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Abstract HER2 antagonists remain the cornerstone of therapy for patients with HER2-positive breast cancer. This study introduces a novel small-molecule inhibitor of DNA methyltransferase 1 (DNMT-1), referred to as DI-1, designed to synergize with HER2 antagonists in treating HER2-positive breast cancer cells. Clinical data reveal a negative correlation between DNMT-1 expression and PTEN levels, and a positive correlation with the methylation rates of PTEN's promoter. In experiments with SKBR3 and BT474 cells, DI-1 effectively reduced the methylation of PTEN's promoter region, thereby upregulating PTEN expression. This upregulation, in turn, enhanced the cells' sensitivity to HER2 antagonists, indicating that DI-1’s mechanism involves inhibiting DNMT-1’s recruitment to PTEN's promoter region. Consequently, by increasing PTEN expression, DI-1 amplifies the sensitivity of HER2-positive breast cancer cells to treatment, suggesting its potential as a promising therapeutic strategy in this context.

The family Lycaenidae is a widely distributed and species-rich group with approximately 5300 described species. The rare genus Qinorapala Chou & Wang, with Q. qinlingana Chou & Wang as its type species was established as monotypic. In the original description, Q. qinlingana was described from a male holotype; the female remained unknown. To date, the genus is only recorded from the Qinling Mountains (Shaanxi and Gansu Provinces). In this study, two female specimens, from Shaanxi Province and western Sichuan Province (bordering Yunnan Province) are described and illustrated for the first time.Female specimens of Q. qinlingana from Shaanxi and Sichuan are described for the first time. The species' distribution is updated and a distribution map is provided.

The family Stephanidae (Hymenoptera) constitutes a unique group within the Apocrita, playing a pivotal role in the evolution of parasitoid wasps. Although the phylogeny of Stephanidae has been previously inferred, it remains at a low resolution when considering both extinct and extant genera, as well as the enigmatic extinct genus †Electrostephanus. Here, we undertake a revision of Stephanidae extinct, presenting descriptions of new specimens from late Cretaceous Burmese amber and early Eocene Baltic amber. Combining all extant and extinct genera, the phylogeny of Stephanidae was analyzed, incorporating 57 species within 21 genera based on 64 morphological characters. We apply both under maximum parsimony with equal weighting and implied weighting methods, with four species representing early Apocrita as outgroups. Divergence times are estimated by utilizing extinct taxa as calibration points. A new basal subfamily of stephanid wasp, †Lagenostephaninae subf. nov. was established, encompassing †Lagenostephanus and the newly described genera †Tumidistephanus gen. nov and †Neurastephanus gen. nov. The genus †Electrostephanus is redefined, with two species assigned under distinct genera, †Neurastephanus gen. nov. and †Aphanostephanus gen. nov.. We discuss some of the putative morphological synapomorphies of evolutionary significance within the phylogenetic framework. Our results complement several characteristics of great taxonomic importance for Stephanidae and provide new insights into the early evolution of the family.

Background It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. Methods and findings This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus [greater than or equal to]5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade [greater than or equal to] 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade [greater than or equal to] 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. Conclusions The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. Trial Registration ClinicalTrials.gov Identifier: NCT03493048., Author(s): De-Shen Wang 1, Chao Ren 1, Shan-Shan Li 2, William Pat Fong 1, Xiao-Jun Wu 3, Jian Xiao 2,4, Bin-Kui Li 5, Yun Zheng 5, Pei-Rong Ding 3, Gong [...]

A new crown wasp species, Megischus shixiangi Ge & Tan, sp. nov. from Vietnam (Hymenoptera: Stephanidae), is described and illustrated. In addition, M. kuafu Ge & Tan is first recorded in Vietnam. A distribution map of the Vietnamese species is provided.

Abstract Growing evidence indicates that handgrip strength (HGS) is a conspicuous marker for assessing some diseases affecting middle-aged and elderly individuals. However, research regarding HGS and heart failure (HF) is sparse and controversial. Hence, we aimed to investigate the association between HGS and HF among adults aged 45 years and older in the United States. In this cross-sectional study, we included 4524 adults older than 45 years who were part of the National Health and Nutrition Examination Survey. A generalized additive model was used to estimate the association between HGS and HF. Age, gender, race, income, education, body mass index, smoking status, drinking status, diabetes, hypertension, stroke, vigorous physical activity, total energy intake, total protein intake, total sugars intake, and total fat intake covariates were adjusted using multiple regression models. And further subgroup analysis was conducted. We documented 189 cases of HF, including 106 men and 83 women. HGS was negatively associated with HF after adjusting for all the covariates (odds ratio = 0.97, 95% confidence interval = 0.96–0.99; P

Summary: Adaptation to host plants is of great significance in the ecology of xylophagous insects. The specific adaptation to woody tissues is made possible through microbial symbionts. We investigated the potential roles of detoxification, lignocellulose degradation, and nutrient supplementation of Monochamus saltuarius and its gut symbionts in host plant adaptation using metatranscriptome. The gut microbial community structure of M. saltuarius that fed on the two plant species were found to be different. Plant compound detoxification and lignocellulose degradation genes have been identified in both beetles and gut symbionts. Most differentially expressed genes associated with host plant adaptations were up-regulated in larvae fed on the less suitable host (Pinus tabuliformis) compared to larvae fed on the suitable host (Pinus koraiensis). Our findings indicated that M. saltuarius and its gut microbes respond to plant secondary substances through systematic transcriptome responses, allowing them to adapt to unsuitable host plants.

The first discovery of the genus Megischus Brullé, 1846 (Hymenoptera: Stephanidae) from Ryukyu Islands is reported and Megischus baogong Ge & Tan, sp. nov., is described and illustrated.

China operates a national surveillance program for acute respiratory infections and sampled over 200,000 patients between 2009–2019. Here, the authors present results from this program and describe patterns by age, pathogen type, presence of pneumonia, and season.

Chronic kidney disease (CKD) is a major worldwide public health problem. The increase in the number of patients with CKD and end-stage kidney disease requesting renal dialysis or transplantation will progress to epidemic proportions in the next several decades. Although blocking the renin-angiotensin system (RAS) has been used as a first-line standard therapy in patients with hypertension and CKD, patients still progress towards end-stage kidney disease, which might be closely associated with compensatory renin expression subsequent to RAS blockade through a homeostatic mechanism. The Wnt/β-catenin signalling pathway is the master upstream regulator that controls multiple intrarenal RAS genes. As Wnt/β-catenin regulates multiple RAS genes, we inferred that this pathway might also be implicated in blood pressure control. Therefore, discovering new medications to synchronously target multiple RAS genes is necessary and essential for the effective treatment of patients with CKD. We hypothesized that Shenkang injection (SKI), which is widely used to treat CKD patients, might ameliorate CKD by inhibiting the activation of multiple RAS genes via the Wnt/β-catenin signalling pathway. To test this hypothesis, we used adenine-induced CKD rats and angiotensin II (AngII)-induced HK-2 and NRK-49F cells. Treatment with SKI inhibited renal function decline, hypertension and renal fibrosis. Mechanistically, SKI abrogated the increased protein expression of multiple RAS elements, including angiotensin-converting enzyme and angiotensin II type 1 receptor, as well as Wnt1, β-catenin and downstream target genes, including Snail1, Twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1 and fibroblast-specific protein 1, in adenine-induced rats, which was verified in AngII-induced HK-2 and NRK-49F cells. Similarly, our results further indicated that treatment with rhein isolated from SKI attenuated renal function decline and epithelial-to-mesenchymal transition and repressed RAS activation and the hyperactive Wnt/β-catenin signalling pathway in both adenine-induced rats and AngII-induced HK-2 and NRK-49F cells. This study first revealed that SKI repressed epithelial-to-mesenchymal transition by synchronously targeting multiple RAS elements by blocking the hyperactive Wnt/β-catenin signalling pathway.

A new species of the genus Megischus Brullé, 1846, Megischus kuafu Ge & Tan, sp. nov., is described and illustrated from Guizhou Province, China. The key to all four species from China is included. A distribution map of the Chinese species is added.

Family Pieridae is a large group of butterflies which contains many important pollinators as well as potential pests. Pieridae is a cosmopolitan family while the tropics harbour higher species richness. In a very recent expedition to the China-Indian border area in Tibet Autonomous Region, a migratory species, Belenois aurota (Fabricius, 1793), was discovered for the first time, which comprises the first record of the genus Belenois in China and the highest altitude record of this species.The species B. aurota (Fabricius, 1793) is the first record of the genus Belenois from China. The specimen was collected at an altitude about 3,000 m in Tibet Autonomous Region. Relevant details are presented for the species.

Abstract. Background. Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans. Methods. We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed. Results. Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown β-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor. Conclusion. A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.

Abstract Background None of study mentioned about contrast-induced acute kidney injury (CI-AKI) in people who have received contrast agents twice within in a short period of time. This study is trying to identify the predictors. Methods We enrolled 607 patients between Oct. 2010 and Jul. 2015 who received contrast agents twice within 30 days in the Department of Cardiology of the General Hospital of Shenyang Military Region. The primary outcome was CI-AKI within 72 h after contrast agent exposure. Patients were divided into groups A (n = 559) and group B (n = 48) according to whether CI-AKI occurred after the second agent. Results Patients in group B (CI-AKI occurred after the second agent) had a more rapid heart rate and more usage of diuretics and digitalis. In group B, CI-AKI occurred more frequently after the first agent. Multivariate logistic regression showed that diuretic (P = 0.006) and intra-aortic balloon pump (IABP) usage (P = 0.012) were independent predictors of CI-AKI after the first agent. Angiotensin-converting enzyme inhibitor/Angiotensin II receptor antagonist (ACEI/ARB) usage (P = 0.039), IABP usage (P = 0.040) and CI-AKI occurring after administration of the first agent (P = 0.015) were independent predictors of CI-AKI after the second. Furthermore, dividing the patients into tertiles of the time interval between the two agents showed that CI-AKI occurred more frequently when the second agent was administered within 1–3 days after the first exposure than within 4–6 days (12.4% vs. 5.0%, P = 0.008) or ≥ 7 days (12.4% vs. 6.4%, P = 0.039). Conclusions Diuretic and IABP usage are independent predictors of CI-AKI following exposure to a first contrast agent. The major predictors of CI-AKI after exposure to a second agent are time since the first contrast exposure, ACEI/ARB usage, and IABP usage. More importantly, a three-day interval between the two agents is associated with a higher incidence of CI-AKI following the second administration.

Oxidative stress and inflammation are important and critical mediators in the development and progression of chronic kidney disease (CKD) and its complications. Shenkang injection (SKI) has been widely used to treat patients with CKD. Although the anti-oxidative and anti-inflammatory activity was involved in SKI against CKD, its bioactive components and underlying mechanism remain enigmatic. A rat model of adenine-induced chronic renal failure (CRF) is associated with, and largely driven by, oxidative stress and inflammation. Hence, we identified the anti-oxidative and anti-inflammatory components of SKI and further revealed their underlying mechanism in the adenine-induced CRF rats. Compared with control rats, the levels of creatinine, urea, uric acid, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in serum were significantly increased in the adenine-induced CRF rats. However, treatment with SKI and its three anthraquinones including chrysophanol, emodin, and rhein could reverse these aberrant changes. They could significantly inhibit pro-fibrotic protein expressions including collagen I, α-SMA, fibronectin, and vimentin in the kidney tissues of the adenine-induced CRF rats. Of note, SKI and rhein showed the stronger inhibitory effect on these pro-fibrotic protein expressions than chrysophanol and emodin. Furthermore, they could improve dysregulation of IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways. Chrysophanol and emodin showed the stronger inhibitory effect on the NF-κB p65 protein expression than SKI and rhein. Rhein showed the strongest inhibitory effect on p65 downstream target gene products including NAD(P)H oxidase subunits (p47phox, p67phox, and gp91phox) and COX-2, MCP-1, iNOS, and 12-LO in the kidney tissues. However, SKI and rhein showed the stronger inhibitory effect on the significantly downregulated anti-inflammatory and anti-oxidative protein expression nuclear Nrf2 and its target gene products including HO-1, catalase, GCLC, and NQO1 in the Keap1/Nrf2 signaling pathway than chrysophanol and emodin. This study first demonstrated that SKI and its major components protected against renal fibrosis by inhibiting oxidative stress and inflammation via simultaneous targeting IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways, which illuminated the potential molecular mechanism of anti-oxidative and anti-inflammatory effects of SKI.

Monochamus saltuarius (Coleoptera: Cerambycidae) is an important native pest in the pine forests of northeast China and a dispersing vector of an invasive species Bursaphelenchus xylophilus. To investigate the bacterial gut diversity of M. saltuarius larvae in different host species, and infer the role of symbiotic bacteria in host adaptation, we used 16S rRNA gene Illumina sequencing and liquid chromatography-mass spectrometry metabolomics processing to obtain and compare the composition of the bacterial community and metabolites in the midguts of larvae feeding on three host tree species: Pinus koraiensis, Pinus sylvestris var. mongolica, and Pinus tabuliformis. Metabolomics in xylem samples from the three aforementioned hosts were also performed. Proteobacteria and Firmicutes were the predominant bacterial phyla in the larval gut. At the genus level, Klebsiella, unclassified_f__Enterobacteriaceae, Lactococcus, and Burkholderia–Caballeronia–Paraburkholderia were most dominant in P. koraiensis and P. sylvestris var. mongolica feeders, while Burkholderia–Caballeronia–Paraburkholderia, Dyella, Pseudoxanthomonas, and Mycobacterium were most dominant in P. tabuliformis feeders. Bacterial communities were similar in diversity in P. koraiensis and P. sylvestris var. mongolica feeders, while communities were highly diverse in P. tabuliformis feeders. Compared with the other two tree species, P. tabuliformis xylems had more diverse and abundant secondary metabolites, while larvae feeding on these trees had a stronger metabolic capacity for secondary metabolites than the other two host feeders. Correlation analysis of the association of microorganisms with metabolic features showed that dominant bacterial genera in P. tabuliformis feeders were more negatively correlated with plant secondary metabolites than those of other host tree feeders.

Abstract Background Waardenburg syndrome (WS) is the consequence of an inherited autosomal dominant mutation which causes the early degeneration of intermediate cells of cochlear stria vascularis (SV) and profound hearing loss. Patients with WS may also experience primary vestibular symptoms. Most of the current WS studies did not discuss the relationship between WS and abnormal vestibular function. Our study found that a spontaneous mutant pig showed profound hearing loss and depigmentation. MITF-M, a common gene mutation causes type WS which affect the development of the intermediate cell of SV, was then identified for animal modeling. Results In this study, the degeneration of vestibular hair cells was found in pigs with MITF-M. The morphology of hair cells in vestibular organs of pigs was examined using electron microscopy from embryonic day E70 to postnatal two weeks. Significant hair cell loss in the mutant saccule was found in this study through E95 to P14. Conversely, there was no hair cell loss in either utricle or semi-circular canals. Conclusions Our study suggested that MITF-M gene mutation only affects hair cells of the saccule, but has no effect on other vestibular organs. The study also indicated that the survival of cochlear and saccular hair cells was dependent on the potassium release from the cochlear SV, but hair cells of the utricle and semi-circular canals were independent on SV.

Abstract Background Auditory function and cochlear morphology have previously been described in a porcine model with spontaneous WS2-like phenotype. In the present study, cochlear histopathology was further investigated in the inner ear of the developing spontaneous deafness pig. Results We found that the stria vascularis transformed into a complex tri-laminar tissue at embryonic 85 days (E85) in normal pigs, but not in the MITF−/− pigs. As the neural crest (NC) of cochlea was derived by melanocytes. MITF mutation caused failure of development of melanocytes which caused a subsequent collapse of cochlear duct and deficits of the epithelium after E100. Furthermore, the spiral ganglion neurons of cochlea in the MITF−/− pigs began to degenerate at postnatal 30 days (P30). Thus, our histopathological results indicated that the malformation of the stria vascularis was a primary defect in MITF−/− induced WT pigs which was resulted from the loss of NC-derived melanocytes. Subsequently, the cochleae underwent secondary degeneration of the vestibular organs. As the degeneration of spiral ganglion neurons happened after P30, it suggests that WS patients should be considered as candidates for cochlear implant. Conclusions Our porcine model of MITF-M mutation may provide a crucial animal model for cochlear implant, cell therapy in patients with congenital hereditary hearing loss.

Background: The latissimus dorsi (LD) flap procedure remains a popular and useful breast reconstruction tool in China and Western countries, and donor site seroma formation is the main complication. This study was conducted in Chinese patients to determine whether stable cases of seromas would resolve without treatment. Methods: A retrospective review of 45 consecutive cases of immediate breast reconstruction with LD flap from April 2012 to February 2017 was conducted. The scope of the seroma was demarcated with a marker pen, and cases that remained stable over time (i.e. the size of the seroma did not increase) were observed without treatment. The measured outcomes included the incidence of seromas, the volume and duration of postoperative wound drainage, and other demographic characteristics. Results: Twenty-four patients (53.3%) developed a seroma at the donor site. Of these, 21 patients (87.5%) did not require treatment, and the seroma resolved over time. The mean duration of a sustained seroma was 6.8 ± 1.4 weeks (range: 4–9 weeks). Conclusions: This study observed the scope and progression of the seromas and found that seromas at the LD donor sites resolved over time without treatment.

Fibrosis is the abnormal accumulation of extracellular matrix proteins such as collagen and fibronectin. Aging, injury, infections, and inflammation can cause different types of tissue fibrosis. Numerous clinical investigations have shown a correlation between the degree of liver and pulmonary fibrosis in patients and telomere length and mitochondrial DNA content, both of which are signs of aging. Aging involves the gradual loss of tissue function over time, which results in the loss of homeostasis and, ultimately, an organism's fitness. A major feature of aging is the accumulation of senescent cells. Senescent cells abnormally and continuously accumulate in the late stages of life, contributing to age-related fibrosis and tissue deterioration, among other aging characteristics. Furthermore, aging generates chronic inflammation, which results in fibrosis and decreases organ function. This finding suggests that fibrosis and aging are closely related. The transforming growth factorbeta (TGF-ß) superfamily plays a crucial role in the physiological and pathological processes of aging, immune regulation, atherosclerosis, and tissue fibrosis. In this review, the functions of TGF-ß in normal organs, aging, and fibrotic tissues is discussed: TGF-ß signalling is altered with age and is an indicator of pathology associated with tissue fibrosis. In addition, this review discusses the potential targeting of noncoding. [ABSTRACT FROM AUTHOR]

Dastarcus helophoroides Fairmaire (Coleoptera: Bothrideridae) is an effective predatory beetle of larvae and pupae of several cerambycid beetles including Monochamus alternatus and Anoplophora glabripennis. Electroantennography (EAG) and a dynamic two-choice olfactometer were respectively used to measure the antennal and behavioral responses of both sexes to selected volatile compounds. Female and male D. helophoroides exhibited similar EAG and behavioral responses. Significant dose-dependent EAG responses in both sexes were elicited by nonanal, octanal, cis-3-hexenol, 3-carene, (R)-(+)-α-pinene, (S)-(-)-α-pinene, (R)-(+)-limonene and (S)-(-)-limonene. Female and male beetles were repelled at high concentration by cis-3-hexenol and (S)-(-)-limonene, respectively. Both sexes of D. helophoroides were significantly attracted to nonanal, cis-3-hexenol, 3-carene and (R)-(+)-limonene even at low concentrations. These compounds might be used either individually or in mixtures for developing biological control methods to attract this predatory beetle into forest stands threatened by cerambycid beetles.