The loop position of shRNAs and pre-miRNAs is critical for the accuracy of dicer processing in vivo.

Short hairpin RNA (shRNA)-induced RNAi is used for biological discovery and therapeutics. Dicer, whose normal role is to liberate endogenous miRNAs from their precursors, processes shRNAs into different biologically active siRNAs, affecting their efficacy and potential for off-targeting. We found that, in cells, Dicer induced imprecise cleavage events around the expected sites based on the previously described 5'/3' counting rules. These promiscuous noncanonical cleavages were abrogated when the cleavage site was positioned 2 nt from a bulge or loop. Interestingly, we observed that the ~1/3 of mammalian endogenous pre-miRNAs that contained such structures were more precisely processed by Dicer. Implementing a "loop-counting rule," we designed potent anti-HCV shRNAs with substantially reduced off-target effects. Our results suggest that Dicer recognizes the loop/bulge structure in addition to the ends of shRNAs/pre-miRNAs for accurate processing. This has important implications for both miRNA processing and future design of shRNAs for RNAi-based genetic screens and therapies.

Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes.

For nearly 60 years, significant research efforts have been focused on developing strategies for the cycloaddition of bicyclobutanes (BCBs). However, higher-order cycloaddition and catalytic asymmetric cycloaddition of BCBs have been long-standing formidable challenges. Here, we report Pd-catalyzed ligand-controlled, tunable cycloadditions for the divergent synthesis of bridged bicyclic frameworks. The dppb ligand facilitates the formal (5+3) cycloaddition of BCBs and vinyl oxiranes, yielding valuable eight-membered ethers with bridged bicyclic scaffolds in 100% regioselectivity. The Cy-DPEphos ligand promotes selective hetero-[2σ+2σ] cycloadditions to access pharmacologically important 2-oxabicyclo[3.1.1]heptane (O-BCHeps). Furthermore, the corresponding catalytic asymmetric synthesis of O-BCHeps with 94-99% ee has been achieved using chiral (S)-DTBM-Segphos, representing the first catalytic asymmetric cross-dimerization of two strained rings. The obtained O-BCHeps are promising bioisosteres for ortho-substituted benzenes.

Hydrogen-Bonded Organic Cocrystal-Encapsulated Perovskite Nanocrystals as Coreactant-Free Electrochemiluminescent Luminophore for the Detection of Uranium.

Lead halide perovskite nanocrystals with excellent photophysical properties are promising electrochemiluminescence (ECL) candidates, but their poor stability greatly restricts ECL applications. Herein, hydrogen-bonded cocrystal-encapsulated CsPbBr3 perovskite nanocrystals (PeNCs@NHS-M) were synthesized by using PeNCs as nuclei for inducing the crystallization of melamine (M) and N-hydroxysuccinimide (NHS). The as-synthesized composite exhibits multiplicative ECL efficiencies (up to 24-fold that of PeNCs) without exogenous coreactants and with excellent stability in the aqueous phase. The enhanced stability can be attributed to the well-designed heterostructure of the PeNCs@NHS-M composite, which benefits from both moiety passivation and protection of the peripheral cocrystal matrix. Moreover, the heterostructure with covalent linkage facilitates charge transfer between PeNCs and NHS-M cocrystals, realizing effective ECL emission. Meanwhile, the NHS and M components act as coreactants for PeNCs, shortening the electron-transport distance and resulting in a significant increase in the ECL signal. Furthermore, by taking advantage of the specific binding effect between NHS-M and uranyl (UO22+), an ECL system with both a low detection limit (1 nM) and high selectivity for monitoring UO22+ in mining wastewater is established. The presence of UO22+ disrupted the charge-transfer effect within PeNCs@NHS-M, weakening the ECL signals. This work provides an efficient design strategy for obtaining stable and efficient ECLs from perovskite nanocrystals, offering a new perspective for the discovery and application of perovskite-based ECL systems.

A General Strategy toward Self-assembled Nanovaccine Based on Cationic Lentinan to Induce Potent Humoral and Cellular Immune Responses.

Adjuvants play a critical role in the induction of effective immune responses by vaccines. Here, a self-assembling nanovaccine platform that integrates adjuvant functions into the delivery vehicle is prepared. Cationic Lentinan (CLNT) is mixed with ovalbumin (OVA) to obtain a self-assembling nanovaccine (CLNTO nanovaccine), which induces the uptake and maturation of bone marrow dendritic cells (BMDCs) via the toll-like receptors 2/4 (TLR2/4) to produce effective antigen cross-presentation. CLNTO nanovaccines target lymph nodes (LNs) and induce a robust OVA-specific immune response via TLR and tumor necrosis factor (TNF) signaling pathways, retinoic acid-inducible gene I (RIG-I) receptor, and cytokine-cytokine receptor interactions. In addition, CLNTO nanovaccines are found that promote the activation of follicular helper T (Tfh) cells and induce the differentiation of germinal center (GC) B cells into memory B cells and plasma cells, thereby enhancing the immune response. Vaccination with CLNTO nanovaccine significantly inhibits the growth of ovalbumin (OVA)-expressing B16 melanoma cell (B16-OVA) tumors, indicating its great potential for cancer immunotherapy. Therefore, this study presents a simple, safe, and effective self-assembling nanovaccine that induces helper T cell 1 (Th1) and helper T cell (Th2) immune responses, making it an effective vaccine delivery system.

Hydrogen-Bonded Cocrystals Encapsulating CsPbBr3 Perovskite Nanocrystals with Enhancement of Charge Transport for Photocatalytic Reduction of Uranium.

At present, poor stability and carrier transfer efficiency are the main problems that limit the development of perovskite-based photoelectric technologies. In this work, hydrogen-bonded cocrystal-coated perovskite composite (PeNCs@NHS-M) is easily obtained by inducing rapid crystallization of melamine (M) and N-hydroxysuccinimide (NHS) with PeNCs as the nuclei. The outer NHS-M cocrystal passivates the undercoordinated lead atoms by forming covalent bonds, thereby greatly reducing the trap density while maintaining good structure stability for perovskite nanocrystals. Moreover, benefiting from the interfacial covalent band linkage and long-range ordered structures of cocrystals, the charge transfer efficiency is effectively enhanced and PeNCs@NHS-M displays superior photoelectric performance. Based on the excellent photoelectric performance and abundant active sites of PeNCs@NHS-M, photocatalytic reduction of uranium is realized. PeNCs@NHS-M exhibits U(VI) reduction removal capability of up to 810.1 mg g-1 in the presence of light. The strategy of cocrystals trapping perovskite nanocrystals provides a simple synthesis method for composites and opens up a new idea for simultaneously improving the stability and photovoltaic performance of perovskite.

Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia.

BACKGROUND: Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement. METHODS: GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement. RESULTS: Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. CONCLUSIONS: GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.

TIM22 and TIM29 inhibit HBV replication by up-regulating SRSF1 expression.

Hepatitis B virus (HBV) infection is a serious global health problem. After the viruses infect the human body, the host can respond to the virus infection by coordinating various cellular responses, in which mitochondria play an important role. Evidence has shown that mitochondrial proteins are involved in host antiviral responses. In this study, we found that the overexpression of TIM22 and TIM29, the members of the inner membrane translocase TIM22 complex, significantly reduced the level of intracellular HBV DNA and RNA and secreted HBV surface antigens and E antigen. The effects of TIM22 and TIM29 on HBV replication and transcription is attributed to the reduction of core promoter activity mediated by the increased expression of SRSF1 which acts as a suppressor of HBV replication. This study provides new evidence for the critical role of mitochondria in the resistance of HBV infection and new targets for the development of treatment against HBV infection.

Construction of a Bifunctional Redox-Site Conjugated Covalent-Organic Framework for Photoinduced Precision Trapping of Uranyl Ions.

The performance of covalent-organic frameworks (COFs) for the photocatalytic extraction of uranium is greatly limited by the number of adsorption sites. Herein, inspired by electronegative redox reactions, we designed a nitrogen-oxygen rich pyrazine connected COF (TQY-COF) with multiple redox sites as a platform for extracting uranium via combining superaffinity and enhanced photoinduction. The preorganized bisnitrogen-bisoxygen donor configuration on TQY-COF is entirely matched with the typical geometric coordination of hexavalent uranyl ions, which demonstrates high affinity (tetra-coordination). In addition, the presence of the carbonyl group and pyrazine ring effectively stores and controls electron flow, which efficaciously facilitates the separation of e-/h+ and enhances photocatalytic performance. The experimental results show that TQY-COF removes up to 99.8% of uranyl ions from actual uranium mine wastewater under the light conditions without a sacrificial agent, and the separation coefficient reaches 1.73 × 106 mL g-1 in the presence of multiple metal ions, which realizes the precise separation in the complex environment. Importantly, DFT calculations further elucidate the coordination mechanism of uranium and demonstrate the necessity of the presence of N/O atoms in the photocatalytic adsorption of uranium.

Circular RNAs: emerging players in brain aging and neurodegenerative diseases.

Brain aging is closely related to neurodegenerative diseases. Circular RNAs (circRNAs) are a type of conserved RNAs with covalently closed continuous loops. Emerging evidence has shown that circRNAs are implicated in the biology of brain aging and the pathology of age-related neurodegenerative diseases. Here, we summarize current studies on circRNAs associated with brain aging and neurodegenerative diseases by discussing their expression features, pathophysiological roles, and mechanisms of action. We also discuss the potential challenges of circRNA-based therapy against brain aging and neurodegenerative diseases, as well as their potential as diagnostic biomarkers of neurodegenerative diseases. The review provides insights into current progress in the functions of circRNAs in the process of brain aging and neurodegenerative diseases. © 2022 The Pathological Society of Great Britain and Ireland.

Caffeic acid alleviates cerebral ischemic injury in rats by resisting ferroptosis via Nrf2 signaling pathway.

There are few effective and safe neuroprotective agents for the treatment of ischemic stroke currently. Caffeic acid is a phenolic acid that widely exists in a number of plant species. Previous studies show that caffeic acid ameliorates brain injury in rats after cerebral ischemia/reperfusion. In this study we explored the protective mechanisms of caffeic acid against oxidative stress and ferroptosis in permanent cerebral ischemia. Ischemia stroke was induced on rats by permanent middle cerebral artery occlusion (pMCAO). Caffeic acid (0.4, 2, 10 mg·kg-1·d-1, i.g.) was administered to the rats for 3 consecutive days before or after the surgery. We showed that either pre-pMCAO or post-pMCAO administration of caffeic acid (2 mg·kg-1·d-1) effectively reduced the infarct volume and improved neurological outcome. The therapeutic time window could last to 2 h after pMCAO. We found that caffeic acid administration significantly reduced oxidative damage as well as neuroinflammation, and enhanced antioxidant capacity in pMCAO rat brain. We further demonstrated that caffeic acid down-regulated TFR1 and ACSL4, and up-regulated glutathione production through Nrf2 signaling pathway to resist ferroptosis in pMCAO rat brain and in oxygen glucose deprivation/reoxygenation (OGD/R)-treated SK-N-SH cells in vitro. Application of ML385, an Nrf2 inhibitor, blocked the neuroprotective effects of caffeic acid in both in vivo and in vitro models, evidenced by excessive accumulation of iron ions and inactivation of the ferroptosis defense system. In conclusion, caffeic acid inhibits oxidative stress-mediated neuronal death in pMCAO rat brain by regulating ferroptosis via Nrf2 signaling pathway. Caffeic acid might serve as a potential treatment to relieve brain injury after cerebral ischemia. Caffeic acid significantly attenuated cerebral ischemic injury and resisted ferroptosis both in vivo and in vitro. The regulation of Nrf2 by caffeic acid initiated the transcription of downstream target genes, which were shown to be anti-inflammatory, antioxidative and antiferroptotic. The effects of caffeic acid on neuroinflammation and ferroptosis in cerebral ischemia were explored in a primary microglia-neuron coculture system. Caffeic acid played a role in reducing neuroinflammation and resisting ferroptosis through the Nrf2 signaling pathway, which further suggested that caffeic acid might be a potential therapeutic method for alleviating brain injury after cerebral ischemia.

Effect and mechanism of gomisin D on the isoproterenol induced myocardial injury in H9C2 cells and mice.

We established myocardial injury models in vivo and in vitro to investigate the cardioprotective effect of gomisin D obtained from Schisandra chinensis. Gomisin D significantly inhibited isoproterenol-induced apoptosis and hypertrophy in H9C2 cells. Gomisin D decreased serum BNP, ANP, CK-MB, cTn-T levels and histopathological alterations, and inhibited myocardial hypertrophy in mice. In mechanisms research, gomisin D reversed ISO-induced accumulation of intracellular ROS and Ca2+. Gomisin D further improved mitochondrial energy metabolism disorders by regulating the TCA cycle. These results demonstrated that gomisin D had a significant effect on isoproterenol-induced myocardial injury by inhibiting oxidative stress, calcium overload and improving mitochondrial energy metabolism.

Baricitinib relieves DSS-induced ulcerative colitis in mice by suppressing the NF-κB and JAK2/STAT3 signalling pathways.

Ulcerative colitis (UC) is a relapsing inflammatory disease with a unique aetiology. The treatment of UC is challenging, and the current clinical therapeutics for colitis have limited efficacy. Thus, finding new and effective treatment options remains urgent. Baricitinib, an inhibitor of Janus kinase (JAK), has been clinically used to treat rheumatoid arthritis (RA). However, its potential effects on UC have not been fully elucidated. In this study, we aimed to explore the effects of baricitinib on UC and its underlying mechanism. Dextran sulphate sodium (DSS)-induced murine model of chronic colitis was used to investigate the intervention efficacy following oral administration of baricitinib. The levels of key cytokines, such as IL-6, IFN-γ and IL-17A, were determined. Moreover, western blotting for IκBα, p-IκBα, JAK2, p-JAK2, STAT3 and p-STAT3 protein expression was performed to investigate the associated signalling pathways. Our findings demonstrated that baricitinib can significantly relieve DSS-induced UC in mice. After baricitinib intervention, IL-6, IFN-γ and IL-17A levels were decreased both in vitro and in vivo. Moreover, the elevated expression levels of p-IκBα, p-JAK2, and p-STAT3 were significantly reduced after treatment. Collectively, these results suggest that baricitinib is a potential therapeutic agent for alleviation of DSS-induced colitis. This study provides a method for subsequent investigations on potential curative drugs development of the for colitis.

Silencing of the calcium-dependent protein kinase TaCDPK27 improves wheat resistance to powdery mildew.

BACKGROUND: Calcium ions (Ca2+), secondary messengers, are crucial for the signal transduction process of the interaction between plants and pathogens. Ca2+ signaling also regulates autophagy. As plant calcium signal-decoding proteins, calcium-dependent protein kinases (CDPKs) have been found to be involved in biotic and abiotic stress responses. However, information on their functions in response to powdery mildew attack in wheat crops is limited. RESULT: In the present study, the expression levels of TaCDPK27, four essential autophagy-related genes (ATGs) (TaATG5, TaATG7, TaATG8, and TaATG10), and two major metacaspase genes, namely, TaMCA1 and TaMCA9, were increased by powdery mildew (Blumeria graminis f. sp. tritici, Bgt) infection in wheat seedling leaves. Silencing TaCDPK27 improves wheat seedling resistance to powdery mildew, with fewer Bgt hyphae occurring on TaCDPK27-silenced wheat seedling leaves than on normal seedlings. In wheat seedling leaves under powdery mildew infection, silencing TaCDPK27 induced excess contents of reactive oxygen species (ROS); decreased the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT); and led to an increase in programmed cell death (PCD). Silencing TaCDPK27 also inhibited autophagy in wheat seedling leaves, and silencing TaATG7 also enhanced wheat seedling resistance to powdery mildew infection. TaCDPK27-mCherry and GFP-TaATG8h colocalized in wheat protoplasts. Overexpressed TaCDPK27-mCherry fusions required enhanced autophagy activity in wheat protoplast under carbon starvation. CONCLUSION: These results suggested that TaCDPK27 negatively regulates wheat resistance to PW infection, and functionally links with autophagy in wheat.

Diatom Frustules Decorated with Co Nanoparticles for the Advanced Anode of Li-Ion Batteries.

Silica is regarded as a promising anode material for lithium-ion batteries (LIBs) because of its high theoretical capacity. However, large volume variation and poor electrical conductivity are limiting factors for the development of SiO2 anode materials. To solve this problem, combining SiO2 with a conductive phase and designing hollow porous structures are effective ways. In this work, The Co(II)-EDTA chelate on the surface of diatom biosilica (DBS) frustules and obtained DBS@C-Co composites decorated with Co nanoparticles by calcination without a reducing atmosphere is first precipitated. The unique three-dimensional structure of diatom frustules provides enough space for the volume change of silica during lithiation/delithiation. Co nanoparticles effectively improve the electrical conductivity and electrochemical activity of silica. Through the synergistic effect of the hollow porous structure, carbon layer and Co nanoparticles, the DBS@C-Co-60 composite delivers a high reversible capacity of >620 mAh g-1 at 100 mA g-1 after 270 cycles. This study provides a new method for the synthesis of metal/silica composites and an opportunity for the development of natural resources as advanced active materials for LIBs.

A Prospective Long-Term Follow-Up Study: The Application of Circulating Tumor Cells Analysis to Guide Adjuvant Therapy in Stage II Colorectal Cancer.

BACKGROUND: The efficacy of circulating tumor cells (CTCs) in the selection of stage II colorectal cancer (CRC) patients for adjuvant chemotherapy remains inconclusive. OBJECTIVE: The aim of this study was to validate the necessity of adjuvant chemotherapy for stage II CRC patients with positive postoperative CTCs. METHODS: The clinicopathological features and overall survival (OS) of a cohort of 70 patients with confirmed CRC were collected and analyzed. RESULTS: The total rate of positive CTCs was 55.7%, while the average OS was 70.8 months and the OS rate was 75.7% (53/70). These 70 patients were divided into four subgroups, including a CTC-negative group with non-adjuvant chemotherapy (CHEMO-/CTC-) versus a CTC-positive group with non-adjuvant chemotherapy (CHEMO-/CTC+), CHEMO+/CTC- versus CHEMO+/CTC+, CHEMO-/CTC- versus CHEMO+/CTC-, and CHEMO+/CTC+ versus CHEMO-/CTC+; the total numbers in each subgroup were 25 versus 32, 6 versus 7, 25 versus 6, and 7 versus 32, respectively. The average OS of the CHEMO-/CTC- and CHEMO-/CTC+ groups was 82.0 and 68.1 months, respectively (p = 0.020); the average OS of the CHEMO+/CTC- and CHEMO+/CTC+ groups was 83.6 months and 76.4 months, respectively (p = 0.963); the average OS of the CHEMO-/CTC- and CHEMO+/CTC- groups was 82.0 months and 83.6 months, respectively (p = 0.999); and the average OS of the CHEMO+/CTC+ and CHEMO-/CTC+ groups was 76.4 months and 68.1 months, respectively (p = 0.247). CONCLUSIONS: Positive CTCs are a potential prognostic marker for stage II CRC.

Frailty and postoperative outcomes in brain tumor patients: a systematic review subdivided by tumor etiology.

PURPOSE: Frailty has gained prominence in neurosurgical oncology, with more studies exploring its relationship to postoperative outcomes in brain tumor patients. As this body of literature continues to grow, concisely reviewing recent developments in the field is necessary. Here we provide a systematic review of frailty in brain tumor patients subdivided by tumor type, incorporating both modern frailty indices and traditional Karnofsky Performance Status (KPS) metrics. METHODS: Systematic literature review was performed using PRISMA guidelines. PubMed and Google Scholar were queried for articles related to frailty, KPS, and brain tumor outcomes. Only articles describing novel associations between frailty or KPS and primary intracranial tumors were included. RESULTS: After exclusion criteria, systematic review yielded 52 publications. Amongst malignant lesions, 16 studies focused on glioblastoma. Amongst benign tumors, 13 focused on meningiomas, and 6 focused on vestibular schwannomas. Seventeen studies grouped all brain tumor patients together. Seven studies incorporated both frailty indices and KPS into their analyses. Studies correlated frailty with various postoperative outcomes, including complications and mortality. CONCLUSION: Our review identified several patterns of overall postsurgical outcomes reporting for patients with brain tumors and frailty. To date, reviews of frailty in patients with brain tumors have been largely limited to certain frailty indices, analyzing all patients together regardless of lesion etiology. Although this technique is beneficial in providing a general overview of frailty's use for brain tumor patients, given each tumor pathology has its own unique etiology, this combined approach potentially neglects key nuances governing frailty's use and prognostic value.

Fermented foods and metabolic outcomes in diabetes and prediabetes: A systematic review and meta-analysis of randomized controlled trials.

Several randomized controlled trials (RCTs) have investigated the effects of fermented foods on metabolic outcomes in adult patients suffering from diabetes and prediabetes. However, the results of these RCTs are conflicting. This systematic review and meta-analysis was carried out on data from RCTs to evaluate the effects of fermented foods in patients with diabetes and prediabetes. The PubMed, Web of Science, Embase, the Cochrane Library and Scopus databases were searched up to 21 June, 2022. English-language RCTs of fermented foods consumption were included which gave metabolic outcomes on body composition, glucose control, insulin sensitivity, lipid profile, as well as blood pressure. Eighteen RCTs met the inclusion criteria and 843 participants were included in the final analysis. The pooled results showed a significant reduction of fasting blood glucose (FBG), the homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), low density lipid cholesterol (LDL-C) and diastolic blood pressure (DBP) in the intervention group versus the control group. The results of this research showed that fermented foods have the potential to improve some metabolic outcomes, including FBG, HOMA-IR, TC, LDL-C, and DBP in patients with diabetes and prediabetes.

Metabolic and bariatric surgery in China: A summary of the Greater China Metabolic and Bariatric Surgery Database and comparison with other international registry databases.

AIMS: To summarize the Greater China Metabolic and Bariatric Surgery Database (GC-MBD) and to compare patient characteristics and different procedures performed with data from published reports from other international bariatric surgery registries. MATERIALS AND METHODS: Data were extracted from the GC-MBD registry in 2021. Baseline demographic characteristics, obesity-related comorbidities and operational information were analysed. Descriptive comparisons of these data were made with the published reports from four other international/national databases, including the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) registry, the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database of the United States, the National Bariatric Surgical Registry (NBSR) of the United Kingdom, and the Scandinavian Obesity Surgery Registry (SOReg). RESULTS: Fifty-three centres in China registered 6807 cases in the GC-MBD. Compared with published data from the IFSO registry, MBSAQIP, NBSR and SOReg, patients in China undergoing surgery were younger and had a lower body mass index. The incidence of other obesity-related comorbidities, except for gastroesophageal reflux disease, was also higher than in Western countries. Furthermore, more patients underwent sleeve gastrectomy, less revisional bariatric surgery was reported in China, and jejunojejunal bypass with sleeve gastrectomy, uncommon in other countries, was China's second-leading bariatric procedure. CONCLUSIONS: By establishing comprehensive national registries such as the GC-MBD, real-world information can be gathered on clinical practice and patient outcomes. Insights into variations in clinical practice can be identified by comparing reports from different countries, which can help in making and evaluating healthcare policies on the best clinical practices at a national level.

Integrative genomic and transcriptomic profiling reveals distinct molecular subsets in adult mixed phenotype acute leukemia.

Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co-expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T-lymphoid/myeloid MPAL (T/My MPAL-NOS), 42 with Ph+ MPAL, 36 with B-lymphoid/myeloid MPAL (B/My MPAL-NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL-NOS was similar to B/T MPAL-NOS but differed from Ph+ MPAL and B/My MPAL-NOS. T/My MPAL-NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL-NOS showed higher NOTCH1 mutations. By integrating next-generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1-G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement-like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement-like characteristics. Subsequently, we analyzed single-cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease-like and common myeloid progenitor disease-like signatures, G5 and G6 had high expression of granulocyte-monocyte progenitor disease-like and monocyte disease-like signatures, and G7 and G8 had common lymphoid progenitor disease-like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.

Gamma-Aminobutyric Acid Type A Receptor Subunit Pi is a potential chemoresistance regulator in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the cancers with high morbidity and mortality worldwide. Chemotherapy is commonly used for metastatic or more advanced CRC. The mechanism of CRC chemoresistance is still under active investigation. Therefore, we identify and validate differentially expressed genes (DEGs) between oxaliplatin/5-FU resistant and sensitive CRC cells. METHODS AND RESULTS: Three datasets of colorectal cancer patients (GSE28691, GSE81006, and GSE77932) from the Gene Expression Omnibus (GEO) database were analyzed and volcano plots for DEGs were generated using the GEO2R tool. The intersection of three GEO datasets showed that GABRP was significantly upregulated in chemo-resistant CRC cells or patients with an adjusted p-value less than 0.01. The potential protein-protein interaction (PPI) network with GABRP was analyzed by the Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) website. The PPI network predicted ANKRD66, CLINT1, HAP1, PLCL1, GABARPAP, GABARAPL1, NSF, GABARAPL2, TRAK2, and CLIC3 had a high likelihood to interact with GABRP. Especially, GABARAP, GABARAPL1, ANKRD66, CLINT1, and CLIC3 were enriched as the most possibly associated proteins with GABRP among the networks. GABRP was significantly more expressed in both oxaliplatin/5-FU resistant CRC cells than in those counterpart sensitive CRC cells using quantitative PCR (qPCR) analysis. Consistently, TCGA, Oncomine, and Human Protein Atlas (HPA) databases confirmed that higher expression of GABRP was robustly found in CRC patients than those in other various cancer types or normal colon tissues. CONCLUSION: We identify GABRP as a promising drug target to mediate oxaliplatin or 5-FU resistance in CRC. It provided the theoretical basis and potential clinical value for CRC patients.