Metagenomic and metabolomic analyses reveal differences in rumen microbiota between grass- and grain-fed Sanhe heifers.

Introduction: The aim of this study was to investigate the effects of diets on the composition and function of rumen microbiome and metabolites in Sanhe heifers. Methods: Metagenomic and metabolomic analyses were performed using rumen fluid samples collected from Sanhe heifers (n = 20) with similar body weights and ages from grass-fed and grain-fed systems. Results: The grain-fed group exhibited more intensive rumen fermentation than the grass-fed group. However, the grass-fed group exhibited carbohydrate metabolism and methane production higher than that of the grain-fed group; these increases were observed as a higher abundance of various bacterial phyla (Firmicutes, Bacteroidetes, Actinobacteria, Lentisphaerae, and Verrucomicrobia), families (Lachnospiraceae, Eubacteriaceae, and Eggerthellaceae), and the archaeal family Methanobacteriaceae. A comparison of genes encoding carbohydrate-active enzymes, using Kyoto Encyclopedia of Genes and Genome profiles, revealed noteworthy differences in the functions of rumen microbiota; these differences were largely dependent on the feeding system. Conclusion: These results could help manipulate and regulate feed efficiency in Sanhe cattle.

A nomogram for predicting pathologic node negativity after neoadjuvant chemotherapy in breast cancer patients: a nationwide, multicenter retrospective cohort study (CSBrS-012).

Purpose: This study aimed to investigate the factors associated with pathologic node-negativity (ypN0) in patients who received neoadjuvant chemotherapy (NAC) to develop and validate an accurate prediction nomogram. Methods: The CSBrS-012 study (2010-2020) included female patients with primary breast cancer treated with NAC followed by breast and axillary surgery in 20 hospitals across China. In the present study, 7,711 eligible patients were included, comprising 6,428 patients in the primary cohort from 15 hospitals and 1,283 patients in the external validation cohort from five hospitals. The hospitals were randomly assigned. The primary cohort was randomized at a 3:1 ratio and divided into a training set and an internal validation set. Univariate and multivariate logistic regression analyses were performed on the training set, after which a nomogram was constructed and validated both internally and externally. Results: In total, 3,560 patients (46.2%) achieved ypN0, and 1,558 patients (20.3%) achieved pathologic complete response in the breast (bpCR). A nomogram was constructed based on the clinical nodal stage before NAC (cN), ER, PR, HER2, Ki67, NAC treatment cycle, and bpCR, which were independently associated with ypN0. The area under the receiver operating characteristic curve (AUC) for the training set was 0.80. The internal and external validation demonstrated good discrimination, with AUCs of 0.79 and 0.76, respectively. Conclusion: We present a real-world study based on nationwide large-sample data that can be used to effectively screen for ypN0 to provide better advice for the management of residual axillary disease in breast cancer patients undergoing NAC.

Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial.

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.

Molecular subtype identification and prognosis stratification based on lysosome-related genes in breast cancer.

Background: Lysosomes are known to have a significant impact on the development and recurrence of breast cancer. However, the association between lysosome-related genes (LRGs) and breast cancer remains unclear. This study aims to explore the potential role of LRGs in predicting the prognosis and treatment response of breast cancer. Methods: Breast cancer gene expression profile data and clinical information were downloaded from TCGA and GEO databases, and prognosis-related LRGs were screened for consensus clustering analysis. Lasso Cox regression analysis was used to construct risk features derived from LRGs, and immune cell infiltration, immune therapy response, drug sensitivity, and clinical pathological feature differences were evaluated for different molecular subtypes and risk groups. A nomogram based on risk features derived from LRGs was constructed and evaluated. Results: Our study identified 176 differentially expressed LRGs that are associated with breast cancer prognosis. Based on these genes, we divided breast cancer into two molecular subtypes with significant prognostic differences. We also found significant differences in immune cell infiltration between these subtypes. Furthermore, we constructed a prognostic risk model consisting of 7 LRGs, which effectively divides breast cancer patients into high-risk and low-risk groups. Patients in the low-risk group have better prognostic characteristics, respond better to immunotherapy, and have lower sensitivity to chemotherapy drugs, indicating that the low-risk group is more likely to benefit from immunotherapy and chemotherapy. Additionally, the risk score based on LRGs is significantly correlated with immune cell infiltration, including CD8 T cells and macrophages. This risk score model, along with age, chemotherapy, clinical stage, and N stage, is an independent prognostic factor for breast cancer. Finally, the nomogram composed of these factors has excellent performance in predicting overall survival of breast cancer. Conclusions: In conclusion, this study has constructed a novel LRG-derived breast cancer risk feature, which performs well in prognostic prediction when combined with clinical pathological features.

The rumen-derived Lact. mucosae LLK-XR1 exhibited greater free gossypol degradation capacity during solid-state fermentation of cottonseed meal and probiotic potential.

BACKGROUND: This study aimed to isolate the rumen-derived bacteria with the ability to degrade free gossypol (FG), and to evaluate the probiotic potential in vitro for ensuring safe utilization. METHODS: The strains were anaerobically isolated from fresh rumen fluid of sheep with long-term fed cottonseed meal (CSM) with the screening agar medium containing gossypol as the sole carbon source. Afterwards, the isolated strain incubated with CSM was subjected to the determination of the FG degradation and in vitro evaluation of probiotic characteristics. RESULTS: The target strain labeled Lact. mucosae LLK-XR1 [Accession number: OQ652016.1] was obtained, and its growth on MRS Liquid medium exhibited degradation efficiency of FG up to 69.5% which was significantly greater than its growth on Man-Rogosa-Sharpe medium with glucose free for 24 h (p < 0.01). Meanwhile, LLK-XR1 showed 40.652% degradation rate of FG for unautoclaved, non-pulverized, and no additional nutrients supplementation CSM. Furthermore, LLK-XR1 presented good survivability at pH 3.0 (above 88.6%), and 0.3% bile (78.5%). LLK-XR1 showed sensitivity to broad-spectrum antibiotics except Sulfamethoxazole, Ciprofloxacin and Gentamycin and significantly inhibited E. coli CICC 10,899, Staph. aureus CICC 21,600, and Salmonella. Typhimurium CICC 21,483. LLK-XR1 demonstrated good cell surface hydrophobicity and auto-aggregation ability. CONCLUSIONS: Taken together, this study for the first time noted that rumen-originated Lact. mucosae LLK-XR1 with probiotic properties exhibited substantial FG degradation capacity when it was applied to the solid-state fermentation of CSM.

Axillary lymph node dissection in triple-negative or HER2-positive breast cancer patients with clinical N2 achieving pathological complete response after neoadjuvant therapy: Is it necessary?

AIM: This study aims to identify suitable candidates for axillary sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) among clinical N2 (cN2) triple-negative (TN) or HER2 positive (HER2+）breast cancer patients following neoadjuvant therapy（NAT）. BACKGROUND: Despite the substantial axillary burden in cN2 breast cancer patients, high pathological response rates can be achieved with NAT in TN or HER2+ subtypes, thus enabling potential downstaging of axillary surgery. METHODS: A retrospective analysis was conducted on data from the CSBrS-012 study, screening 709 patients with initial cN2, either HER2+ or TN subtype, from January 1, 2010 to December 31, 2020. The correlation between axillary pathologic complete response (pCR) (yPN0) and breast pCR was examined. RESULTS: Among the 177 cN2 patients who achieved breast pCR through NAT, 138 (78.0 %) also achieved axillary pCR. However, in the 532 initial clinical N2 patients who did not achieve breast pCR, residual axillary lymph node metastasis persisted in 77.4 % (412/532) of cases. The relative risk of residual axillary lymph node metastasis in patients who did not achieve breast pCR was 12.4 (8.1-19.1), compared to those who did achieve breast pCR, P < 0.001. CONCLUSION: For cN2 TN or HER2+ breast cancer patients who achieve breast pCR following NAT, consideration could be given to downstaging and performing an axillary SLNB or TAD.

Roles of lncRNA in the diagnosis and prognosis of triple-negative breast cancer. / LncRNAåœ¨ä¸‰é˜´æ€§ä¹³è ºç™Œè¯Šæ–­å’Œé¢„åŽä¸­çš„ä½œç”¨.

Breast cancer is a malignant tumor that seriously endangers women's lives. The prognosis of breast cancer patients differs among molecular types. Compared with other subtypes, triple-negative breast cancer (TNBC) has been a research hotspot in recent years because of its high degree of malignancy, strong invasiveness, rapid progression, easy of recurrence, distant metastasis, poor prognosis, and high mortality. Many studies have found that long non-coding RNA (lncRNA) plays an important role in the occurrence, proliferation, migration, recurrence, chemotherapy resistance, and other characteristics of TNBC. Some lncRNAs are expected to become biomarkers in the diagnosis and prognosis of TNBC, and even new targets for its treatment. Based on a PubMed literature search, this review summarizes the progress in research on lncRNAs in TNBC and discusses their roles in TNBC diagnosis, prognosis, and chemotherapy with the hope of providing help for future research.

Wheat silage partially replacing oaten hay exhibited greater feed efficiency and fibre digestion despite low feed intake by feedlot lambs.

This study aimed to investigate the feeding effect of wheat silage on growth performance, nutrient digestibility, rumen fermentation, and microbiota composition in feedlot lambs. Sixty-four male crossbred Chinese Han lambs (BW = 27.8 ± 0.67 kg, 3 months of age) were randomly assigned to four ration groups with wheat silage replacing 0% (WS0), 36% (WS36), 64% (WS64), and 100% (WS100) of oaten hay on forage dry matter basis. The concentrate-to-forage ratio was 80:20 and the feeding trial lasted 52 d. Increasing wheat silage inclusion linearly decreased dry matter intake by 4% to 27% (P < 0.01). However, increasing the wheat silage replacement of oaten hay by no more than 64% improved the feed efficiency by 14% as noted by the feed-to-gain ratio (P = 0.04). Apparent digestibility of organic matter (P < 0.01), neutral detergent fibre (P = 0.04) and acid detergent fibre (P < 0.01) quadratically increased. Ammonia nitrogen (P = 0.01) decreased while microbial protein production (P < 0.01) increased with the increase of wheat silage inclusion. Total volatile fatty acids concentration increased quadratically with the increase of wheat silage inclusion (P < 0.01), and the highest occurred in WS64. The molar proportion of acetate (P < 0.01) and acetate-to-propionate ratio (P = 0.04) decreased while butyrate (P < 0.01) and isovalerate (P = 0.04) increased. Increasing wheat silage inclusion increased the Firmicutes-to-Bacteroidota ratio by 226% to 357%, resulting in Firmicutes instead of Bacteroidota being the most abundant phylum. The relative abundance of cellulolytic Ruminococcus numerically increased but that of amylolytic Prevotella (P < 0.01) decreased as increasing wheat silage inclusion. Taken together, increasing wheat silage replacement of oaten hay by no more than 64% exhibited greater feed efficiency and fibre digestion despite low feed intake by feedlot lambs due to the change of Firmicutes-to-Bacteroidota ratio in the rumen.

Advantages of contrast-enhanced ultrasound in the localization and diagnostics of sentinel lymph nodes in breast cancer. / è¶ å£°é€ å½±åœ¨ä¹³è ºç™Œå‰å“¨æ·‹å·´ç»“å®šä½å’Œè¯Šæ–­ä¸­çš„ä¼˜åŠ¿.

Sentinel lymph nodes (SLNs) are the first station of lymph nodes that extend from the breast tumor to the axillary lymphatic drainage. The pathological status of these LNs can predict that of the entire axillary lymph node. Therefore, the accurate identification of SLNs is necessary for sentinel lymph node biopsy (SLNB) to replace axillary lymph node dissection (ALND). The quality of life and prognosis of breast cancer patients are related to proper surgical treatment after the precise identification of SLNs. Some of the SLN tracers that have been identified include radioisotope, nano-carbon, indocyanine green (ICG), and methylene blue (MB). However, these tracers have certain limitations, such as pigmentation, radiation dangers, and the requirement for costly detection equipment. Ultrasound contrast agents (UCAs) have good specificity and sensitivity, and thus can compensate for some shortcomings of the mentioned tracers. This technique is also being applied to SLNB in patients with breast cancer, and can even provide an initial judgment on SLN status. Contrast-enhanced ultrasound (CEUS) has the advantages of high distinguishability, simple operation, no radiation harm, low cost, and accurate localization; therefore, it is expected to replace the traditional biopsy methods. In addition, it can significantly enhance the accuracy of SLN localization and shorten the operation time.

Neoadjuvant Pyrotinib plus Trastuzumab, Docetaxel, and Carboplatin in Early or Locally Advanced Human Epidermal Receptor 2-Positive Breast Cancer in China: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

INTRODUCTION: This multicenter, randomized, double-blind, placebo-controlled phase 2 trial compared the efficacy, and safety of adding pyrotinib to trastuzumab, docetaxel, and carboplatin versus placebo, trastuzumab, docetaxel, and carboplatin in Chinese patients with human epidermal receptor 2 (HER2)-positive early or locally advanced breast cancer (ClinicalTrials.gov identifier: NCT03756064). METHODS: Sixty-nine women with HER2-positive early (T1-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) were recruited from October 1, 2019, to June 1, 2021. Before surgery, patients received 6 cycles of orally pyrotinib (400 mg once per day), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), docetaxel (75 mg/m2), and carboplatin (AUC = 6 mg/mL·min) or orally placebo, trastuzumab, and docetaxel, and carboplatin every 3 weeks. The primary end point was independent review committee-assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by age, hormone receptor status, tumor stage, nodal status, cTNM stage, and Ki-67 level was used to compare rates between treatment groups. RESULTS: In total, 69 female patients were randomized (pyrotinib, 36; and placebo, 33; median age, 53 [31-69] years). In the intention-to-treat population, total pathologic complete response rates were 65.5% (19/29) in the pyrotinib group and 33.3% (10/30) in the placebo group (difference, 32.2%, p = 0.013). Diarrhea was been reported in 86.1% of patients (31/36) in the pyrotinib group as the most common adverse events (AEs) and 15.2% of patients (5/33) in the placebo group. But no grade 4 or 5 AEs were reported. CONCLUSION: Treatment with pyrotinib, trastuzumab, docetaxel, and carboplatin resulted in a statistically significant improvement in the total pathologic complete response rate versus placebo, trastuzumab, docetaxel, and carboplatin for the neoadjuvant treatment of HER2-positive early or locally advanced breast cancer in Chinese patients. Safety data were in line with the known pyrotinib safety profile and generally comparable between treatment groups.

New progress in the role of microRNAs in the diagnosis and prognosis of triple negative breast cancer.

Triple negative breast cancer is distinguished by its high malignancy, aggressive invasion, rapid progression, easy recurrence, and distant metastases. Additionally, it has a poor prognosis, a high mortality, and is unresponsive to conventional endocrine and targeted therapy, making it a challenging problem for breast cancer treatment and a hotspot for scientific research. Recent research has revealed that certain miRNA can directly or indirectly affect the occurrence, progress and recurrence of TNBC. Their expression levels have a significant impact on TNBC diagnosis, treatment and prognosis. Some miRNAs can serve as biomarkers for TNBC diagnosis and prognosis. This article summarizes the progress of miRNA research in TNBC, discusses their roles in the occurrence, invasion, metastasis, prognosis, and chemotherapy of TNBC, and proposes a treatment strategy for TNBC by interfering with miRNA expression levels.

Nomogram for predicting axillary upstaging in clinical node-negative breast cancer patients receiving neoadjuvant chemotherapy.

PURPOSE: The prediction of axillary lymph node status after neoadjuvant chemotherapy (NAC) becoming critical because of the advocation of the de-escalation of axillary management. We investigate associated factors of axillary upstaging in clinical node-negative (cN0) breast cancer patients receiving NAC to develop and validate an accurate prediction nomogram. METHODS: We retrospectively analyzed 1892 breast cancer patients with stage of cT1-3N0 treated by NAC and subsequent surgery between 2010 and 2020 in twenty hospitals across China. Patients randomly divided into a training set and validation set (3:1). Univariate and multivariate logistic regression analysis were performed, after which a nomogram was constructed and validated. RESULTS: In total, pathologic node negativity (ypN0) achieved in 1406 (74.3%) patients and another 486 (25.7%) patients upstaged to pathologic node positive (ypN+). Breast pathologic complete response (bpCR) was achieved in 445 (23.5%) patients and non-bpCR in 1447 (76.5%) patients. A nomogram was established by ER, tumor histology, HER2 status, cycle of NAC treatment, and the bpCR, which were confirmed by multivariate logistic analysis as independent predictors of nodal upstaging in the training cohort (n = 1419). The area under the receiver operating characteristic curve (AUC) of the training cohort and validation cohort (n = 473) were 0.73 (95% CI 0.693-0.751) and 0.77 (95% CI 0.723-0.812) respectively. CONCLUSION: We present a nomogram with a nationwide large sample data which can effectively predict axillary upstaging after neoadjuvant chemotherapy to give better advice for individualized axillary lymph node management of breast cancer.

The expression profile of Gasdermin C-related genes predicts the prognosis and immunotherapy response of pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) has a poor prognosis and is relatively unresponsive to immunotherapy. Gasdermin C (GSDMC) induces pyroptosis in cancer cells and inflammation in the tumor microenvironment. However, whether GSDMC expression in PAAD is associated with survival or response to immunotherapy remains unknown. GSDMC expression and the relationship between GSDMC and patient survival or immune infiltration in PAAD were examined using data in the The Cancer Genome Atlas (TCGA), Gene Expression Ominbus (GEO), Genotype-Tissue Expression (GTEx) and Cancer Cell Line Encyclopedia (CCLE) databases. The TCGA PAAD cohort could be divided into two distinct risk groups based on the expression of GSDMC-related genes (GRGs). The TIDE algorithm predicted that the low-risk group was more responsive to immune checkpoint blockade therapy than the high-risk group. A novel 15-gene signature was constructed and could predict the prognosis of PAAD. In addition, the 15-gene signature model predicted the infiltration of immune cells and Immune checkpoint blockade (ICB) treatment response. Immunohistochemical staining assessment of patient-derived human tissue microarray (TMA) from 139 cases of local PAAD patients revealed a positive correlation between GSDMC expression and PD-L1 expression but a negative correlation between GSDMC expression and infiltration of low CD8+ T cells. Moreover, the overexpression of GSDMC was related to poor overall survival (OS). This study suggests that GSDMC is a valuable biomarker for predicting PAAD prognosis and predicts the immunotherapy response of PAAD.

Growth performance, blood metabolites, ruminal fermentation, and bacterial community in preweaning dairy calves fed corn silage-included starter and total mixed ration.

The objective of this study was to evaluate the effects of the inclusion of whole-plant corn silage (WPCS) in a starter or total mixed ration (TMR) on growth, blood metabolites, ruminal fermentation, and microbial community in preweaning dairy calves. A total of 45 healthy dairy calves were blocked by date of birth and randomly assigned to 1 of 3 treatments: 100% calf starter (CONS), a mix of 85% calf starter and 15% WPCS [dry matter (DM) basis; CSCS], or 100% WPCS-based lactation TMR (CTMR). Pasteurized normal milk was fed to all the animals under the same regimen. The experiment ran from when the calves were 2 d old to weaning at 63 d. Milk and feed intakes were recorded daily. Growth performance data and blood samples were collected on wk 3, 5, 7, and 9 of the experiment. Rumen fluid was sampled at 40 and 60 d. The 3 treatments had different particle size fractions. The CSCS group had greater medium fraction (<19 mm, >8 mm) and particles retained on 8-mm sieves than the other 2 groups, whereas the CTMR group had the greatest long (>19 mm) and fine (<4 mm) fractions and physically effective neutral detergent fiber (NDF) on 8- and 4-mm sieves, but had the smallest short fraction (<8 mm, >4 mm) and particles retained on 4-mm sieves. The 24-h in vitro digestibility of DM, crude protein (CP), NDF, and acid detergent fiber (ADF) were decreased in order by the CONS, CSCS, and CTMR groups. Compared with the CONS group, the digestibility of ether extract (EE) was lower in the CSCS and CTMR groups, whereas the digestibility of starch was similar among treatments. During the experimental period, the DM, CP, and metabolizable energy intakes from milk, solid feed, and total feed were not affected by treatments. The NDF, ADF, and EE intakes and potentially digestible intakes were greater in the CTMR group than in the other 2 groups. With the exception that body barrel was greater for calves fed CSCS, growth parameters and blood metabolites were similar among treatments. Compared with the CSCS group, the CTMR group had greater rumen pH and total volatile fatty acids, propionate, and isovalerate concentrations, but a lower acetate:propionate ratio. The CTMR group had greater relative abundances of some cellulolytic bacteria (Rikenellaceae RC9 gut group, Christensenellaceae R7, Ruminococcaceae NK4A214, Ruminococcaceae UCG, Ruminococcus, and Erysipelotrichaceae UCG) in the rumen, which may be beneficial for the early acquisition of specific adult-associated microorganisms. In summary, a WPCS-based lactation TMR, but not the WPCS-included starter, had the potential to be an alternative starter in preweaning calves without having significant adverse effects. These findings provide theoretical and practical implications for the rational application of TMR in the early life of dairy calves.

Risk factors for the development of severe breast cancer-related lymphedema: a retrospective cohort study.

BACKGROUND: Severe lymphedema presents a challenge in terms of treatment due to the significant formation of scar tissue that accompanies it. The aim of this study was to identify intraoperative and preoperative risk factors of severe lymphedema and to develop a nomogram for estimating the risk of severe lymphedema within 3 years of surgery. METHOD: Data was collected from a retrospective cohort of 326 patients with BCRL at the Zhejiang Cancer Hospital from November 2015 to November 2018. Univariate and multivariate logistic regression analysis was conducted to identify predictive indicators of severe lymphedema. A nomogram was developed to further improve the clinical applicability. RESULTS: In the retrospective cohort, the ratio of severe/non-severe lymphedema within 3 years of surgery was 1:3. Independent risk factors for severe lymphedema were determined to be age, positive lymph nodes, interpectoral (Rotter's) lymph nodes (IPNs) dissection, and educational level. IPNs dissection was found to contribute greatly to the development of severe lymphedema with a higher odds ratio (7.76; 95% CI: 3.87-15.54) than other risk factors. A nomogram was developed by integrating age, positive lymph nodes, IPNs dissection, and educational level, which yielded a C-index of 0.810 and 0.681 in the training and validation cohort, respectively. This suggested a moderate performance of the nomogram in predicting the risk of severe lymphedema within 3 years of surgery. The cut-off values of the low-, medium- and high-risk probabilities were 0.0876 and 0.3498, and the severe lymphedema exhibited a significantly higher risk probability as compared with the non-severe lymphedema. CONCLUSION: This study identified the risk factors of severe lymphedema and highlighted the substantial contribution of IPNs dissection to the severity of lymphedema.

Effects of altitude on the gut microbiome and metabolomics of Sanhe heifers.

Introduction: Extreme environments at high altitudes pose a significant physiological challenge to animals. We evaluated the gut microbiome and fecal metabolism in Sanhe heifers from different altitudes. Methods: Twenty Sanhe heifers (body weight: 334.82 ± 13.22 kg, 15-month-old) selected from two regions of China: the Xiertala Cattle Breeding Farm in Hulunbeier, Inner Mongolia [119°57' E, 47°17' N; approximately 700 m altitude, low altitude (LA)] and Zhizhao Dairy Cow Farm in Lhasa, Tibet [91°06' E, 29°36' N; approximately 3,650 m altitude, high altitude (HA)], were used in this study. Fecal samples were collected and differences in the gut microbiota and metabolomics of Sanhe heifers were determined using 16S rRNA gene sequencing and metabolome analysis. Results and discussion: The results showed that altitude did not significantly affect the concentrations of fecal volatile fatty acids, including acetate, propionate, butyrate, and total volatile fatty acids (p > 0.05). However, 16S rRNA gene sequencing showed that altitude significantly affected gut microbial composition. Principal coordinate analysis based on Bray-Curtis dissimilarity analysis revealed a significant difference between the two groups (p = 0.001). At the family level, the relative abundances of Peptostreptococcaceae, Christensenellaceae, Erysipelotrichaceae, and Family_XIII were significantly lower (p < 0.05) in LA heifers than in HA heifers. In addition, the relative abundances of Lachnospiraceae, Domibacillus, Bacteroidales_S24-7_group, Bacteroidales_RF16_group, Porphyromonadaceae, and Spirochaetaceae were significantly higher in HA heifers than in LA heifers (p < 0.05). Metabolomic analysis revealed the enrichment of 10 metabolic pathways, including organismal systems, metabolism, environmental information processing, genetic information processing, and disease induction. The genera Romboutsia, Paeniclostridium, and g_unclassified_f_Lachnospiraceae were strongly associated with the 28 differential metabolites. This study is the first to analyze the differences in the gut microbiome and metabolome of Sanhe heifers reared at different altitudes and provides insights into the adaptation mechanism of Sanhe heifers to high-altitude areas.

Dietary Guanidine Acetic Acid Improves Ruminal Antioxidant Capacity and Alters Rumen Fermentation and Microflora in Rapid-Growing Lambs.

Guanidine acetic acid (GAA) has been reported to improve growth performance, nutrient utilization, and meat quality in livestock. This study aimed to investigate whether coated GAA (CGAA) in comparison with uncoated GAA (UGAA) could have different effects on rumen fermentation, antioxidant capacity, and microflora composition in the rumen. Seventy-two lambs were randomly arranged in a 2 × 3 factorial experiment design with two diets of different forage type (OH: oaten hay; OHWS: oaten hay plus wheat silage) and three GAA treatments within each diet (control, diet without GAA addition; UGAA, uncoated GAA; CGAA, coated GAA). The whole feeding trial lasted for 120 days. The lambs in the OH group presented lower total volatile fatty acid (VFA), alpha diversity, Firmicutes, NK4A214_group, and Lachnospiraceae_NK3A20_group than those on the OHWS diet in the last 60 days of the feeding stage (p < 0.05). Regardless of what GAA form was added, dietary GAA supplementation increased the total VFA, microbial crude protein (MCP), adenosine triphosphate (ATP), and antioxidant capacity in rumen during lamb feedlotting (p < 0.05). However, molar propionate proportion, acetate:propionate ratio (A:P), and relative Succiniclasticum abundance decreased with GAA addition in the first 60 days of the growing stage, while the molar butyrate proportion and NK4A214_group (p < 0.05) in response to GAA addition increased in the last 60 days of feeding. These findings indicated that dietary GAA enhanced antioxidant capacity and fermentation characteristics in the rumen, but the addition of uncoated GAA in diets might cause some dysbacteriosis of the rumen microbiota.

Cell adhesion molecules and immunotherapy in advanced non-small cell lung cancer: Current process and potential application.

Advanced non-small cell lung cancer (NSCLC) is a severe disease and still has high mortality rate after conventional treatment (e.g., surgical resection, chemotherapy, radiotherapy and targeted therapy). In NSCLC patients, cancer cells can induce immunosuppression, growth and metastasis by modulating cell adhesion molecules of both cancer cells and immune cells. Therefore, immunotherapy is increasingly concerned due to its promising anti-tumor effect and broader indication, which targets cell adhesion molecules to reverse the process. Among these therapies, immune checkpoint inhibitors (mainly anti-PD-(L)1 and anti-CTLA-4) are most successful and have been adapted as first or second line therapy in advanced NSCLC. However, drug resistance and immune-related adverse reactions restrict its further application. Further understanding of mechanism, adequate biomarkers and novel therapies are necessary to improve therapeutic effect and alleviate adverse effect.

Efficacy analysis of neoadjuvant chemotherapy with or without anthracyclines in female patients with HER2-positive breast cancer in China: a nationwide, multicenter, 10-year retrospective study (CSBrS-012).

Background: In the era of targeted therapy, whether patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are exempted from anthracycline usage in the neoadjuvant setting is controversial. Objectives: Our objective was to retrospectively analyze the differences in pathological complete remission (pCR) rates between the anthracycline group and the nonanthracycline group. Design: The CSBrS-012 study (2010-2020) included female primary breast cancer patients with neoadjuvant chemotherapy (NAC) who underwent standard breast and axillary surgery post-NAC. Methods: A logistic proportional hazard model was applied to estimate the association of covariates with pCR. Propensity score matching (PSM) was performed to balance the differences in baseline characteristics, and subgroup analyses were performed using the Cochran-Mantel-Haenszel test. Results: A total of 2507 patients were enrolled: the anthracycline group (n = 1581, 63%) and the nonanthracycline group (n = 926, 37%). A pCR was recorded in 17.1% (271/1581) of patients in the anthracycline group and in 29.3% (271/926) in the nonanthracycline group, and the difference in the pCR rate between the two groups was statistically significant [odds ratio (OR) = 2.00, 95% confidence interval (CI) (1.65-2.43); p < 0.001). In the subsequent subgroup analysis, substantial differences in pCR rates between the anthracycline and nonanthracycline groups were detected in the nontargeted [OR = 1.91, 95% CI (1.13-3.23); p = 0.015] and dual-HER2-targeted populations [OR = 0.55, 95% CI (0.33-0.92); p = 0.021) before PSM, whereas differences vanished after PSM. The pCR rates between the anthracycline and nonanthracycline groups did not differ for the single target population, either before or after PSM. Conclusion: In the presence of trastuzumab and/or pertuzumab, the pCR rate of patients with HER2-positive breast cancer receiving anthracycline was not superior to that of patients receiving nonanthracycline. Thus, our study further provides clinical evidence for exempting anthracycline treatment in HER2-positive breast cancer in the era of targeted therapy.