Hypoglycemic TCM formulas (Huangqi-Gegen drug pair) have the potential as an Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurological disorder. There is a considerable unmet medical need among those suffering from it. HYPOTHESIS AND PURPOSE: Given the link between type-2 diabetes mellitus (T2DM) and AD, hypoglycemic traditional Chinese medicine formulas (TCMFs) may be a treatment for AD. We investigated the possibility of identifying anti-AD medicines in hypoglycemic TCMFs and presented another option for the screening of AD medications. STUDY DESIGN AND METHODS: Paralysis of the transgenic Caenorhabditis elegans (C. elegans) strain CL4176 (caused by amyloid beta (Aß)1-42 aggregates) was used to evaluate the anti-AD effect. The toxicity and neurodegeneration induced by neuronal expression of Aß in the transgenic C. elegans strain CL2355 were determined using a 5-hydroxytryptamine (5-HT) assay. The transgenic Aß-expressing strain CL 2006 and transgenic tau-expressing strain BR5270 were used to explore the effect of TCMFs on protein expression in C. elegans using ELISAs. Then, network pharmacology was used to determine the mechanism of action. The Traditional Chinese Medicine Inheritance Support System platform was used to investigate prescription patterns, core drugs, and optimum combinations of hypoglycemic TCMFs for AD. RESULTS: Sixteen hypoglycemic TCMFs prolonged the PT50 (half paralysis time) of the CL4176 strain of C. elegans, reduced the percentage of worms paralyzed. The results of network pharmacology showed that prostaglandin-endoperoxide synthase 2 (PTGS2) and acetylcholine esterase (AChE) are main targets of hypoglycemic TCMFs. Enriched pathway analysis showed that the cholinergic receptor-related pathway was the core pathway of hypoglycemic TCMFs. According to the "four qi and five flavors" system of TCM theory, the main pharmacological qualities were "cold" and "sweet." Through the analysis by TCMISS, we found that Huangqi-Gegen drug pair as the significant Chinese herbs of hypoglycemic TCMFs. The Huangqi-Gegen pairing had the most robust therapeutic effect when delivered at a 2:1 (v/v) ratio. It reduced the paralysis caused by 5-HT, decreased protein expression of AChE and PTGS2, and reduced Aß deposition in the brain of the CL2006 strain of C. elegans. CONCLUSIONS: Huangqi-Gegen is a promising treatment of AD, and its mechanism may be induced by suppressing the protein production of AChE and PTGS2, reducing 5-HT intake, and then decreasing Aß deposition.

Mex-3 RNA binding family member A (MEX3A)/circMPP6 complex promotes colorectal cancer progression by inhibiting autophagy.

RNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the patterns of circRNA-protein interactions in colorectal cancer (CRC) are still lacking. Processing bodies (PBs) formed through liquid-liquid phase separation (LLPS) are membrane-less organelles (MLOs) consisting of RBPs and RNA. Previous evidence suggests a connection between PBs dynamics and cancer progression. Despite the increasingly acknowledged crucial role of RBPs and RNA in the accumulation and maintenance of MLOs, there remains a lack of specific research on the interactions between PBs-related RBPs and circRNAs in CRC. Herein, we identify that MEX-3 RNA binding family member A (MEX3A), frequently upregulated in CRC tissues, predicts poorer patient survival. Elevated MEX3A accelerates malignance and inhibits autophagy of CRC cells. Importantly, MEX3A undergoes intrinsically disordered regions (IDRs)-dependent LLPS in the cytoplasm. Specifically, circMPP6 acts as a scaffold to facilitate the interaction between MEX3A and PBs proteins. The MEX3A/circMPP6 complex modulates PBs dynamic and promotes UPF-mediated phosphodiesterase 5A (PDE5A) mRNA degradation, consequently leading to the aggressive properties of CRC cells. Clinically, CRC patients exhibiting high MEX3A expression and low PDE5A expression have the poorest overall survival. Our findings reveal a collaboration between MEX3A and circMPP6 in the regulation of mRNA decay through triggering the PBs aggregation, which provides prognostic markers and/or therapeutic targets for CRC.

MdTPR16, an apple tetratricopeptide repeat (TPR)-like superfamily gene, positively regulates drought stress in apple.

The Tetratricopeptide repeat (TPR)-like superfamily with TPR conserved domains is widely involved in the growth and abiotic stress in many plants. In this report, the gene MdTPR16 belongs to the TPR family in apple (Malus domestica). Promoter analysis reveal that MdTPR16 incorporated various stress response elements, including the drought stress response elements. And different abiotic stress treatments, drought especially, significantly induce the response of MdTPR16. Overexpression of MdTPR16 result in better drought tolerance in apple and Arabidopsis by up-regulating the expression levels of drought stress-related genes, achieving a higher chlorophyll content level, more material accumulation, and overall better growth compared to WT in the drought. Under drought stress, the overexpressed MdTPR16 also mitigate the oxidative damage in cells by reducing the electrolyte leakage, malondialdehyde content, and the H2O2 and O2- accumulation in apples and Arabidopsis. In conclusion, MdTPR16 act as a beneficial regulator of drought stress response by regulating the expression of related genes and the cumulation of reactive oxygen species (ROS).

First report of Fusarium commune Causing Bulb Rot on Lily (Lilium brownii var. Viridulum Baker) in Hunan Province of China.

Lily (Lilium brownii var. Viridulum Baker) is a well-known edible plant with large, white and sweet bulb scales that has important medicinal value (Zhou et al. 2021) and is grown mainly in the Hebei, Shanxi and Henan provinces of China. In May 2021, a case of bulb rot was discovered in a 3.33 hm2 plantation in Huaihua, Hunan Province, affecting 20% of the area (27°59'30″N, 110°32'20″E). The disease is most severe during the rainy season in May and June. In the early stage, irregular brown spots appeared on the lily scales, the necrosis was depressed and gradually enlarges, and in the later stage, the scales were scattered from the base of the disc and slough off. Ten samples were taken randomly from different plants in the plantation area to isolate the pathogens. After washing with sterile water, they were cut into small pieces and sterilised with 3% hydrogen peroxide for 30 s, 75% ethanol for 90 s, rinsed three times with sterile water and dried on sterile filter paper, then placed on a water agar plate and incubated in the dark in a constant temperature incubator at 28℃ for 3 to 5 days. After 2 days, the mycelium at the edge of the colony was transferred to a PDA plate and incubated for 3-5 days at 28°C in the dark to obtain pure fungal isolates. Eighteen purified fungal isolates were obtained, of which sixteen looked like Fusarium (88.9% isolation rate) and three representative isolates (BHBR2, BHBR3 and BHBR5) were selected for further study. The surface of this fungus was white with dense aerial mycelium. Some had an orange centre in the medium. Microconidia were oval in shape and appeared either straight or slightly curved. These microconidia were colourless, had 0-1 septa and measured 3.334 to 14.724 × 2.216 to 5.385 µm (n=100). Macroconidia were predominantly three-septate, crescent-shaped structures that were thin-walled and slightly curved. Cells at the apex and base were similarly curved. Macroconidia measured 17.956 to 32.150 × 2.788 to 4.492 µm (n=100). The mitochondrial small subunit (mtSSU) and translation elongation factor 1-α (TEF1) genes were amplified and sequenced using the NMS1/NMS2 and TEF-R/TEF-F primers to verify the identity of the pathogens (Stewart et al. 2006). The sequences were submitted to GenBank (BHBR2: mtSSU, PP273435; TEF, OR900976; BHBR3: mtSSU, PP277729; TEF, OR900977; BHBR5: mtSSU, PP277728; TEF, OR900978). A concatenated phylogenetic tree of the two genes was constructed and analysis showed that BHBR2, BHBR3 and BHBR5 were significantly clustered with Fusarium commune. Based on the results of morphological identification and phylogenetic tree analysis, the three isolates were identified as Fusarium commune. We carried out pathogenicity tests using two methods, one in which 6 × 6 mm fungal blocks were inoculated on lily (L. brownie var. viridulum Baker) scales and controls inoculated with sterile blocks, and the other in which strain BHBR2 was selected to carry out pathogenicity tests on bulbs of live plants soaked with 50 ml of a 1 × 106 conidial suspension and bulbs of control plants soaked with sterile water, all in three replicates. They were placed in a growth chamber at 28°C and 80% relative humidity, and the scales were moistened with moistened sterile filter paper. After 3 days of rearing treated scales, lesions appeared on lily scales inoculated with mycelial blocks and expanded with time, whereas no lesions appeared on lily scales inoculated with sterile blocks. One month later, whole plants soaked in the spore suspension wilted, while the control plants grew well. The pathogens re-isolated from the diseased tissues had the same morphological characteristics as representative isolates. This confirms Koch's hypothesis. Fusarium commune has been shown to be the most important pathogenic fungus causing root rot in Alfalfa (Medicago sativa) (Yang et al. 2022) and blueberry (Vaccinium uliginosum L.) (Li et al. 2023) in China. To our knowledge, this is the first report of Fusarium commune causing lily bulb rot in the world, which will lay the foundation for future control of lily bulb rot.

Dual specific phosphatase 4 suppresses ferroptosis and enhances sorafenib resistance in hepatocellular carcinoma.

AIMS: This investigation aims to elucidate the mechanism underlying sorafenib-induced ferroptosis in hepatocellular carcinoma (HCC). METHODS: The role of dual specificity phosphatase 4 (DUSP4) in sorafenib-treated HCC was investigated using comprehensive assessments both in vitro and in vivo, including Western blotting, qRT-PCR, cell viability assay, lipid reactive oxygen species (ROS) assay, immunohistochemistry, and xenograft tumor mouse model. Additionally, label-free quantitative proteomics was employed to identify potential proteins associated with DUSP4. RESULTS: Our study revealed that suppression of DUSP4 expression heightens the susceptibility of HCC cells to ferroptosis inducers, specifically sorafenib and erastin, in both in vitro and in vivo settings. Furthermore, we identified DUSP4-mediated regulation of key ferroptosis-related markers, such as ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1). Notably, label-free quantitative proteomics unveiled the phosphorylation of threonine residue T148 on YTH Domain Containing 1 (YTHDC1) by DUSP4. Further investigations unraveled that YTHDC1, functioning as an mRNA nuclear export regulator, is a direct target of DUSP4, orchestrating the subcellular localization of FTL and FTH1 mRNAs. Significantly, our study highlights a strong correlation between elevated DUSP4 expression and sorafenib resistance in HCC. CONCLUSIONS: Our findings introduce DUSP4 as a negative regulator of sorafenib-induced ferroptosis. This discovery opens new avenues for the development of ferroptosis-based therapeutic strategies tailored for HCC treatment.

Review and Progress in the Treatment of Renal Light Chain Amyloidosis / 罕见病研究

Renal light chain amyloidosis (AL amyloidosis) had poor prognosis before the 21st century. However, the treatment of AL amyloidosis has made great progress in the last decade. We reviewed traditional treatments of AL amyloidosis such as alkylating agents, proteasome inhibitors, and recent advances such as monoclonal antibodies. Bortezomib improved the hematological response and survival effectively of the patients, and the combination of Daratumumab brings faster and deeper hematological response, increasing the response rate of target organs such as the kidneys and heart. The renal response was significant higher in the patients with the therapy of Daratumumab, part of them could achieve very good partial response or better renal response. Autologous hematopoietic stem cell transplantation(auto-HSCT)improves hematological as well as organ response, and could be the first choice among eligible patients. Kidney transplantation is a feasible option for those with good hematological response.

Reconstruction and analysis of K-Clip surgery process based on finite element method / 中国胸心血管外科临床杂志

@#Objective     To investigate the effects of different types of tricuspid regurgitation, implantation positions, and device models on the treatment outcomes of K-Clip for tricuspid regurgitation using numerical simulations. Methods     Three-dimensional reconstruction of the heart model was performed based on CT images. Two different regurgitation orifices were obtained by modifying the standard parameterized tricuspid valve leaflets and chordae tendineae. The effects of different K-Clip models at different implantation positions (posterior leaflet midpoint, anterior-posterior commissure, anterior leaflet midpoint, posterior septal commissure) were simulated using commercial explicit dynamics software Ls-Dyna. Conclusion     For the two types of regurgitation in this study, clipping at the posterior leaflet midpoint resulted in a better reduction of the regurgitation orifice (up to 75% reduction in area). Higher clamping forces were required for implantation at the anterior leaflet midpoint and posterior septal commissure, which was unfavorable for the smooth closure of the clipping components. There was no statistical difference in the treatment outcomes between the 18T and 16T K-Clip components, and the 16T component required less clamping force. Therefore, the use of the 16T K-Clip component is recommended.

Cell atlas of CCl 4-induced progressive liver fibrosis reveals stage-specific responses.

Chronic liver injury leads to progressive liver fibrosis and ultimately cirrhosis, a major cause of morbidity and mortality worldwide. However, there are currently no effective anti-fibrotic therapies available, especially for late-stage patients, which is partly attributed to the major knowledge gap regarding liver cell heterogeneity and cell-specific responses in different fibrosis stages. To reveal the multicellular networks regulating mammalian liver fibrosis from mild to severe phenotypes, we generated a single-nucleus transcriptomic atlas encompassing 49 919 nuclei corresponding to all main liver cell types at different stages of murine carbon tetrachloride (CCl 4)-induced progressive liver fibrosis. Integrative analysis distinguished the sequential responses to injury of hepatocytes, hepatic stellate cells and endothelial cells. Moreover, we reconstructed cell-cell interactions and gene regulatory networks implicated in these processes. These integrative analyses uncovered previously overlooked aspects of hepatocyte proliferation exhaustion and disrupted pericentral metabolic functions, dysfunction for clearance by apoptosis of activated hepatic stellate cells, accumulation of pro-fibrotic signals, and the switch from an anti-angiogenic to a pro-angiogenic program during CCl 4-induced progressive liver fibrosis. Our dataset thus constitutes a useful resource for understanding the molecular basis of progressive liver fibrosis using a relevant animal model.

Membrane fusion-mediated delivery of small-molecule HER2 tyrosine kinase inhibitor for effective tumor chemosensitization.

Although nanocarriers have been widely applied in the delivery of anticancer drugs, many commercialized anticancer nanodrug systems still suffer from the problem of being easily trapped by lysosomes, which severely limits the drug delivery efficiency of a nanodrug system. Meanwhile, in drug-resistant tumors, the efflux of anticancer therapeutic drugs via the drug efflux transporters on the plasma membrane of cancer cells can significantly decrease the intracellular drug concentration and lead to the failure of the drug treatment. Here, we developed a small-molecule tyrosine kinase inhibitor (TKI)- and doxorubicin (Dox, a common anticancer drug)-loaded membrane fusion liposome (MFL) (termed Dox@Lapa-MFL) to achieve tumor cell membrane fusion-mediated drug delivery and enhanced chemotherapy of drug-resistant tumor. MFL could deliver drugs in a membrane fusion manner, circumventing the capture by lysosomes. Lapatinib, as the TKI doped in the MFL, could inhibit the efflux of Dox by ATP-binding cassette transporters (ABC transporters), further promoting the intracellular Dox accumulation. As a result, Dox achieved effective killing of drug-resistant tumors under the dual effect of MFL and lapatinib. To the best of our knowledge, it is the first example that employs membrane fusion-mediated TKI delivery for achieving tumor chemosensitization with good biosafety. This work presents an efficient and easily achievable strategy for treating drug-resistant tumors, which may hold promise for clinical applications.

Risk Factors for Thirty-Day Readmission Following Lumbar Surgery: A Meta-Analysis.

OBJECTIVE: Thirty-day readmission is one of the common complications after lumbar surgery. More 30-day readmission increases the total hospitalization, economic burden, and physical pain of patients, delays the progress of postoperative rehabilitation, and even lead to die. Therefore, it is necessary to analyze the risk factors of 30-day readmission following lumbar surgery. METHODS: We searched for all the clinical trials published from the establishment of the database to May 1, 2022 through the Cochrane Library, Web of Science, Embase, and PubMed. Data including age, American Society of Anesthesiology physical status class, preoperative hematocrit (Hct), diabetes mellitus (DM), current smoker, chronic obstructive pulmonary disease (COPD), length of hospital stay (LHS), operation time, and surgical site infection (SSI) were extracted. We used Review Manager 5.4 for data analysis. RESULTS: Six studies with 30,989 participants were eligible for this meta-analysis. The analysis revealed that there were statistically significant differences in the age (95% confidence interval [CI]: -3.35-2.90, P < 0.001), preoperative Hct (95% CI: 0.75-1.33, P < 0.001), DM (95% CI: 0.56-0.74, P < 0.001), COPD (95% CI: 0.38-0.58, P < 0.001), operation time (95% CI: -35.54-16.18, P < 0.001), LHS (95% CI: -0.54-0.50, P < 0.001), and SSI (95% CI: 0.02-0.03, P < 0.001) between no readmission and readmission groups. In terms of the American Society of Anesthesiology physical status class and current smoker, there was no significant effect on the 30-day readmission (P = 0.16 and P = 0.35 respectively). CONCLUSIONS: Age, preoperative Hct, DM, COPD, operation time, LHS, and SSI are the danger factors of 30-day readmission following lumbar surgery.

Meta-analysis comparing long-term outcomes of intersphincteric resection versus abdominoperineal resection for low rectal cancer / 中华胃肠外科杂志

Objective: To compare the long-term outcomes of intersphincteric (trans-internal and external) sphincter resection (ISR) and abdominoperineal proctocolectomy (APR) for low-grade rectal cancer. Methods: We used a meta-analytic approach to compare these procedures . Published reports comparing ISR and APR for low rectal cancer in Pubmed, Medline, EMBASE and Cochrane, China Knowledge Network (CNKI), China Biomedical Literature Database, and Vipers databases between January 2005 and January 2023 were searched and those meeting the eligibility criteria were selected for extraction of data for analysis. Inclusion criteria were as follows: (1) all reports comparing ISR and APR for low rectal cancer before January 2023; and (2) prospective randomized controlled studies or well-designed cohort studies. Exclusion criteria were as follows: (1) full text not available; (2) duplicate publications, missing primary outcome indicators, and unknown data; and (3) invalid statistical analysis. Results: Sixteen studies with 2498 patients were included in this study. Compared with the APR group, patients in the ISR group were relatively younger (weighted mean difference [WMD]=-1.82, 95%CI=-2.94 to -0.70, P=0.01), had tumors farther from the anal verge (WMD=0.43, 95%CI=0.18 to 0.67, P<0.01), and lower pathological T-stage (T3-4 stage: OR=0.54, 95%CI=0.36 to 0.81, P<0.01). In contrast, there were no statistically significant differences between the two groups in gender (P=0.78), body mass index (P=0.77), or pathological N stage (P=0.09). Compared with the APR group, patients in the ISR group had a lower rate of postoperative complications (OR=0.77, 95%CI=0.60 to 0.99, P=0.04), shorter hospital stay (WMD=-4.30, 95%CI=-7.07 to -1.53, P<0.01), higher 5-year overall survival (HR=0.54, 95%CI=0.33 to 0.88, P=0.01), and higher 5-year disease-free survival (HR=0.65, 95%CI=0.47 to 0.90, P<0.01). Five-year locoregional failure (HR=0.66, 95%CI=0.40 to 1.10, P=0.11) and time to surgery (WMD=-9.71, 95%CI=-41.89 to 22.47, P=0.55) did not differ significantly between the two groups. Conclusion: ISR is a safe and effective alternative to APR for early-stage low-grade rectal cancer.

The clinical effect of combining electroacupuncture with long needle sacral nerve stimulation in the treatment of diabetic overactive bladder / 中华物理医学与康复杂志

Objective:To observe the clinical efficacy of combining electroacupuncture with long needle sacral nerve acupuncture in the treatment of diabetic overactive bladder.Methods:A total of 90 patients with diabetic overactive bladder were randomly divided into an observation group and a control group, each of 45. In addition to the basic treatment for diabetes, the observation group received electroacupuncture combined with long needle sacral nerve acupuncture 5 times a week for 4 weeks, while the control group was given 5mg of oral solinax succinate once a day as a course of treatment. One week before the beginning of the experiment and one week before its end, urination diary cards were used to record the average number of times of daytime and nighttime urination daily, as well as any urgent urination and urinary incontinence during the week. Bladder overactivity syndrome score (OABSS), the bladder overactivity quality of life questionnaire (OAB-q), maximum urine flow rate (Qmax) and mean urine flow rate (Qave) were employed to quantify urination status, life quality and the urodynamics of the 2 groups before and after the treatment.Results:After the treatment, significant improvement was observed in the average weekly incidence of daytime and nighttime urination, of urgent urination and of urinary incontinence. The average OABSS, OAB-q, Qmax and Qave scores improved in both groups, but the experimental group showed significantly better improvement than the control group.Conclusion:Electroacupuncture combined with sacral nerve needling can significantly reduce the frequency of urination, relieve the symptoms of urgent urination and incontinence, and improve the rate of urine flow, improving the life quality of patients with diabetic overactive bladder.

An EGFR L858R mutation identified in 1862 Chinese NSCLC patients can be a promising neoantigen vaccine therapeutic strategy.

Background: This study aimed to develop a vaccine that targets mutation-derived neoantigen in Chinese non-small-cell lung cancer (NSCLC). Methods: A cohort of 1862 Chinese NSCLC patients who underwent targeted sequencing with a 1021-gene panel was investigated. HLA typing was done using OptiType v1.0 and neoantigens were predicted by netMHCpan v4.0. HLA LOH was inferred using the lohhla algorithm and TMB were quantified by counting the total number of non-synonymous ones based on our panel data. CIBERSORT was utilized to estimate the TME in different EGFR mutant subtype by using TCGA data. Results: HLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th. EGFR L858R (22.61%) was the most prevalent gene variant. The binding affinity (IC50 MT = 22.9 nM) and shared frequency (2.93%) of EGFR L858R in combination with HLA-A*33:03 were optimal. In a subsequent further analysis on immunological features of EGFR mutant subtypes, 63.1% HLA loss of heterozygosity LOH (HLA LOH) and 0.37% (7 of 1862) B2M aberrations were found in our population, both had no significant association with EGFR mutant subtypes suggesting that the process of antigen presentation involved HLA LOH and B2M mechanisms in EGFR L858R is working. Tumor mutation burden (TMB) was investigated by utilizing our panel and showed that EGFR L858R had the lowest TMB compared with other EGFR mutant subtypes. In addition, analysis of 22 immune cell types from The Cancer Genome Atlas (TCGA) data showed EGFR L858R was correlated with low level of CD8 T cells, activated CD4 memory T cells and elevated level of macrophage M2 suggesting an inhibited tumor microenvironment (TME). Conclusion: Our study identified that EGFR L858R neoantigen had the potential to generate cancer vaccines in NSCLC patients with HLA A*33:03. The neoantigen-based vaccines may become an effective salvage regimen for EGFR L858R subgroup after targeted therapy or immune checkpoint inhibitors (ICIs) failure.

Jujuboside A ameliorates tubulointerstitial fibrosis in diabetic mice through down-regulating the YY1/TGF-ß1 signaling pathway.

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus, which is characterized in renal tubulointerstitial fibrosis (TIF). The current study was designed to investigate the protective effect of Jujuboside A (Ju A) on TIF in type 2 diabetes (T2DM) mice, and explore its underlying anti-fibrosis mechanism. A mouse T2DM model was established using high fat diet (HFD) feeding combined with intraperitoneal injection of streptozotocin (STZ). Then, diabetic mice were treated with Ju A (10, 20 and 40 mg·kg-1·d-1, i.g.) for 12 weeks. Results showed that administration of Ju A not only down-regulated fasting blood glucose (FBG) levels, but also improved hyperlipidemia and renal function in diabetic mice. Moreover, the reduced ECM accumulation was observed in the renal cortex of Ju A treated diabetic mice, while the TIF progression was also attenuated by Ju A through blocking the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells (RTECs). Further mechanism studies showed that Ju A treatment effectively down-regulated the protein expression and subsequent nuclear translocation of Yin Yang 1 (YY1) in the renal cortex of diabetic mice, and reduced the levels of transforming growth factor-ß1 (TGF-ß1) in the serum and renal cortex of Ju A treated mice. According to invitro studies, the up-regulated YY1/TGF-ß1 signaling pathway was restored by Ju A in high glucose (HG) cultured HK-2 cells. Taken together, these findings demonstrated that Ju A can ameliorate the TIF of DN through down-regulating the YY1/TGF-ß1 signaling pathway.

KLF16 enhances stress tolerance of colorectal carcinomas by modulating nucleolar homeostasis and translational reprogramming.

Translational reprogramming is part of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, which acts to the advantage of cancer growth and development in different stress conditions, but the mechanism of ER stress-related translational reprogramming in colorectal carcinoma (CRC) progression remains unclear. Here, we identified that Krüppel-like factor 16 (KLF16) can promote CRC progression and stress tolerance through translational reprogramming. The expression of KLF16 was upregulated in CRC tissues and associated with poor prognosis for CRC patients. We found that ER stress inducers can recruit KLF16 to the nucleolus and increase its interaction with two essential proteins for nucleolar homeostasis: nucleophosmin1 (NPM1) and fibrillarin (FBL). Moreover, knockdown of KLF16 can dysregulate nucleolar homeostasis in CRC cells. Translation-reporter system and polysome profiling assays further showed that KLF16 can effectively promote cap-independent translation of ATF4, which can enhance ER-phagy and the proliferation of CRC cells. Overall, our study unveils a previously unrecognized role for KLF16 as an ER stress regulator through mediating translational reprogramming to enhance the stress tolerance of CRC cells and provides a potential therapeutic vulnerability.

Severe tinnitus and migraine headache in a 37-year-old woman treated with trastuzumab for breast cancer: A case report.

BACKGROUND: Trastuzumab is a generally safe agent prescribed in the systemic treatment of breast cancer. Tinnitus is not a currently known adverse event related to trastuzumab. Here, we describe a rare case of severe tinnitus and a migraine headache induced by trastuzumab used for adjuvant therapy. CASE SUMMARY: A 37-year-old woman was diagnosed with hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer. After surgery, she was treated with four cycles of epirubicin and cyclophosphamide; she then received docetaxel and a loading dose of trastuzumab plus pertuzumab. Less than half an hour after trastuzumab infusion, the patient complained of severe tinnitus and left-sided migraine headache. Trastuzumab monotherapy was discontinued immediately, and symptoms disappeared after 10 min. Trastuzumab was readministered, and severe tinnitus and migraine headache recurred. Trastuzumab was stopped, and severe tinnitus diminished after 10 min. Pertuzumab and docetaxel therapy was then administered, and no adverse events were observed. Subsequent infusions of trastuzumab every three weeks did not show the same symptoms. CONCLUSION: Although trastuzumab is well-tolerated in most patients, we should pay attention to the risk of severe tinnitus and migraine.

Comparison of comfort and complications of Implantable Venous Access Port (IVAP) with ultrasound guided Internal Jugular Vein (IJV) and Axillary Vein/Subclavian Vein (AxV/SCV) puncture in breast cancer patients: a randomized controlled study.

BACKGROUND: Axillary vein/subclavian vein (AxV/SCV) and Internal jugular vein (IJV) are commonly used for implantable venous access port (IVAP) implantation in breast cancer patients for chemotherapy. Previous research focused on comparison of complications while patient comfort was ignored. This study aims to compare patient comfort, surgery duration and complications of IVAP implantation between IJV and AxV/SCV approaches. METHODS: Two hundred forty-eight breast cancer patients were enrolled in this randomized controlled study from August 2020 to June 2021. Patients scheduled to undergo IVAP implantation were randomly and equally assigned to receive central venous catheters with either AxV /SCV or IJV approaches. All patients received comfort assessment using a comfort scale table at day 1, day 2 and day 7 after implantation. Patient comfort, procedure time of operation as well as early complications were compared. RESULTS: Patient comfort was significantly better in the AxV/SCV group than that of IJV group in day 1 (P < 0.001), day 2 (P < 0.001) and day 7(P = 0.023). Procedure duration in AxV/SCV group was slightly but significantly shorter than IJV group (27.14 ± 3.29 mins vs 28.92 ± 2.54 mins, P < 0.001). More early complications occurred in AxV/SCV group than IJV group (11/124 vs 2/124, P = 0.019). No difference of complications of artery puncture, pneumothorax or subcutaneous hematoma between these two groups but significantly more catheter misplacement in AxV/SCV group than IJV group (6/124 vs 0/124, P = 0.029). Absolutely total risk of complications was rather low in both groups (8.87% in AxV/SCV group and 1.61% in IJV group). CONCLUSIONS: Our study indicates that patients with AxV/SCV puncture have higher comfort levels than IJV puncture. AxV/SCV puncture has shorter procedure duration but higher risk of early complications, especially catheter misplacement. Both these two approaches have rather low risk of complications. Consequently, our study provides an alternative choice for breast cancer patients to reach better comfort.

Highly penetrable nanoparticles co-loading doxorubicin and IDO1 siRNA enhance tumor immunotherapy / 药学学报

There are two serious obstacles to tumor immunotherapy. Firstly, the immune response of the tumor is seriously reduced due to immunosuppressive tumor microenvironment (ITM) and low immunogenicity of tumor. The second obstacle is the dense and complex heterogeneous structures, which seriously prevent the nanoparticles (NPs) from penetrating deeper into tumor tissue. Immunogenic cell death (ICD) induced by doxorubicin (DOX) is an effective method to enhance tumor immune activity. However, interferon-γ (IFN-γ) secreted by cytotoxic T lymphocytes (CTL) after ICD induction would increase the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and enhance ITM. IDO1 siRNA would reduce the expression of IDO1 protein, regulate the tumor immunosuppressive microenvironment and regulate ITM, so as to enhance the ICD effect of DOX. In this paper, a novel charge conversional, particle size reduction and highly penetrable NPs based on a pH sensitive copolymer poly(ethylene glycol)-poly-L-lysine-2,3-dimethylmaleic anhydride (mPEG-PLL-DMA, PLD) and polyamidoamine (PAMAM) dendrimers to achieve deep delivery of tumor tissue. DOX and IDO1 siRNA were encapsulated to achieve efficient tumor immunotherapy. Preparation and cell level experiments showed that PLD material had significant pH sensitivity. Results of 3D tumor penetrable experiment in vitro showed that adding the pH sensitive material PLD significantly improved the permeability of the preparation. In addition, 4T1 tumor model was established for BALB/c mice and all animal experiments were displayed in according with the requirements of the Animal Experiment Ethics Committee of Shenyang Pharmaceutical University. The results of in vivo efficacy experiments and tissue experiments evaluated that IDO1 siRNA significantly improved the ICD effect owing to DOX, so as to significantly inhibit tumor growth.

Birth weight curves of singleton neonates with a gestational age of 24-42 weeks and their regional differences in 11 cities of China: an analysis of 93 720 cases / 中国当代儿科杂志

OBJECTIVES@#To develop the birth weight curve of singleton neonates with a gestational age of 24-42 weeks, and to investigate the regional differences of the birth weight curve.@*METHODS@#A total of 11 maternal and child health hospitals with more than 7 000 neonates delivered annually were selected in 11 cities of China (Haikou, Guangzhou, Shenzhen, Liuzhou, Guilin, Quanzhou, Chongqing, Chengdu, Changsha, Ningbo, and Lianyungang), and all live singleton neonates delivered in the 11 hospitals from January 1, 2017 to December 31, 2020 were enrolled for the development of birth weight curves.@*RESULTS@#A total of 93 720 singleton neonates with a gestational age of 24-42 weeks from the 11 cities were included in the study. The reference values of the 3rd-97th percentiles of birth weight of singleton neonates for the total of the 11 cities and for each of the 11 cities were established, and the birth weight percentile curves were drawn. The birth weight curve level of singleton neonates in Shenzhen and Quanzhou was almost the same as the average level of the 11 cities; the birth weight curve level of singleton neonates in Haikou, Guangzhou, Guilin, and Liuzhou was slightly lower than the average level of the 11 cities; the birth weight curve level of singleton neonates in Chongqing, Chengdu, and Changsha was slightly higher than the average level of the 11 cities; the birth weight curve level of singleton neonates in Ningbo and Lianyungang was higher than the average level of the 11 cities. The average birth weight curve level of singleton neonates in the 11 cities were very close to that of China Neonatal Cooperation Network in 2011-2014.@*CONCLUSIONS@#The reference values of the 3rd-97th percentiles of birth weight of singleton neonates for the total of the 11 cities and for each of the 11 cities are developed, which can be used as a reference for evaluating the intrauterine growth of singleton neonates in the region. The level of intrauterine growth of neonates in some cities is different from the national level.

Research progress of tumor microenvironmentally regulating organelle targeted drug delivery system / 药学学报

In recent years, the use of the body's immune system for anti-tumor immunotherapy has received extensive attention. However, the immunosuppressive tumor microenvironment (TME) limits the effect of immunotherapy. Therefore, overcoming the limitations of TME and immunosuppressive cells plays an important role in tumor immunotherapy. Nano agents have great potential to reprogram the immunosuppressive microenvironment and provide an effective strategy for immunotherapy. With the continuous development of active targeting nano carrier technology and the deepening of the research on drug action sites, subcellular organ targeting nano carrier materials with more accurate active targeting function have also attracted more and more attention. This review will briefly introduce the relationship between subcellular organelles and tumor, summarize the design strategy and research progress of targeted nano drug delivery system based on the characteristics of acidity, reactive oxygen species (ROS) activity, immunogenicity, and TME of immunosuppressive cells, to provide reference for the construction of subcellular pathway targeted drug delivery system in tumor immunotherapy.