PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway.

Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase ß1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway.

N4-acetylcytidine modifies primary microRNAs for processing in cancer cells.

N4 acetylcytidine (ac4C) modification mainly occurs on tRNA, rRNA, and mRNA, playing an important role in the expression of genetic information. However, it is still unclear whether microRNAs have undergone ac4C modification and their potential physiological and pathological functions. In this study, we identified that NAT10/THUMPD1 acetylates primary microRNAs (pri-miRNAs) with ac4C modification. Knockdown of NAT10 suppresses and augments the expression levels of mature miRNAs and pri-miRNAs, respectively. Molecular mechanism studies found that pri-miRNA ac4C promotes the processing of pri-miRNA into precursor miRNA (pre-miRNA) by enhancing the interaction of pri-miRNA and DGCR8, thereby increasing the biogenesis of mature miRNA. Knockdown of NAT10 attenuates the oncogenic characters of lung cancer cells by regulating miRNA production in cancers. Moreover, NAT10 is highly expressed in various clinical cancers and negatively correlated with poor prognosis. Thus, our results reveal that NAT10 plays a crucial role in cancer initiation and progression by modulating pri-miRNA ac4C to affect miRNA production, which would provide an attractive therapeutic strategy for cancers.

Prediabetes is associated with increased cardiac events in patients with cancer who are prescribed anthracyclines.

BACKGROUND: Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. METHODS: The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. RESULTS: Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. CONCLUSIONS: In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. PLAIN LANGUAGE SUMMARY: Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.

Deletion of GPR81 activates CREB/Smad7 pathway and alleviates liver fibrosis in mice.

BACKGROUND: Enhanced glycolysis is a crucial metabolic event that drives the development of liver fibrosis, but the molecular mechanisms have not been fully understood. Lactate is the endproduct of glycolysis, which has recently been identified as a bioactive metabolite binding to G-protein-coupled receptor 81 (GPR81). We then questioned whether GPR81 is implicated in the development of liver fibrosis. METHODS: The level of GPR81 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and in transforming growth factor beta 1 (TGF-ß1)-activated hepatic stellate cells (HSCs) LX-2. To investigate the significance of GPR81 in liver fibrosis, wild-type (WT) and GPR81 knockout (KO) mice were exposed to CCl4, and then the degree of liver fibrosis was determined. In addition, the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) was supplemented in CCl4-challenged mice and TGF-ß1-activated LX-2 cells to further investigate the pathological roles of GPR81 on HSCs activation. RESULTS: CCl4 exposure or TGF-ß1 stimulation significantly upregulated the expression of GPR81, while deletion of GPR81 alleviated CCl4-induced elevation of aminotransferase, production of pro-inflammatory cytokines, and deposition of collagen. Consistently, the production of TGF-ß1, the expression of alpha-smooth muscle actin (α-SMA) and collagen I (COL1A1), as well as the elevation of hydroxyproline were suppressed in GPR81 deficient mice. Supplementation with DHBA enhanced CCl4-induced liver fibrogenesis in WT mice but not in GPR81 KO mice. DHBA also promoted TGF-ß1-induced LX-2 activation. Mechanistically, GPR81 suppressed cAMP/CREB and then inhibited the expression of Smad7, a negative regulator of Smad3, which resulted in increased phosphorylation of Smad3 and enhanced activation of HSCs. CONCLUSION: GPR81 might be a detrimental factor that promotes the development of liver fibrosis by regulating CREB/Smad7 pathway.

Alteration of the gut microbiome in patients with heart failure: A systematic review and meta-analysis.

Recent research has revealed that alterations of the gut microbiome (GM) play a comprehensive role in the pathophysiology of HF. However, findings in this field remain controversial. In this study, we focus on differences in GM diversity and abundance between HF patients and non-HF people, based on previous 16 S ribosomal RNA (16rRNA) gene sequencing. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search of PubMed, Web of Science, Embase, Cochrane Library, and Ovid databases using the keyword "Heart failure" and "Gastrointestinal Microbiome". A significant decrease in alpha diversity was observed in the HF patients (Chao1, I2 = 87.5 %, p < 0.001; Shannon index, I2 = 62.8 %, p = 0.021). At the phylum level, the HF group exhibited higher abundances of Proteobacteria (I2 = 92.0 %, p = 0.004) and Actinobacteria (I2 = 82.5 %, p = 0.010), while Bacteroidetes (I2 = 45.1 %, p = 0.017) and F/B ratio (I2 = 0.0 %, p＜0.001) were lower. The Firmicutes showed a decreasing trend but did not reach statistical significance (I2 = 82.3 %, p = 0.127). At the genus level, the relative abundances of Streptococcus, Bacteroides, Alistipes, Bifidobacterium, Escherichia-Shigella, Enterococcus and Klebsiella were increased in the HF group, whereas Ruminococcus, Faecalibacterium, Dorea and Megamona exhibited decreased relative abundances. Dialister, Blautia and Prevotella showed decreasing trends but without statistical significance. This observational meta-analysis suggests that GM changes are associated with HF, manifesting as alterations in GM abundance, disruptions in the production of short-chain fatty acids (SCFAs) bacteria, and an increase in trimethylamine N-oxide (TMAO) producing bacteria.

A Comprehensive Investigation of Dietary Micronutrient Intakes and Risk of Alcoholic Liver Disease.

BACKGROUND: The investigation of dietary micronutrient intakes and risk of alcoholic liver disease (ALD) based on observational studies was limited. OBJECTIVES: Our study aimed to explore the associations of 30 dietary micronutrients intakes with risk of ALD, interactions between dietary micronutrients and genetic variation, and mediation effects of blood and urinary biomarkers on the associations between dietary micronutrients and risk of ALD. METHODS: A case-control study was conducted within the UK Biobank cohort, with 231 incident ALD cases and 1386 controls. Dietary data were collected using a dietary questionnaire that relied on a 24-h dietary recall of the previous day. Logistic regression models were employed to assess the associations of dietary micronutrient intakes with risk of ALD. We conducted stratified analyses on the associations between dietary micronutrient intakes and risk of ALD by PNPLA3 rs738409 and tested the interactions between dietary micronutrients and genetic variation. In addition, we conducted mediation analyses to investigate the mediating effects of biomarkers on the associations between dietary micronutrients and risk of ALD. RESULTS: Our findings indicated significant inverse associations of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B-6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese with risk of ALD (all false discovery rate-Ptrend < 0.050). We also found a significant interaction between PNPLA3 rs738409 and magnesium (Pinteraction = 0.028). Creatinine (enzymatic) in urine, aspartate aminotransferase, and insulin-like growth factor 1 were the top 3 biomarkers with the highest number of significant mediation effects on the associations between the dietary micronutrients and risk of ALD. CONCLUSIONS: Dietary intakes of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B-6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese were inversely associated with risk of ALD.

Olverembatinib treatment in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

Olverembatinib is a novel orally administered third-generation tyrosine kinase inhibitor (TKI) with definitive responses in T315I-mutant chronic myeloid leukemia (CML) patients. However, its value in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remained unclarified. In this multiple-center study, 20 patients with de novo Ph + ALL were treated with olverembatinib-based regimens as frontline therapy. All patients acquired complete remission (CR) after induction. 85% of patients achieved complete molecular response (CMR) within three months, contributed mainly by the addition of blinatumomab. A total of 45% of patients experienced mild hematological treatment-related adverse events (TRAEs). Olverembatinib-based treatment led to promising outcomes in de novo Ph + ALL patients but warranted further studies to investigate the best-combined strategy.

Development and Validation of MRI Radiomics Models to Differentiate HER2-Zero, -Low, and -Positive Breast Cancer.

BACKGROUND. Breast cancer HER2 expression has been redefined using a three-tiered system, with HER2-zero cancers considered ineligible for HER2-targeted therapy, HER2-low cancers considered candidates for novel HER2-targeted drugs, and HER2-positive cancers treated with traditional HER2-targeted medications. OBJECTIVE. The purpose of this study was to assess MRI radiomics models for a three-tiered classification of HER2 expression of breast cancer. METHODS. This retrospective study included 592 patients with pathologically confirmed breast cancer (mean age, 47.0 ± 18.0 [SD] years) who underwent breast MRI at either of a health system's two hospitals from April 2016 through June 2022. Three-tiered HER2 status was pathologically determined. Radiologists assessed the conventional MRI features of tumors and manually segmented the tumors on multiparametric sequences (T2-weighted images, DWI, ADC maps, and T1-weighted delayed contrast-enhanced images) to extract radiomics features. Least absolute shrinkage and selection operator analysis was used to develop two radiomics signatures, to differentiate HER2-zero cancers from HER2-low or HER2-positive cancers (task 1) as well as to differentiate HER2-low cancers from HER2-positive cancers (task 2). Patients from hospital 1 were randomly assigned to a discovery set (task 1: n = 376; task 2: n = 335) or an internal validation set (task 1: n = 161; task 2: n = 143); patients from hospital 2 formed an external validation set (task 1: n = 55; task 2: n = 50). Multivariable logistic regression analysis was used to create nomograms combining radiomics signatures with clinicopathologic and conventional MRI features. RESULTS. AUC, sensitivity, and specificity in the discovery, internal validation, and external validation sets were as follows: for task 1, 0.89, 99.4%, and 69.0%; 0.86, 98.6%, and 76.5%; and 0.78, 100.0%, and 0.0%, respectively; for task 2, 0.77, 93.8%, and 32.3%; 0.75, 92.9%, and 6.8%; and 0.77, 97.0%, and 29.4%, respectively. For task 1, no nomogram was created because no clinicopathologic or conventional MRI feature was associated with HER2 status independent of the MRI radiomics signature. For task 2, a nomogram including an MRI radiomics signature and three pathologic features (histologic grade of III, high Ki-67 index, and positive progesterone receptor status) that were independently associated with HER2-low expression had an AUC of 0.87, 0.83, and 0.80 in the three sets. CONCLUSION. MRI radiomics features were used to differentiate HER2-zero from HER2-low cancers or HER2-positives cancers as well as to differentiate HER2-low cancers from HER2-positive cancers. CLINICAL IMPACT. MRI radiomics may help select patients for novel or traditional HER2-targeted therapies, particularly those patients with ambiguous results of immunohistochemical staining results or limited access to fluorescence in situ hybridization.

Agrimol B alleviates cisplatin-induced acute kidney injury by activating the Sirt1/Nrf2 signaling pathway in mice.

Cisplatin (CDDP) is a widely used chemotherapeutic agent that has remarkable antineoplastic effects. However, CDDP can cause severe acute kidney injury (AKI), which limits its clinical application. Agrimol B is the main active ingredient found in Agrimonia pilosa Ledeb and has a variety of pharmacological activities. The effect of agrimol B on CDDP-induced renal toxicity has not been determined. To investigate whether agrimol B has a protective effect against CDDP-induced AKI, we first identify Sirtuin 1 (Sirt1) as a critical target protein of agrimol B in regulating AKI through network pharmacology analysis. Subsequently, the AKI mouse model is induced by administering a single dose of CDDP via intraperitoneal injection. By detecting the serum urea nitrogen and creatinine levels, as well as the histopathological changes, we confirm that agrimol B effectively reduces CDDP-induced AKI. In addition, treatment with agrimol B counteracts the increase in renal malondialdehyde level and the decrease in superoxide dismutase (SOD), catalase and glutathione levels induced by CDDP. Moreover, western blot results reveal that agrimol B upregulates the expressions of Sirt1, SOD2, nuclear factor erythroid2-related factor 2, and downstream molecules, including heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1. However, administration of the Sirt1 inhibitor EX527 abolishes the effects of agrimol B. Finally, we establish a tumor-bearing mouse model and find that agrimol B has a synergistic antitumor effect with CDDP. Overall, agrimol B attenuates CDDP-induced AKI by activating the Sirt1/Nrf2 signaling pathway to counteract oxidative stress, suggesting that this compound is a potential therapeutic agent for the treatment of CDDP-induced AKI.

A fluorescent terbium-metal-organic framework material for high-sensitivity detection of vomitoxin and oxytetracycline hydrochloride in water.

A unique luminescent lanthanide metal-organic framework (LnMOF)-based fluorescence detection platform was utilized to achieve sensitive detection of vomitoxin (VT) and oxytetracycline hydrochloride (OTC-HCL) without the use of antibodies or biomolecular modifications. The sensor had a fluorescence quenching constant of 9.74 × 106 M-1 and a low detection limit of 0.68 nM for vomitoxin. Notably, this is the first example of a Tb-MOF sensor for fluorescence detection of vomitoxin. We further investigated its response to two mycotoxins, aflatoxin B1 and ochratoxin A, and found that their Stern-Volmer fluorescence quenching constants were lower than those of VT. In addition, the fluorescence sensor realized sensitive detection of OTC-HCL with a detection limit of 0.039 µM. In conclusion, the method has great potential as a sensitive and simple technique to detect VT and OTC-HCL in water.

Discovery of a Pimaradiene that Decreases Viability of MDA-MB-468 Cells Through Inhibition of EGFR Signaling Pathway.

Triple-negative breast cancer (TNBC) is characterized by strong invasiveness, high relapse rates, and poor overall survival. It occurs in approximately 15-20 % of all breast cancer cases. Natural compounds are a promising option for managing breast cancer. ent-8(14),15-Pimaradiene-2ß,19-diol (JXE-23), is a pimaradiene isolated from the fern Aleuritopteris albofusca. However, the effects and molecular mechanisms of JXE-23 on cancer cells are still unknown. Thus, this study was designed to determine the potential of JXE-23 for its anticancer properties in TNBC cells. JXE-23 was evaluated for its antiproliferative activity in vitro against human breast cancer cell lines, and showed selectively cytotoxic activity against MDA-MB-468, an EGFR-overexpressing TNBC cancer cell line, with an IC50 value of 1.17±0.04 µM. Moreover, mechanistic investigations indicated that JXE-23 was significantly capable of inhibiting cell proliferation and viability in MDA-MB-468 cells. In addition, JXE-23 exerted an anticancer effect against MDA-MB-468 cells via restraining cell migration in a dose-dependent mode. Moreover, after treatment with JXE-23, the protein expressions of pEGFR, pERK, pAkt and p-p70S6K were significantly reduced in MDA-MB-468 cells. The results underscored that JXE-23 could be a potential lead compound for the treatment of EGFR-overexpressing TNBC cells.

LPS-induced senescence of macrophages aggravates calcification and senescence of vascular smooth muscle cells via IFITM3.

BACKGROUND: Cellular senescence, macrophages infiltration, and vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation participate in the pathophysiology of vascular calcification in chronic kidney disease (CKD). Senescent macrophages are involved in the regulation of inflammation in pathological diseases. In addition, senescent cells spread senescence to neighboring cells via Interferon-induced transmembrane protein3 (IFITM3). However, the role of senescent macrophages and IFITM3 in VSMCs calcification remains unexplored. AIMS: To explore the hypothesis that senescent macrophages contribute to the calcification and senescence of VSMCs via IFITM3. METHODS: Here, the macrophage senescence model was established using Lipopolysaccharides (LPS). The VSMCs were subjected to supernatants from macrophages (MCFS) or LPS-induced macrophages (LPS-MCFS) in the presence or absence of calcifying media (CM). Senescence-associated ß-galactosidase (SA-ß-gal), Alizarin red (AR), immunofluorescent staining, and western blot were used to identify cell senescence and calcification. RESULTS: The expression of IFITM3 was significantly increased in LPS-induced macrophages and the supernatants. The VSMCs transdifferentiated into osteogenic phenotype, expressing higher osteogenic differentiation markers (RUNX2) and lower VSMCs constructive makers (SM22α) when cultured with senescent macrophages supernatants. Also, senescence markers (p16 and p21) in VSMCs were significantly increased by senescent macrophages supernatants treated. However, IFITM3 knockdown inhibited this process. CONCLUSIONS: Our study showed that LPS-induced senescence of macrophages accelerated the calcification of VSMCs via IFITM3. These data provide a new perspective linking VC and aging, which may provide clues for diagnosing and treating accelerated vascular aging in patients with CKD.

The other-ethnicity effect in facial recognition of Tibetan and Han individuals: Evidence from behavioural and eye-movement data.

Studies have shown that facial recognition among racial groups exhibits not only an other-race effect but also an other-ethnicity effect within the same racial group. To explore differences in facial recognition and visual scanning patterns due to the other-ethnicity effect, behavioural and eye-movement data were used to investigate the other-ethnicity effect in the facial perception of Tibetan and Han Chinese individuals and whether the visual scanning patterns varied between them. Behavioural data revealed an other-ethnicity effect on facial recognition of Tibetan and Han individuals. Eye-movement data indicated that Tibetan and Han individuals fixated more on the eye and mouth regions when recognising Han faces and on the eye and nose regions when recognising Tibetan faces. The other-ethnicity effect appeared to influence facial recognition in Tibetan and Han individuals, who adopted similar visual scanning patterns when scanning the faces of individuals of their own ethnicity and those of other ethnicities.

Ubiquitin ligase Triad1 promotes neurite outgrowth by inhibiting MDM2-mediated ubiquitination of the neuroprotective factor pleiotrophin.

Spinal cord injury (SCI) is the most severe result of spine injury, but no effective therapy exists to treat SCI. We have previously shown that the E3 ubiquitin ligase Two RING fingers and DRIL 1 (Triad1) promotes neurite outgrowth after SCI. However, the mechanism by which Triad1 affects neuron growth and the potential involvement of its ubiquitination activity is unclear. Neuroprotective cytokine pleiotrophin (PTN) can promote microglia proliferation and neurotrophic factor secretion to achieve neuroprotection. We find using immunostaining and behavioral assays in rats that the expression of Triad1 and the PTN was peaked at 1 day after SCI and Triad1 improved motor function and histomorphological injury after SCI. We show using flow cytometry and astrocyte/neuronal coculture assays that Triad1 overexpression promoted PTN protein levels, neurotrophic growth factor (NGF) expression, brain-derived neurotrophic factor (BDNF) expression, astrocyte and neuronal viability, and neurite outgrowth but suppressed astrocyte apoptosis, while shRNA-mediated knockdown of Triad1 and PTN had the opposite effects. Ubiquitin ligase murine double mutant 2 (MDM2) has previously been demonstrated to participate in the process of neurite outgrowth and mediate ubiquitination of p53. Furthermore, we demonstrate overexpression of MDM2 downregulated PTN protein levels, NGF expression and BDNF expression in astrocytes, and inhibited neurite outgrowth of neurons. In addition, MDM2 facilitated PTN ubiquitination, which was reversed by Triad1. Finally, we show simultaneous sh-PTN and MDM2 overexpression attenuated the neurite outgrowth-promoting effect of Triad1 overexpression. In conclusion, we propose Triad1 promotes astrocyte-dependent neurite outgrowth to accelerate recovery after SCI by inhibiting MDM2-mediated PTN ubiquitination.

Pyrotinib combined with trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer: a single-arm exploratory phase II trial.

PURPOSE: A substantial need for effective and safe treatment options is still unmet for patients with heavily pre-treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Herein, we assessed the efficacy and safety of pyrotinib plus trastuzumab and chemotherapy in patients with heavily treated HER2-positive MBC. METHODS: In this single-arm exploratory phase II trial, patients with HER2-positive MBC previously treated with trastuzumab plus lapatinib or pertuzumab, received pyrotinib plus trastuzumab and chemotherapy. The primary end point was progression-free survival (PFS) in the total population (TP). Secondary end points included PFS in the subgroup with brain metastases (Sub-BrM), confirmed objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), exploration of predictive factors of PFS, and safety. RESULTS: Between November 1, 2018, and March 31, 2021, 40 patients were eligible for this study. The median PFS reached 7.5 months (95% confidence interval [CI] 4.7 to 9.9 months) and 9.4 months (95% CI 6.6 to 12.1 months) in the TP and Sub-BrM, respectively. ORR was 50.5% (20/40). CBR was 75.5% (30/40) and DCR reached 97.5% (39/40). Cox univariate and multivariate analyses demonstrated that liver or/and lung metastases was the significant adverse prognostic factor for PFS (p = 0.018; p = 0.026; respectively). The most frequent grade 3 or 4 treatment-related adverse events were diarrhea, neutropenia and leukopenia. No new safety signals were observed. CONCLUSION: Pyrotinib plus trastuzumab and chemotherapy offered a promising option with manageable safety profile for heavily pre-treated HER2-positive MBC, especially for those without liver or/and lung metastases.

The possibilities of LOXL4 as a prognostic marker for carcinomas.

Lysyl oxidase-like 4 (LOXL4), a member of lysyl oxidase family, is a copper and lysine tyrosylquinone-dependent amine oxidase that serves the role of catalyzing the cross-linking of elastin and collagen in the extracellular matrix. Numerous studies have shown a significant association between LOXL4 expression levels and tumor proliferation, migration, invasion and patients' prognosis and overall survival in different types of tumors. Here we review their relationship and the molecular pathogenesis behind them, aiming to explore the possibilities of LOXL4 as a prognostic marker for diverse carcinomas and provide some indications for further research in this field.

Chronic kidney disease begets heart failure and vice versa: temporal associations between heart failure events in relation to incident chronic kidney disease in type 2 diabetes.

AIM: To investigate the interplay of incident chronic kidney disease (CKD) and/or heart failure (HF) and their associations with prognosis in a large, population-based cohort with type 2 diabetes (T2DM). METHODS: Patients aged ≥18 years with new-onset T2DM, without renal disease or HF at baseline, were identified from the territory-wide Clinical Data Analysis Reporting System between 2000 and 2015. Patients were followed up until December 31, 2020 for incident CKD and/or HF and all-cause mortality. RESULTS: Among 102 488 patients (median age 66 years, 45.7% women, median follow-up 7.5 years), new-onset CKD occurred in 14 798 patients (14.4%), in whom 21.7% had HF. In contrast, among 9258 patients (9.0%) with new-onset HF, 34.6% had CKD. The median time from baseline to incident CKD or HF (4.4 vs. 4.1 years) did not differ. However, the median (interquartile range) time until incident HF after CKD diagnosis was 1.7 (0.5-3.6) years and was 1.2 (0.2-3.4) years for incident CKD after HF diagnosis (P < 0.001). The crude incidence of CKD was higher than that of HF: 17.6 (95% confidence interval [CI] 17.3-17.9) vs. 10.6 (95% CI 10.4-10.9)/1000 person-years, respectively, but incident HF was associated with a higher adjusted-mortality than incident CKD. The presence of either condition (vs. CKD/HF-free status) was associated with a three-fold hazard of death, whereas concomitant HF and CKD conferred a six to seven-fold adjusted hazard of mortality. CONCLUSION: Cardiorenal complications are common and are associated with high mortality risk among patients with new-onset T2DM. Close surveillance of these dual complications is crucial to reduce the burden of disease.

Distribution of fresh foods in food pantries: challenges and opportunities in Illinois during the COVID-19 pandemic.

BACKGROUND: The charitable food system distributes free food to clients across the U.S., but many nutrition and health-focused efforts encounter barriers to success, which were exacerbated during the COVID-19 pandemic. The objective of the current study was to understand barriers and facilitators to distributing nutritious, fresh foods in food pantries across Illinois during the COVID-19 pandemic. METHODS: Forty-nine pantry representatives participated in focus groups in October 2021. A codebook was created based on relevant literature, stakeholder interests, and an initial review of the recordings. Transcripts of each group were coded and analyzed using a basic interpretive approach. RESULTS: Pantries distribution of fresh foods was impacted by community partners, food bank policies and practices, and the quality of the donated fresh foods. Physical constraints of pantries limit fresh food storage capacity. The COVID-19 pandemic magnified stressors in the charitable food system which highlighted how community partners might improve fresh food distribution. CONCLUSION: Focus groups with food pantry representatives across Illinois provided key insights that can inform future efforts to facilitate fresh food distribution in the charitable food system. Future studies should evaluate the effects of the suggested initiatives and changes at the food pantry, food bank, and policy levels.

Clinical application of a template-guided automated planning routine.

PURPOSE: Determine the dosimetric quality and the planning time reduction when utilizing a template-based automated planning application. METHODS: A software application integrated through the treatment planning system application programing interface, QuickPlan, was developed to facilitate automated planning using configurable templates for contouring, knowledge-based planning structure matching, field design, and algorithm settings. Validations are performed at various levels of the planning procedure and assist in the evaluation of readiness of the CT image, structure set, and plan layout for automated planning. QuickPlan is evaluated dosimetrically against 22 hippocampal-avoidance whole brain radiotherapy patients. The required times to treatment plan generation are compared for the validations set as well as 10 prospective patients whose plans have been automated by QuickPlan. RESULTS: The generations of 22 automated treatment plans are compared against a manual replanning using an identical process, resulting in dosimetric differences of minor clinical significance. The target dose to 2% volume and homogeneity index result in significantly decreased values for automated plans, whereas other dose metric evaluations are nonsignificant. The time to generate the treatment plans is reduced for all automated plans with a median difference of 9' 50″ ± 4' 33″. CONCLUSIONS: Template-based automated planning allows for reduced treatment planning time with consistent optimization structure creation, treatment field creation, plan optimization, and dose calculation with similar dosimetric quality. This process has potential expansion to numerous disease sites.

Exogenous H2S Attenuates Hypertension by Regulating Renin Exocytosis under Hyperglycaemic and Hyperlipidaemic Conditions.

Obesity, along with type 2 diabetes mellitus (T2DM), is a major contributor to hypertension. The renin-angiotensin-aldosterone system is involved in the occurrence of diabetes and hypertension. However, the mechanism by which obesity is related to T2DM induced hypertension is unclear. In this study, we observed that blood pressure and serum renin content were increased in patients with diabetes and hypertension. Hydrogen sulfide (H2S), as an endogenous bioactive molecule, has been shown to be a vasodilator. Db/db mice, characterized by obesity and T2DM, and juxtaglomerular (JG) cells, which line the afferent arterioles at the entrance of the glomeruli to produce renin, treated with glucose, palmitic acid (PA) and oleic acid (OA), were used as animal and cellular models. NaHS, the H2S donor, was administered to db/db mice through intraperitoneal injection. NaHS significantly alleviated blood pressure in db/db mice, decreased the renin content in the serum of db/db mice and reduced renin secretion from JG cells. NaHS modulated renin release via cAMP and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), including synaptosome-associated protein 23 (SNAP23) and vesicle-associated membrane protein 2 (VAMP2), which mediate renin exocytosis. Furthermore, NaHS increased the levels of autophagy-related proteins and colocalization with EGFP-LC3 puncta with renin-containing granules and VAMP2 to consume excessive renin to maintain intracellular homeostasis. Therefore, exogenous H2S attenuates renin release and promotes renin-vesicular autophagy to relieve diabetes-induced hypertension.