronic communities due to their solution‐processable nature. However, the poor stability of organic molecules may hinder their practical application in photovoltaic devices. Instead of conventional organometallic 2D nanosheets with low weatherability, an air‐stable π‐conjugated 2D bis(dithiolene)iron(II) (FeBHT) coordination nanosheet (CONASH) is synthesized via bottom‐up liquid/liquid interfacial polymerization using benzenehexathiol (BHT) and iron(II) ammonium sulfate [Fe(NH4)2(SO4)2] as precursors. The uncoordinated thiol groups in FeBHT are easily oxidized, but the Fe(NH4)2(SO4)2 dissociation rate is slow, which facilitates the protection of sulfur groups by iron(II) ions. The density functional theory calculates that the resultant FeBHT network gains the oxygen‐repelling function for oxidation suppression. In air, the FeBHT CONASH exhibits self‐powered photoresponses with short response times (

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.

Abstract The polyp detection rate (PDR) is an important quality indicator for colonoscopy. Several factors have been shown to be associated with PDR. However, whether the moderate sedation is a factor for polyp detection remains controversial. This study aims to assess factors associated with polyp detection including the moderate sedation factor during colonoscopy. Patients who underwent colonoscopy from June 1, 2014 to May 31, 2015 were enrolled into this retrospective study. Patients with poor colon preparation and failure to reach the cecum were excluded. The clinical factors, including patient's sex, age, midazolam/fentanyl sedation, indications, endoscopist colonoscopy volume, and use of antispasmodic agent were evaluated by multivariate analysis. A total of 3373 patients were included in this study. The mean age was 55.8 years, and 1980 patients (58.7%) were male. Among the 3373 patients, 2513 (74.5%) underwent midazolam/fentanyl‐based sedated colonoscopy. The multivariate analysis showed that male sex, age over 50 years old, midazolam/fentanyl sedation and indications of screening and surveillance were significantly associated with polyp detection. Moreover, when stratified by sex and age, the midazolam/fentanyl sedation was associated with polyp detection in male patients and patients over 50 years old. This study has highlighted the role of midazolam/fentanyl sedation administered by colonoscopists as a modifiable factor that may increase polyp detection during colonoscopy.

Background: Energy metabolism in carcinogenesis is poorly understood. It is widely accepted the majority of colorectal cancers (CRCs) arise from adenomatous polyps (APs). We aimed to characterize the bioenergetic alterations in APs and CRCs. Methods: Fifty-six APs, 93 CRCs and adjacent normal mucosae were tested. Oxygen consumption rate (OCR) was measured representing mitochondrial oxidative phosphorylation (OxPhos), and extracellular acidification rate (ECAR)was measured representing glycolysis. Mitochondrial DNA (mtDNA) variants and mutations were studied. Over-expressed metabolic genes in APs were identified by microarray and validated by qRT-PCR, Western blots and immunohistochemistry. Identified genes were knocked down in WiDr and colo205 CRC cell lines, and their expression was analyzed in APs/CRCs with enhanced glycolysis. Findings: ECAR, not OCR, was significantly increased in APs. While no difference of ECAR was found between CRCs and normal mucosae, OCR was significantly reduced in CRCs. OCR/ECAR ratio was decreased in APs over 1 cm, APs with a villous component and CRCs, indicating their glycolytic tendencies. The number of mtDNA mutations was increased in APs and CRCs, but not correlated with metabolic profiles. Two metabolic genes ALDOB and SLC16A4 were up-regulated in APs. Both ALDOB-knockdown and SLC16A4-knockdown CRC cell lines showed increased basal motichondrial OxPhos and decreased basal glycolysis. Moreover, the increase of mitochondrial ATP-linked respiration and the decrease of glycolytic capacity were showed in SLC16A4-knockdown cells. Finally, APs/CRCs with enhanced glycolysis had increased SLC16A4 expression. Interpretation: ATP production shifts from OxPhos to glycolysis in the process of AP enlargement and villous transformation. OxPhos defects are present in CRCs but not in APs. APs and CRCs tend to accumulate mtDNA mutations, but these are not correlated with bioenergetic profiles. Finally, the ALDOB and SLC16A4 may contribute to the glycolytic shift in APs/CRCs. Keywords: Bioenergetics, Mitochondrial oxidative phosphorylation, Glycolysis, Colorectal adenomatous polyp, Colorectal cancer

Ewing sarcoma (EwS), a type of bone and soft tissue tumor, is mainly driven by the expression of the fusion protein EWSR1-FLI1. Upon binding to chromatin, EWSR1-FLI1 reprograms the epigenetic state, alters gene expression, and thus leads to tumorigenesis. Considerable studies have investigated the epigenomic and transcriptomic profiling of EwS. Nevertheless, a comprehensive view of therapeutic targets is still lacking. This review discusses the epigenetic and transcriptional alterations reported in EwS. Specifically, we discuss the binding characteristics of EWSR1-FLI1 on chromatin, the mechanisms of EWSR1-FLI1 in reprograming epigenome, and EWSR1-FLI1-induced transcriptional alterations. Moreover, we summarize the chemical, RNAi, and CRISPR-cas9 high throughput screens conducted in EwS with the goal of assisting in the development of novel therapies to treat this aggressive disease.

This study characterizes and determines the corrosion resistance of Mn-Ce conversion coated LZ91 magnesium alloy that undergoes pretreatments. It is challenging to process large and curved workpieces in the industry because the geometric shapes are complex if they are mechanically ground. This study uses acid pickling instead of mechanical grinding, and a nitric acid solution is used for pickling. After pretreatments, the samples are immersed for 30 s in a conversion coating solution containing 0.1 M KMnO4 and 0.025 M Ce(NO3)3 with a pH of 1.5, as demonstrated in previous studies by the authors. The microstructure of the coating layer and electrochemical behavior of conversion coated samples exposed to 3.5 wt.% NaCl solution are studied. The corrosion behavior of Mn-Ce conversion coating specimens is determined using a salt spray test (SST). Scanning electron microscopy (SEM), energy dispersive X-ray spectrometry (EDS), and X-ray photoelectron spectroscopy (XPS) are used to analyze the interface between the coating layer and the underlying magnesium substrate and to investigate the microstructure of the specimens. The roughness of the coatings is measured using 3D white light interferometry. The results show that the deteriorated area ratio for conversion coated LZ91 decreases to less than 5% after 72 h of SST exposure, and the corrosion resistance is improved 2.25 times with the Mn-Ce conversion coating on LZ91 magnesium alloy.

Metamaterials are a class of engineered materials that often violate the routine assumptions that apply to ordinary materials. While metamaterials are typically assembled from carefully designed mesoscale units, the intended bulk-scale functionality can be obscured by unintended emergent effects driven by non-additive unit-unit interactions. These interactions are often sensitive to the number of units and their overall arrangement, making them extrinsic to the unit-scale design. As such, the emergence of extrinsic effects adds a significant hurdle for the development of general-purpose metamaterial technologies. Here, we reconceptualize bulk-scale extrinsic properties as a design opportunity and develop an approach that repurposes them in a new class of exponentially reconfigurable origami-inspired mechanical metamaterials. We illustrate the use of extrinsic properties to design a single general-purpose structure that can be transformed into a variety of passive mechanical devices including a waveguide, a wave lens, and a wave cloak. Bench-top experiments validate the core concepts of our approach and show how unintentional extrinsic effects become useful for applications of reconfigurable metamaterials.

Prophylactic vaccines remain the best approach for controlling the human immunodeficiency virus-1 (HIV-1) transmission. Despite the limited efficacy of the RV144 trial in Thailand, there is still no vaccine candidate that has been proven successful. Consequently, great efforts have been made to improve HIV-1 antigens design and discover delivery platforms for optimal immune elicitation. Owing to immunogenic, structural, and functional diversity, virus-like particles (VLPs) could act as efficient vaccine carriers to display HIV-1 immunogens and provide a variety of HIV-1 vaccine development strategies as well as prime-boost regimes. Here, we describe VLP-based HIV-1 vaccine candidates that have been enrolled in HIV-1 clinical trials and summarize current advances and challenges according to preclinical results obtained from five distinct strategies. This mini-review provides multiple perspectives to help in developing new generations of VLP-based HIV-1 vaccine candidates with better capacity to elicit specific anti-HIV immune responses.

Abstract Background Liver resection had been regarded as a standard treatment for primary hepatocellular carcinoma (HCC). However, early mortality and recurrence after surgery were still of major concern. RAM (Risk Assessment for early Mortality) scoring system is a newly developed tool for assessing early mortality after hepatectomy for HCC. In this study, we compared RAM scoring system with ALBI and MELD scores for their capability of predicting short-term outcome. Methods We retrospectively reviewed patients with hepatocellular carcinoma who were treated with hepatectomy at Chang Gung Memorial Hospital between 1986 and 2015. Their clinical characteristics and perioperative variables were collected. We applied RAM, albumin-bilirubin (ALBI), and model for end-stage liver disease (MELD) scoring systems to predict early mortality and early recurrence in HCC patients after surgery. We investigated the discriminative power of each scoring system by receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). Results A total of 1935 patients (78% male) who underwent liver resection for HCC were included in this study. The median follow-up period was 41.9 months. One hundred and forty-nine patients (7.7%) died within 6 months after hepatectomy (early mortality). All the three scoring systems were effective predictor for early mortality, with higher score indicating higher risk of early mortality (AUC of RAM = 0.723, p

Conventional fabrication approaches for large-size three-dimensional photonic crystals are problematic. By properly controlling the self-assembly processes, the authors report the fabrication of monocrystalline blue phase liquid crystals that exhibit three-dimensional photonic-crystalline properties.

Rechargeable aluminium ion batteries are an emerging class of energy storage device. Here the authors reveal high-quality natural graphite as a promising cathode for Al-ion batteries, also identifying chloroaluminate anion intercalation in graphite by Raman spectroscopy.

Background: Dexlansoprazole has been shown to be efficacious for the treatment of gastroesophageal reflux disease. However, there is a paucity of data about its efficacy for Helicobacter pylori eradication. The aim of this study was to evaluate the efficacy of dexlansoprazole for H. pylori eradication as triple therapy in real-world practice. Methods: Adult patients with endoscopically proven H. pylori related peptic ulcer diseases or gastritis were recruited for this study. The eradication status was assessed based on the results of the 13 C-urea breath test performed 4 weeks after treatment. According to the different treatment regimens, the patients were allocated to group A: Esomeprazole 40 mg b.i.d. + amoxicillin 1 g b.i.d. + clarithromycin 500 mg b.i.d. for 7 days; group B: Esomeprazole 40 mg q.d. + amoxicillin 1 g b.i.d. + clarithromycin 500 mg b.i.d. for 7 days, or group C: Dexlansoprazole 60 mg q.d. + amoxicillin 1 g b.i.d. + clarithromycin 500 mg b.i.d. for 7 days. Results: A total of 215 patients (49% males) were enrolled in this study, with a mean age of 55 years. The eradication rates in group A, B, and C were 94.7% (71/75), 89.6% (69/77), and 93.7% (59/63) ( p = 0.457), respectively. The adverse events were similar between the three groups ( p = 0.068). Conclusions: This study suggests that dexlansoprazole-based triple therapy has an acceptable eradication rate for H. pylori infection.

Background: Hepatitis C virus (HCV) infection causes many extrahepatic malignancies; whether it increases gastric cancer risk and the risk reverses after anti-HCV therapy remain elusive. Method: A nationwide population-based cohort study of Taiwan National Health Insurance Research Database (TNHIRD) was conducted. In parallel, the risk factors and HCV-core-protein expressions were surveyed in gastric cancer patients from a tertiary care center. Results: From 2003 to 2012, of 11,712,928 patients, three 1:4:4, propensity-score-matched TNHIRD cohorts including HCV-treated (7545 patients with interferon-based therapy ⩾ 6 months), HCV-untreated ( n = 30,180), and HCV-uninfected cohorts ( n = 30,180) were enrolled. The cumulative incidences of gastric cancer [HCV-treated: 0.452%; 95% confidence interval (CI): 0.149–1.136%; HCV-untreated: 0.472%; 95% CI: 0.274–0.776%; HCV-uninfected: 0.146%; 95% CI 0.071–0.280%] were lowest in HCV-uninfected cohort ( p = 0.0028), but indifferent between treated and untreated cohorts. HCV infection [hazards ratio (HR): 2.364; 95% CI: 1.337–4.181], male sex (HR: 1.823; 95% CI: 1.09–3.05) and age ⩾ 49 years (HR: 3.066; 95% CI: 1.56–6.026) were associated with incident gastric cancers. Among 887 (males: 68.4%; mean age: 66.5 ± 12.9 years, 2008–2018) hospitalized gastric cancer patients, HCV Ab-positive rate was 7.8%. None of the investigated factors exhibited different rates between HCV Ab-positive and Ab-negative patients. No HCV-core-positive cells were demonstrated in gastric cancer tissues. Conclusions: HCV infection, male sex and old age were risk factors for gastric cancer development. HCV-associated gastric cancer risk might be neither reversed by interferon-based therapy, nor associated with in situ HCV-core-related carcinogenesis.

Leukemias driven by chromosomal translocation of the mixed-lineage leukemia gene (MLL or KMT2A) are highly prevalent in pediatric oncology. The poor survival rate and lack of an effective targeted therapy for patients with MLL-rearranged (MLL-r) leukemias emphasize an urgent need for improved knowledge and novel therapeutic approaches for these malignancies. The resulting chimeric products of MLL gene rearrangements, i.e., MLL-fusion proteins (MLL-FPs), are capable of transforming hematopoietic stem/progenitor cells (HSPCs) into leukemic blasts. The ability of MLL-FPs to reprogram HSPCs toward leukemia requires the involvement of multiple chromatin effectors, including the histone 3 lysine 79 methyltransferase DOT1L, the chromatin epigenetic reader BRD4, and the super elongation complex. These epigenetic regulators constitute a complicated network that dictates maintenance of the leukemia program, and therefore represent an important cluster of therapeutic opportunities. In this review, we will discuss the role of MLL and its fusion partners in normal HSPCs and hematopoiesis, including the links between chromatin effectors, epigenetic landscapes, and leukemia development, and summarize current approaches to therapeutic targeting of MLL-r leukemias.

The use of Mycobacterium bovis bacillus Calmette–Guérin (BCG) as a live vaccine vehicle is a promising approach for HIV-1-specific T-cell induction. In this study, we used recombinant BCG expressing HIVACAT T-cell immunogen (HTI), BCG.HTI2auxo.int. BALB/c mice immunization with BCG.HTI2auxo.int prime and MVA.HTI boost was safe and induced HIV-1-specific T-cell responses. Two weeks after boost, T-cell responses were assessed by IFN-γ ELISpot. The highest total magnitude of IFN-γ spot-forming cells (SFC)/106 splenocytes was observed in BCG.HTI2auxo.int primed mice compared to mice receiving MVA.HTI alone or mice primed with BCGwt, although the differences between the vaccination regimens only reached trends. In order to evaluate the differences in the breadth of the T-cell immune responses, we examined the number of reactive peptide pools per mouse. Interestingly, both BCG.HTI2auxo.int and BCGwt primed mice recognized an average of four peptide pools per mouse. However, the variation was higher in BCG.HTI2auxo.int primed mice with one mouse recognizing 11 peptide pools and three mice recognizing few or no peptide pools. The recognition profile appeared to be more spread out for BCG.HTI2auxo.int primed mice and mice only receiving MVA.HTI. Here, we describe a useful vaccine platform for priming protective responses against HIV-1/TB and other prevalent infectious diseases.