Promising role of protein arginine methyltransferases in overcoming anti-cancer drug resistance.

Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for epigenetic arginine methylation, which regulates various biological and pathological processes, as a result, they are attractive therapeutic targets for overcoming anti-cancer drug resistance. The ongoing development of small molecules targeting PRMTs has resulted in the generation of chemical probes for modulating most PRMTs and facilitated clinical treatment for the most advanced oncology targets, including PRMT1 and PRMT5. In this review, we summarize various mechanisms underlying protein arginine methylation and the roles of specific PRMTs in driving cancer drug resistance. Furthermore, we highlight the potential clinical implications of PRMT inhibitors in decreasing cancer drug resistance. PRMTs promote the formation and maintenance of drug-tolerant cells via several mechanisms, including altered drug efflux transporters, autophagy, DNA damage repair, cancer stem cell-related function, epithelial-mesenchymal transition, and disordered tumor microenvironment. Multiple preclinical and ongoing clinical trials have demonstrated that PRMT inhibitors, particularly PRMT5 inhibitors, can sensitize cancer cells to various anti-cancer drugs, including chemotherapeutic, targeted therapeutic, and immunotherapeutic agents. Combining PRMT inhibitors with existing anti-cancer strategies will be a promising approach for overcoming anti-cancer drug resistance. Furthermore, enhanced knowledge of the complex functions of arginine methylation and PRMTs in drug resistance will guide the future development of PRMT inhibitors and may help identify new clinical indications.

The role of ABCC10/MRP7 in anti-cancer drug resistance and beyond.

Multidrug resistance protein 7 (MRP7), also known as ATP-binding cassette (ABC) transporter subfamily C10 (ABCC10), is an ABC transporter that was first identified in 2001. ABCC10/MRP7 is a 171 kDa protein located on the basolateral membrane of cells. ABCC10/MRP7 consists of three transmembrane domains and two nucleotide binding domains. It mediates multidrug resistance of tumor cells to a variety of anticancer drugs by increasing drug efflux and results in reducing intracellular drug accumulation. The transport substrates of ABCC10/MRP7 include antineoplastic drugs such as taxanes, vinca alkaloids, and epothilone B, as well as endobiotics such as leukotriene C4 (LTC4) and estradiol 17 ß-D-glucuronide. A variety of ABCC10/MRP7 inhibitors, including cepharanthine, imatinib, erlotinib, tariquidar, and sildenafil, can reverse ABCC10/MRP7-mediated MDR. Additionally, the presence or absence of ABCC10/MRP7 is also closely related to renal tubular dysfunction, obesity, and other diseases. In this review, we discuss: 1) Structure and functions of ABCC10/MRP7; 2) Known substrates and inhibitors of ABCC10/MRP7 and their potential therapeutic applications in cancer; and 3) Role of ABCC10/MRP7 in non-cancerous diseases.

Atomically Dispersed Fe-N4 and Ni-N4 Independent Sites Enable Bidirectional Sulfur Redox Electrocatalysis.

Single-atom catalysts (SACs) with high atom utilization and outstanding catalytic selectivity are useful for improving battery performance. Herein, atomically dispersed Ni-N4 and Fe-N4 dual sites coanchored on porous hollow carbon nanocages (Ni-Fe-NC) are fabricated and deployed as the sulfur host for Li-S battery. The hollow and conductive carbon matrix promotes electron transfer and also accommodates volume fluctuation during cycling. Notably, the high d band center of Fe in Fe-N4 site demonstrates strong polysulfide affinity, leading to an accelerated sulfur reduction reaction. Meanwhile, Li2S on the Ni-N4 site delivers a metallic property with high S 2p electron density of states around the Femi energy level, enabling a low sulfur evolution reaction barrier. The dual catalytic effect on Ni-Fe-NC endows sulfur cathode high energy density, prolonged lifespan, and low polarization.

Clinicopathological and molecular features of indolent natural killer-cell lymphoproliferative disorder of the gastrointestinal tract.

AIMS: Indolent natural killer (NK) cell lymphoproliferative disorder of the gastrointestinal (GI) tract (iNKLPD) is a rare, recently recognised neoplasm. Most of the reported tumours are confined to the GI tract, while a small subset of the tumours harbour JAK3 mutations. We collected four cases of iNKLPD with the goal of adding additional information to the current knowledge of this disease regarding the clinicopathological, immunohistochemical and molecular features. METHODS AND RESULTS: Similar features including medium- to large-sized lymphoid cells with variable amounts of pale or slightly eosinophilic cytoplasm, and no evidence of EBER, TCR rearrangement were found in four cases. JAK3 K563_C565del mutation was found in one of three cases that were subjected to targeted next-generation sequencing. Unique findings of our study include one iNKLPD encountered for the first time in nasopharynx, where lesions could be inadvertently diagnosed as extranodal NK/T cell lymphoma, and one iNKLPD located in the gallbladder extended deeply into muscular and adventitial layers. Exceptional CD8-positive expression was observed in one iNKLPD. In addition, positive staining of phospho-STAT5, phospho-STAT3 and phospho-p38 were found in our cases. None of the four patients received therapy for lymphoma, but all had a benign clinical outcome during a follow-up time of 20-99 months. CONCLUSIONS: We present four iNKLPDs with clinical, immunohistochemical and molecular features similar to the reported cases, as well as some unusual characters, which expand our knowledge on this disease, and further support the neoplastic nature of iNKLPDs.

Dual-Channel Logic Gates Operating on the Chemopalette ssDNA-Ag NCs/GO Nanocomposites.

In this work, we demonstrate that the emission wavelength and intensity of silver nanoclusters (Ag NCs) can be facilely tuned by the configuration transformation from the adsorption of Ag NCs to the graphene oxide (GO) surface to the desorption of Ag NCs from GO. Bicolor Ag NCs tethering the complementary sequence of influenza A virus genes are prepared, named green-emitting G-Ag NCs-CH5N1 (530 nm) and red-emitting R-Ag NCs-CH1N1 (589 nm). As for the high affinity of the complementary fragment of genes to GO, the adsorption of Ag NCs to GO leads to the formation of G-Ag NCs-CH5N1/GO and R-Ag NCs-CH1N1/GO nanocomposites, leading to fluorescent quenching due to energy transfer. By conjugating complementary sequences as capturing probes for targets, the formation of genes/Ag NC duplex-stranded structures results in the desorption of Ag NCs from GO, activating the fluorescence signal. More interestingly, compared with sole single-stranded DNA-templated fluorescent Ag NCs (ssDNA-Ag NCs), the activatable emission wavelength of the G-Ag NCs-CH5N1/H5N1 complex exhibits a notable red shift (555 nm) with a 49% recovery rate, while that of the R-Ag NCs-CH1N1/H1N1 complex shows a distinct blue shift (569 nm) with a 200% recovery rate. Via target-responsive configuration transformation of Ag NCs/GO hybrid materials, the emission wavelength and intensity of Ag NCs are effectively regulated. Based on the output changes according to different input combinations, novel dual-channel logic gates for multiplex simultaneous detection are developed by using the tunable color and intensity of ssDNA-Ag NCs. Our observation may open a new path for multiplex analysis in a facile and rapid way combining the logic gate strategy.

Target-Activating and Toehold Displacement Ag NCs/GO Biosensor-Mediating Signal Shift and Enhancement for Simultaneous Multiple Detection.

Herein, we demonstrate that a new multicolor silver nanoclusters/graphene oxide (Ag NCs/GO) hybrid material, upon target response, undergoes a configuration transformation, based on entropy-driven enzyme-free toehold-mediated strand displacement reaction, achieving emission shift and enhancement. To realize the aim above, two different synthesis routes (route I and II) of synthesizing fluorescent Ag NCs for constructing toehold displacement Ag NCs/GO biosensor is designed and performed. Influenza A virus subtype genes (H1N1 and H5N1) as a model can efficiently initiate the operation of entropy-driven displacement reaction, resulting in activatable fluorescence. Red-emitting and green-emitting Ag NCs tethering the complementary sequence of H1N1 (pDNA1) and H5N1 (pDNA2) are indirectly immobilized on GO surface through binding with capture DNA (cDNA1 and cDNA2), respectively, forming multicolor pDNA-Ag NCs/GO nanohybrid materials. However, they do not exhibit nearly fluorescence signals attributed to energy transfer from donor Ag NCs to acceptor GO. Upon adding targets H1N1 and H5N1 (tDNA1 and tDNA2), pDNA1-Ag NCs and pDNA2-Ag NCs detach from GO, based on toehold-mediated strand displacement reaction, which interferes the energy transfer and leads to significant fluorescence enhancement. More interestingly, the activatable process is accompanied by remarkable hypsochromic shift (19 nm) or bathochromic shift (21 nm) emission with quite high fluorescence recovery rates (823.35% and 693.62%). Therefore, based on these phenomena, a novel multiple approach has been developed with the assistance of toehold displacement and Ag NCs/GO nanohybrid materials. As for the remarkable emission recovery and multichannel signal, the proposed approach displays the promising application prospect in accurate diagnosis and treatment.

PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity.

The Beclin1-VPS34 complex is recognized as a central node in regulating autophagy via interacting with diverse molecules such as ATG14L for autophagy initiation and UVRAG for autophagosome maturation. However, the underlying molecular mechanism that coordinates the timely activation of VPS34 complex is poorly understood. Here, we identify that PAQR3 governs the preferential formation and activation of ATG14L-linked VPS34 complex for autophagy initiation via two levels of regulation. Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L- but not UVRAG-linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation. Deletion of PAQR3 leads to reduction of exercise-induced autophagy in mice, accompanied by a certain degree of disaggregation of ATG14L-associated VPS34 complex. Together, this study uncovers that PAQR3 can not only enhance the capacity of pro-autophagy class III PI3K due to its scaffold function, but also integrate AMPK signal to activation of ATG14L-linked VPS34 complex upon glucose starvation.

Inflammatory Response, a Key Pathophysiological Mechanism of Obesity-Induced Depression.

In recent years, with the acceleration of life rhythm and the increase of social competition, the incidence of obesity and depression has been increasing, which has seriously affected the quality of life and health of people. Obesity and depression, two seemingly unrelated physical and psychological diseases, in fact, are closely related: obese people are more likely to have depression than nonobese ones. We have reviewed and analyzed the relevant research literature and found that the inflammatory response plays a key role in obesity-induced depression. This article will discuss in detail the inflammatory mechanisms by which obesity induces depression.

Castleman disease of the hyaline vascular variant transforming to POEMS syndrome as endpoint: a case report.

BACKGROUND: POEMS syndrome is a rare neoplastic syndrome reflected by plasma cell disorder. It is composed by polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. It is also reported to associate with Castleman disease. The early identification and treatment are pivotal to reduce the morbidity and mortality. CASE PRESENTATION: Here we report a 66-year-old man with treated Castleman disease developing with sequential presence of endocrinopathy polyneuropathy, skin changes, organomegaly and extravascular volume overload within 18 years, which was finally confirmed as POEMS syndrome by positive monoclonal protein. He was thereafter successfully treated with prednisone and azathioprine as primary therapy and thalidomide as maintenance therapy. CONCLUSION: The diagnosis of POEMS is based on a cluster of disorder involved in varied organs. We report a rare case that triggers the need to consider POEMS syndrome diagnosis for patients carrying Castleman disease and polyneuropathy.

Silver Nanoclusters Beacon as Stimuli-Responsive Versatile Platform for Multiplex DNAs Detection and Aptamer-Substrate Complexes Sensing.

An activatable silver nanoclusters beacon (ASNCB) was synthesized through a facile one-pot approach and applied for multiplex DNAs, small molecule, and protein sensing. Multifunctional single-stranded DNA sequences are rationally designed and used for ASNCB in situ synthesis. Via target-responsive structure transformation of ASNCB, target recognition induced ASNCB conformational transition and lit up the fluorescent signal of silver nanoclusters. By further implementing two different color ASNCBs (520 and 600 nm), the parallel multiplexed analysis of two target genes (Influenza A virus genes H1N1 and H5N1) is achieved. Additionally, with the introduction of aptamer for the design of the molecular beacon, the detections of small molecule adenosine triphosphate (ATP) and biomacromolecule thrombin have also been realized. This is the first time that an activatable fluorescent silver nanoclusters (Ag NCs)-based probe and the target recognition have been integrated into a single process, which provides a versatile platform for different analytes in a facile way. The successful application of our proposed ASNCB in real sample analysis and ATP imaging in living cells further displayed its promising potential for fluorescence sensing.

Fluorescence Enhancement of Terminal Amine Assembled on Gold Nanoclusters and Its Application to Ratiometric Lysine Detection.

Ratiometric fluorescent sensors have emerged as an attractive tool for analytical sensing and optical imaging due to their providing a built-in self-calibration for environmental effects. However, cumbersome processes of nanoparticles modified with fluorophores for constructing traditional ratiometric sensors limit their further application. Herein, we report a facile and label-free strategy for constructing a ratiometric sensor based on an aggregation-induced-emission (AIE)-active amine-terminated small molecule on the surface of gold nanoclusters (AuNCs). Intrinsic fluorescence of the terminal primary amine of the small molecule lysine resulting from AIE was first observed in the presence of glutathione-stabilized gold nanoclusters (GSH-AuNCs). Using lysine as both the fluorophore and the analyte, the synthesized GSH-AuNCs showed a good lysine-responsive ratiometric property. The AIE-active dual-emitting fluorescence property of the GSH-AuNCs/lysine complex made it feasible to achieve ratiometrically detection of the analyte without conjugated fluorogen. This AIE-active GSH-AuNC-based biosensor possesses high selectivity, rapid response, and excellent photostability. Moreover, the strategy opens a new pathway for the construction of a label-free ratiometric fluorescent sensor with various applications.

[Study on Simultaneous Mercury and Lead Detection in Water Samples with PGNAA-XRF].

Prompt gamma neutron activation analysis (PGNAA) technology is used in heavy metals measurement. It is found that the detection accuracy of lead (Pb) is impacted heavily by mercury (Hg), because of thermal neutron cross section of mercury is much bigger than lead. In this paper, a new combined detection method was proposed to improve the lead measurement accuracy in situ environmental water rejects analysis by PGNAA-XRF. Thus, a combined measurement facility was developed to analyze the mercury and lead in water simultaneously. The geometry of set-up is determined by a series of simulations with the MCNP code to improve the detection efficiency of the prompt gamma-ray intensity (Iγ) and characteristic X-ray fluorescence intensity (IX) of element. The ideal sample height and cavity are 33 and 16 cm, respectively. The influence of the relationship between Iγ, IX and different concentration (ｃi) of Hg and Pb was researched by MCNP calculations, respectively. The simulation results showed that there were good linear relationships between Iγ, IX and ｃi, respectively. The empirical formula of combined detection method was proposed based on the above calculations. The limits of detection for Hg and Pb with the combined measurement instrument were 3.89 and 4.80 mg·kg-1, respectively. It is a significant increase in performance of the mercury and lead detection simultaneously.

[New methodology for heavy metals measurement in water samples by PGNAA-XRF].

In the present paper, a new combined detection method was proposed using prompt gamma neutron activation analysis (PGNAA) and characteristic X-ray fluorescence to improve the heavy metals measurement accuracy for in-situ environmental water rejects analysis by PGNAA technology. Especially, the characteristic X-ray fluorescence (XRF) of heavy metals is induced by prompt gamma-ray directly instead of the traditional excitation sources. Thus, a combined measurement facility with an 241 AmBe neutron source, a BGO detector and a NaI-Be detector was developed to analyze the pollutants in water. The two detectors were respectively used to record prompt gamma-ray and characteristic X-ray fluorescence of heavy metals. The prompt gamma-ray intensity (I(γ)) and characteristic X-ray fluorescence intensity (I(x)) was determined by MCNP calculations for different concentration (c(i)) of chromium (Cr), cadmium (Cd), mercury (Hg) and lead (Pb), respectively. The simulation results showed that there was a good linear relationship between I(γ), I(x) and (c(i)), respectively. The empirical formula of combined detection method was given based on the above calculations. It was found that the combined detection method was more sensitive for high atomic number heavy metals like Hg and Pb measurement than low atomic number like Cr and Cd by comparing and analyzing I(γ) and I(x). The limits of detection for Hg and Pb by the combined measurement instrument were 17.4 and 24.2 mg x kg(-1), respectively.

Surgical intervention of Lemierre's syndrome: a case report and review of the literature.

BACKGROUND: Lemierre's syndrome is a fatal and rare disease that is typically characterized by oropharyngeal infection and internal jugular vein thrombosis. Timely institution of appropriate antibiotics is the standard treatment. CASE PRESENTATION: The authors report a case of Lemierre's syndrome. A 67-year-old male patient of Han ethnicity in China suffered from a large inflammatory neck mass involving left internal jugular vein thrombosis diagnosed as Lemierre's syndrome and finally cured by surgical treatment. In addition, a literature review was carried out through PubMed using the terms "Lemierre's syndrome/disease and review, meta-analysis or retrospective study" and "Lemierre's syndrome/disease and internal jugular vein". This search yielded six articles that recorded surgical methods such as drainage, craniotomy, tooth extraction, and ligation of the occluded vein to give clinicians more ideas about the treatment of the Lemierre's syndrome. CONCLUSION: This is the first review to summarize the conditions under which surgical treatment are conducted. Additionally, this is the first report of such a large inflammatory neck mass that was completely cured by surgical resection and internal jugular vein ligation. The authors also offer several conclusions regarding surgical intervention in Lemierre's syndrome for the first time.

Improving diagnosis and outcome prediction of gastric cancer via multimodal learning using whole slide pathological images and gene expression.

For the diagnosis and outcome prediction of gastric cancer (GC), machine learning methods based on whole slide pathological images (WSIs) have shown promising performance and reduced the cost of manual analysis. Nevertheless, accurate prediction of GC outcome may rely on multiple modalities with complementary information, particularly gene expression data. Thus, there is a need to develop multimodal learning methods to enhance prediction performance. In this paper, we collect a dataset from Ruijin Hospital and propose a multimodal learning method for GC diagnosis and outcome prediction, called GaCaMML, which is featured by a cross-modal attention mechanism and Per-Slide training scheme. Additionally, we perform feature attribution analysis via integrated gradient (IG) to identify important input features. The proposed method improves prediction accuracy over the single-modal learning method on three tasks, i.e., survival prediction (by 4.9% on C-index), pathological stage classification (by 11.6% on accuracy), and lymph node classification (by 12.0% on accuracy). Especially, the Per-Slide strategy addresses the issue of a high WSI-to-patient ratio and leads to much better results compared with the Per-Person training scheme. For the interpretable analysis, we find that although WSIs dominate the prediction for most samples, there is still a substantial portion of samples whose prediction highly relies on gene expression information. This study demonstrates the great potential of multimodal learning in GC-related prediction tasks and investigates the contribution of WSIs and gene expression, respectively, which not only shows how the model makes a decision but also provides insights into the association between macroscopic pathological phenotypes and microscopic molecular features.

Artificial intelligence-based assessment of PD-L1 expression in diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is an aggressive blood cancer known for its rapid progression and high incidence. The growing use of immunohistochemistry (IHC) has significantly contributed to the detailed cell characterization, thereby playing a crucial role in guiding treatment strategies for DLBCL. In this study, we developed an AI-based image analysis approach for assessing PD-L1 expression in DLBCL patients. PD-L1 expression represents as a major biomarker for screening patients who can benefit from targeted immunotherapy interventions. In particular, we performed large-scale cell annotations in IHC slides, encompassing over 5101 tissue regions and 146,439 live cells. Extensive experiments in primary and validation cohorts demonstrated the defined quantitative rule helped overcome the difficulty of identifying specific cell types. In assessing data obtained from fine needle biopsies, experiments revealed that there was a higher level of agreement in the quantitative results between Artificial Intelligence (AI) algorithms and pathologists, as well as among pathologists themselves, in comparison to the data obtained from surgical specimens. We highlight that the AI-enabled analytics enhance the objectivity and interpretability of PD-L1 quantification to improve the targeted immunotherapy development in DLBCL patients.

A berberine induced disassembly towards zwitterionic surfactant as mimicking cell membrane for light-scattering sensing and logic devices.

A label-free light-scattering sensor for berberine determination was developed based on Gemini zwitterionic surfactant as logic devices. Amphiphilic phosphodiesters quaternary ammonium nanoparticles (PQANPs) with bionic phosphate ester structure were selected as a model for mimicking cell membrane. PQANPs self-assembled and formed the micelle structure, emitting strong light-scattering signal. Interestingly, the addition of berberine induced remarkable decrease of light-scattering attribute to its interfering behavior of PQANPs aggregation. Disassembly of PQANPs could be triggered due to electrostatic interaction and hydrophobic force between PQANPs and berberine. The berberine attached to the PQANPs surface and generated nanocomposites, resulting in significant reduce of light-scattering signal. Hence, it generated a strong light-scattering signal variation according to the change of the concentration of target. Our proposed light-scattering on-off sensor could be applied for berberine detection with detection limit of 27 nM. Moreover, a logic gate system was constructed based on PQANPs sensor with berberine and the interfering substances as the inputs and the light-scattering intensity as an output, which could hold great potential application in future clinical diagnosis and drug analysis.

Enhanced Polysulfide Trapping and Conversion by Amorphous-Crystalline Heterostructured MnO2 Interlayers for Li-S Batteries.

The practical application of lithium-sulfur batteries (LSBs) is still hindered by several technical issues, including severe polysulfide shuttling and sluggish redox kinetics, which reduces the sulfur utilization and further results in low energy density. Herein, amorphous-crystalline heterostructured MnO2 (ACM) prepared through a simple calcination process was employed as the functional interlayer to play a double role as effective trapper and multifunctional electrocatalyst for LSBs. ACM not only combines the strong sulfur chemisorption of the amorphous MnO2 (AM) and fast Li+ transportation of the crystalline MnO2(CM) but also accelerates the interface charge transfer at the amorphous/crystalline interfaces. The LSBs with such unique interlayer exhibited an excellent rate performance of 1155.5 mAh·g-1 at 0.2 C and 692.9 mAh·g-1 at 3 C and a low decay rate of 0.071% per cycle over 500 cycles at 0.5 C. Even for a high sulfur loading of 5 mg·cm-2 at 0.1 C, a high capacity retention of 92.3% could also be achieved after 100 cycles. The concept of amorphous-crystalline heterostructures prepared by crystallization regulation might also be used for other electronic devices and catalyst designs.