Development and Validation of an Interpretable Machine Learning Prediction Model for Total Pathological Complete Response after Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer: Multicenter Retrospective Analysis.

Objective: This study aims to develop an interpretable machine learning (ML) model to accurately predict the probability of achieving total pathological complete response (tpCR) in patients with locally advanced breast cancer (LABC) following neoadjuvant chemotherapy (NAC). Methods: This multi-center retrospective study included pre-NAC clinical pathology data from 698 LABC patients. Post-operative pathological outcomes divided patients into tpCR and non-tpCR groups. Data from 586 patients at Shanghai Ruijin Hospital were randomly assigned to a training set (80%) and a test set (20%). In comparison, data from our hospital's remaining 112 patients were used for external validation. Variable selection was performed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. Predictive models were constructed using six ML algorithms: decision trees, K-nearest neighbors (KNN), support vector machine, light gradient boosting machine, and extreme gradient boosting. Model efficacy was assessed through various metrics, including receiver operating characteristic (ROC) curves, precision-recall (PR) curves, confusion matrices, calibration plots, and decision curve analysis (DCA). The best-performing model was selected by comparing the performance of different algorithms. Moreover, variable relevance was ranked using the SHapley Additive exPlanations (SHAP) technique to improve the interpretability of the model and solve the "black box" problem. Results: A total of 191 patients (32.59%) achieved tpCR following NAC. Through LASSO regression analysis, five variables were identified as predictive factors for model construction, including tumor size, Ki-67, molecular subtype, targeted therapy, and chemotherapy regimen. The KNN model outperformed the other five classifier algorithms, achieving area under the curve (AUC) values of 0.847 (95% CI: 0.809-0.883) in the training set, 0.763 (95% CI: 0.670-0.856) in the test set, and 0.665 (95% CI: 0.555-0.776) in the external validation set. DCA demonstrated that the KNN model yielded the highest net advantage through a wide range of threshold probabilities in both the training and test sets. Furthermore, the analysis of the KNN model utilizing SHAP technology demonstrated that targeted therapy is the most crucial factor in predicting tpCR. Conclusion: An ML prediction model using clinical and pathological data collected before NAC was developed and verified. This model accurately predicted the probability of achieving a tpCR in patients with LABC after receiving NAC. SHAP technology enhanced the interpretability of the model and assisted in clinical decision-making and therapy optimization.

Effective amendment of cadmium in water and soil before and after aging of nitrogen-doped biochar: Preparation optimization, removal efficiency and mechanism.

Nitrogen-doped biochar (NBC) is a green material for remediating heavy metal pollution, but it undergoes aging under natural conditions, affecting its interaction with heavy metals. The preparation conditions of NBC were optimized using response surface methodology (RSM), and NBC was subjected to five different aging treatments to analyze the removal efficiency of Cd(II) and soil remediation capability before and after aging. The results indicated that NBC achieved optimal performance with a mass ratio of 5:2.43, an immersion time of 10.66 h, and a pyrolysis temperature of 900 °C. Aging diminished NBC's adsorption capacity for Cd(II) but did not change the main removal mechanism of monolayer chemical adsorption. Freeze-thaw cycles (FT), UV aging (L), and composite aging (U) treatments increased the proportion of bioavailable-Cd, and all aging treatments facilitated the conversion of potentially bioavailable-Cd to non-bioavailable-Cd. The application of NBC and five aged NBCs reduced the proportion of bioavailable-Cd in the soil through precipitation and complexation, increasing the proportion of non-bioavailable-Cd. Aging modifies the physicochemical properties of NBC, thus influencing soil characteristics and ultimately diminishing NBC's ability to passivate Cd in the soil. This study provides reference for the long-term application of biochar in heavy metal-contaminated environments.

Isolation and whole genomic analysis of mesophilic bacterium Pseudoglutamicibacter cumminsii in epithelial mesothelioma.

The relationship between bacteria and tumors has been the hot spot of clinical research in recent years. Pseudoglutamicibacter cumminsii is an aerobic Gram-positive bacterium commonly found in soil. Recent studies have identified P. cumminsii in patients with cutaneous and urinary tract infections. However, little is known on its pathogenesis as well as involvement in other clinical symptoms. In this study, we first report the isolation of P. cumminsii in blood of an epithelial mesothelioma patient. The clinical and laboratory characteristics of P. cumminsii were first described and evaluated. The pure colony of P. cumminsii was then identified using automated microorganism identification system and mass spectrum. The whole genome of the newly identified strain was sequenced with third generation sequencing (TGS). The assembled genome was further annotated and analyzed. Whole genomic and comparative genomic analysis revealed that the isolated P. cumminsii strain in this study had a genome size of 2,179,930 bp and had considerable unique genes compared with strains reported in previous findings. Further phylogenetic analysis showed that this strain had divergent phylogenetic relationship with other P. cumminsii strains. Based on these results, the newly found P. cumminsii strain was named P. cumminsii XJ001 (PC1). Virulence analysis identified a total of 71 pathogenic genes with potential roles in adherence, immune modulation, nutrition/metabolism, and regulation in PC1. Functional analysis demonstrated that the annotated genes in PC1 were mainly clustered into amino acid metabolism (168 genes), carbohydrate metabolism (107 genes), cofactor and vitamin metabolisms (98 genes), and energy metabolism (68 genes). Specifically, six genes including yodJ, idh, katA, pyk, sodA, and glsA were identified within cancer pathways, and their corresponding homologous genes have been documented with precise roles in human cancer. Collectively, the above results first identified P. cumminsii in the blood of tumor patients and further provide whole genomic landscape of the newly identified PC1 strain, shedding light on future studies of bacteria in tumorigenesis.

Silmitasertib (CX-4945) Disrupts ERα/HSP90 Interaction and Drives Proteolysis through the Disruption of CK2ß Function in Breast Cancer Cells.

Aberrant estrogen receptor (ERα) signaling mediates detrimental effects of tamoxifen including drug resistance and endometrial hyperplasia. ERα36, an alternative isoform of ERα, contributes to these effects. We have demonstrated that CK2 modulates ERα expression and function in breast cancer (BCa). Here, we assess if CX-4945 (CX), a clinical stage CK2 inhibitor, can disrupt ERα66 and ERα36 signaling in BCa. Using live cell imaging, we assessed the antiproliferative effects of CX in tamoxifen-sensitive and tamoxifen-resistant BCa cells in monolayer and/or spheroid cultures. CX-induced alterations in ERα66 and ERα36 mRNA and protein expression were assessed by RT-PCR and immunoblot. Co-immunoprecipitation was performed to determine the differential interaction of ERα isoforms with HSP90 and CK2 upon CX exposure. CX caused concentration-dependent decreases in proliferation in tamoxifen-sensitive MCF-7 and tamoxifen-resistant MCF-7 Tam1 cells and significantly repressed spheroid growth in 3D models. Additionally, CX caused dramatic decreases in endogenous or exogenously expressed ERα66 and ERα36 protein. Silencing of CK2ß, the regulatory subunit of CK2, resulted in destabilization and decreased proliferation, similar to CX. Co-immunoprecipitation demonstrated that ERα66/36 show CK2 dependance for interaction with molecular chaperone HSP90. Our findings show that CK2 functions regulate the protein stability of ERα66 and ERα36 through a mechanism that is dependent on CK2ß subunit and HSP90 chaperone function. CX may be a component of a novel therapeutic strategy that targets both tamoxifen-sensitive and tamoxifen-resistant BCa, providing an additional tool to treat ERα-positive BCa.

Safety and efficacy of minimally invasive gastrectomy for older patients with gastric cancer after neoadjuvant chemotherapy and immunotherapy: a propensity score-matched analysis.

BACKGROUND: The effect of neoadjuvant immunotherapy on minimally invasive gastrectomy (MIG) in older patients with gastric cancer remains controversial. This study aimed to evaluate the safety, and efficacy of MIG for older patients who underwent neoadjuvant chemotherapy and immunotherapy (NICT). METHODS: The clinical data of 726 older patients aged over 65 years who underwent upfront MIG or MIG after NICT in the Department of General Surgery, Chinese PLA General Hospital First Medical Center between Jan 2020 and Nov 2023 were retrospectively analyzed. Propensity score-matched (PSM) analysis at a ratio of 1:2 was performed to reduce bias from confounding patient-related variables, short- and long-term outcomes were compared between the two groups. RESULTS: The baseline characteristics were comparable between 61 patients in the NICT-MIG group and 114 patients in the MIG group after PSM (P > 0.05). The major pathological response (MPR) rate and pathological complete response (pCR) rate were 44.2% and 21.3%, respectively, in the NICT-MIG group. Patients in the NICT-MIG group had longer operation times (P = 0.005) and postoperative days (P = 0.030) than those in the MIG group. No significant differences were found in intraoperative bleeding, number of retrieved lymph nodes, first flatus day, R0 resection rate, overall postoperative complication (POC) morbidity, severe POC morbidity, 2-year overall, and recurrence-free survival between the MIG and NICT-MIG groups (P > 0.05). Multivariate logistic analysis revealed that an estimated blood loss > 200 mL (P = 0.010) and a lymphocyte-to-monocyte ratio (LMR) ≤ 3.25 (P = 0.006) were independent risk factors for POCs after MIG in older patients. CONCLUSION: The safety, and efficacy of NICT-MIG were comparable to those of upfront MIG in older patients with GC. Patients with an estimated blood loss > 200 mL or an LMR ≤ 3.25 should be carefully evaluated for an increased risk of POCs in older patients who undergo MIG. TRIAL REGISTRATION: Chinese Clinical Trial Registry (Registration Number: ChiCTR2400086827).

Akkermansia muciniphila-derived pentadecanoic acid enhances oxaliplatin sensitivity in gastric cancer by modulating glycolysis.

Accumulating evidence has proved the close association between alterations in gut microbiota and resistance to chemotherapeutic drugs. However, the potential roles of gut microbiota in regulating oxaliplatin sensitivity in gastric cancer (GC) have not been investigated before. We first found that antibiotic treatment diminished the therapeutic efficacy of oxaliplatin in a GC mouse model. Importantly, this effect could be transmitted to germ-free mice via fecal microbiota transplantation, indicating a potential role of gut microbiota modulation in oxaliplatin efficacy. Further, metagenomics data showed that Akkermansia muciniphila (A. muciniphila) ranked first among the bacterial species with decreased relative abundances after antibiotic treatment. Metabolically active A. muciniphila promotes oxaliplatin efficacy. As shown by metabolomics analysis, the metabolic pattern of gut microbiota was disrupted with significantly downregulated levels of pentadecanoic acid (PEA), and the use of PEA significantly promoted oxaliplatin efficacy. Mechanistically, FUBP1 positively regulated aerobic glycolysis of GC cells to hinder the therapeutic efficacy of oxaliplatin. A. muciniphila-derived PEA functioned as an inhibitory factor of glycolysis by directly antagonizing the activity of FUBP1, which potentiated GC responses to oxaliplatin. Our research suggested a key role for intestinal A. muciniphila and its metabolite PEA in promoting oxaliplatin efficacy, thus providing a new perspective for probiotic and prebiotic intervention in GC patients during chemotherapy.

Foliar application of selenium and gibberellins reduce cadmium accumulation in soybean by regulating interplay among rhizosphere soil metabolites, bacteria community and cadmium speciation.

Both selenium (Se) and gibberellins (GA3) can alleviate cadmium (Cd) toxicity in plants. However, the application of Se and GA3 as foliar spray to against Cd stress on soybean and its related mechanisms have been poorly explored. Herein, this experiment evaluated the effects of Se and GA3 alone and combined application on soybean rhizosphere microenvironment, Cd accumulation and growth of soybean seedlings. The results revealed that both Se and GA3 can effectively decrease the accumulation of Cd in soybean seedlings. Foliar application of Se, GA3 and their combination reduced Cd contents in soybean seedlings respectively by 21.70 %, 27.53 % and 45.07 % when compared with the control treatment, suggest a synergistic effect of Se and GA3 in decreasing Cd accumulation. Se and GA3 also significantly increased diversity and abundance of the metabolites in rhizosphere, which consequently played an important role in shaping rhizosphere bacteria community and improve rhizosphere soil physicochemical properties of Cd contaminated soil, as well as decreased the Cd available forms contents but enhance the immobilized form levels. Overall, this study affords a novel approach on mitigating Cd accumulation in soybean seedlings which is attributed to Se and GA3 regulated interplay among rhizosphere soil metabolites, bacteria community and cadmium speciation.

Jag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool.

Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.

S100 protein family: Emerging role and mechanism in digestive tract cancer (Review).

Digestive tract cancer is one of the most common types of cancers globally, with ~4.8 million new cases and 3.4 million cancer­associated deaths in 2018, accounting for 26% of cancer incidence and 35% of cancer­related deaths worldwide. S100 protein family is involved in regulating cancer cell proliferation, angiogenesis, epithelial­mesenchymal transition (EMT), metastasis, metabolism and immune microenvironment homeostasis. The critical role of S100 protein family in digestive tract cancer involves complicated mechanisms, such as cancer stemness remodeling, anaerobic glycolysis regulation, tumor­associated macrophage differentiation and EMT. The present study systematically reviewed published studies on the compositions, function and the underlying molecular mechanisms of the S100 family, as well as guidance for diagnosis, treatment and prognosis of digestive tract cancer. Systematic review of the roles and underlying molecular mechanisms of S100 protein family may provide new insight into exploring potential cancer biomarkers and the optimized therapeutic strategies for digestive tract cancer.

[Pseudo-targeted metabolomics study of immune stress-mediated idiosyncratic liver injury induced by synergistic effects of bavachin and epimedin B].

Chinese patent medicine preparations containing Epimedii Folium and Psoraleae Fructus have been associated with the occurrence of idiosyncratic drug-induced liver injury(IDILI). However, the specific toxic biomarkers and mechanisms underlying these effects remain unclear. This study aimed to comprehensively assess the impact of bavachin and epimedin B, two principal consti-tuents found in Psoraleae Fructus and Epimedii Folium, on an IDILI model induced by tumor necrosis factor-α(TNF-α) treatment, both in vitro and in vivo. To evaluate the extent of liver injury, various parameters were assessed. Lactate dehydrogenase(LDH) release in the cell culture supernatant, as well as the levels of alanine aminotransferase(ALT) and aspartate transaminase(AST) in mouse plasma were measured. Additionally, histological analysis employing hematoxylin-eosin staining was performed to observe liver tissue changes indicative of the severity of liver injury. Furthermore, a pseudo-targeted metabolomics approach was employed, followed by multivariate analysis, to identify differential metabolites. These identified metabolites were subsequently subjected to Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. The results showed that at the cellular level, after 2 hours of TNF-α stimulation, bavachin significantly increased the release of LDH in HepG2 cells compared to the normal group and the group treated alone; after the combination of bavachin and epimedin B, the release of LDH further significantly increased on the original basis. Similarly, although the individual or combination treatments of bavachin and epimedin B did not induce liver injury in normal mice, the combination of both drugs induced marked liver injury in TNF-α treated mice, leading to a significant elevation in plasma AST and ALT levels and substantial infiltration of inflammatory immune cells in the liver tissue. Pseudo-targeted metabolomics analysis identified seven common differential metabolites. Among these, D-glucosamine-6-phosphate, N1-methyl-2-pyridone-5-carboxamide, 17beta-nitro-5a-androstane, irisolidone-7-O-glucuronide, and N-(1-deoxy-1-fructosyl) valine emerged as potential biomarkers, with an area under the curve(AUC) exceeding 0.9. Furthermore, our results suggest that the metabolism of nicotinic acid and nicotinamide, as well as the linoleic acid metabolic pathway, may play pivotal roles in bavachin and epimedin B-induced IDILI. In conclusion, within an immune-stressed environment mediated by TNF-α, bavachin and epimedin B appear to induce IDILI through disruptions in metabolic processes.

Protective role of pyrroloquinoline quinone against gentamicin induced cochlear hair cell ototoxicity.

Gentamicin (GM) is one of the commonly used antibiotics in the aminoglycoside class but is ototoxic, which constantly impacts the quality of human life. Pyrroloquinoline quinone (PQQ) as a redox cofactor produced by bacteria was found in soil and foods that exert an antioxidant and redox modulator. It is well documented that the PQQ can alleviate inflammatory responses and cytotoxicity. However, our understanding of PQQ in ototoxicity remains unclear. We reported that PQQ could protect against GM-induced ototoxicity in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells in vitro. To evaluate reactive oxygen species (ROS) production and mitochondrial function, ROS and JC-1 staining, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) measurements in living cells, mitochondrial dynamics analysis was performed. GM-mediated damage was performed by reducing the production of ROS and inhibiting mitochondria biogenesis and dynamics. PQQ ameliorated the cellular oxidative stress and recovered mitochondrial membrane potential, facilitating the recovery of mitochondrial biogenesis and dynamics. Our in vitro findings improve our understanding of the GM-induced ototoxicity with therapeutic implications for PQQ.

Total versus proximal gastrectomy for proximal gastric cancer after neoadjuvant chemotherapy: a multicenter retrospective propensity score-matched cohort study.

BACKGROUND: This study aimed to analyze and compare the short-term and long-term outcomes of proximal gastrectomy (PG) and total gastrectomy (TG) in patients with locally advanced proximal gastric cancer (GC) following neoadjuvant chemotherapy (NACT). METHOD: A multicenter retrospective cohort study and propensity score matching (PSM) were employed. The authors examined 367 patients with proximal GC who received NACT followed by PG ( n =164) or TG ( n =203) at two Chinese medical institutions between December 2009 and December 2022. Clinical and pathological parameters, postoperative complications, and 5-year overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups. The dissection status and metastasis rate of each lymph node station were assessed. RESULTS: After PSM, 80 patients were enrolled in both TG and PG group, and baseline characteristics were comparable between the groups (all P >0.05). The TG group had a higher total number of lymph nodes retrieved ( P <0.001) and longer operative time ( P =0.007) compared to the PG group. The incidence of Clavien-Dindo grade II or higher postoperative complications was similar between the TG group (21.3%, 17/80) and the PG group (17.5%, 14/80) ( P =0.689). The 5-year OS rates were 68.4 for the PG group and 66.0% for the TG group ( P =0.881), while the 5-year RFS rates were 64.8 and 61.9%, respectively ( P =0.571), with no statistically significant differences. Metastasis rates at lymph node stations #4d, #5, #6, and #12a were notably low in the TG group, with values of 2.74, 0.67, 1.33, and 1.74%, respectively. CONCLUSION: For proximal GC patients following NACT, PG maintains comparable curative potential and oncological efficacy to TG, making it a safe option.

Collectin 11 has a pivotal role in host defense against kidney and bladder infection in mice.

The urinary tract is constantly exposed to microorganisms. Host defense mechanisms in protection from microbial colonization and development of urinary tract infections require better understanding to control kidney infection. Here we report that the lectin collectin 11 (CL-11), particularly kidney produced, has a pivotal role in host defense against uropathogen infection. CL-11 was found in mouse urine under normal and pathological conditions. Mice with global gene ablation of Colec11 had increased susceptibility to and severity of kidney and to an extent, bladder infection. Mice with kidney-specific Colec11 ablation exhibited a similar disease phenotype to that observed in global Colec11 deficient mice, indicating the importance of kidney produced CL-11 for protection against kidney and bladder infection. Conversely, intravesical or systemic administration of recombinant CL-11 reduced susceptibility to and severity of kidney and bladder infection. Mechanism analysis revealed that CL-11 can mediate several key innate defense mechanisms (agglutination, anti- adhesion, opsonophagocytosis), and limit local inflammatory responses to pathogens. Furthermore, CL-11-mediated innate defense mechanisms can act on clinically relevant microorganisms including multiple antibiotic resistant strains. CL-11 was detectable in eight of 24 urine samples from patients with urinary tract infections but not detectable in urine samples from ten healthy individuals. Thus, our findings demonstrate that CL-11 is a key factor of host defense mechanisms in kidney and bladder infection with therapeutic potential for human application.

Enhancing surgical precision: unveiling the impact of preoperative colonoscopy in anal fistula patients.

BACKGROUND: Anal fistula is a common benign anorectal disease that often requires surgical intervention for effective treatment. In recent years, preoperative colonoscopy as a diagnostic tool in patients with anal fistula has garnered increasing attention due to its potential clinical application value. By investigating underlying inflammatory bowel disease (IBD), polyps, and other abnormalities, preoperative colonoscopy can offer insights to refine surgical strategies and improve patient outcomes. METHODS: This retrospective study focused on 1796 patients with various benign anorectal diseases who underwent preoperative intestinal endoscopy and met surgical criteria within the preceding three years at the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine. Among these patients, 949 diagnosed with anal fistula comprised group A, while 847 patients without anal fistula were assigned to group B for comparison. The investigation encompassed an analysis of general patient information, endoscopic findings, polyp histopathology, distribution of bowel inflammation sites, and results of inflammatory bowel disease assessments between the two patient cohorts. A subgroup analysis was also conducted on 2275 anal fistula patients with no surgical contraindications. This subgroup was categorized into Group A (949 patients who underwent preoperative intestinal endoscopy) and Group C (1326 patients who did not undergo preoperative colonoscopy). The study compared the rates of detecting endoscopic lesions and IBD-related findings between the two subgroups. RESULTS: The study initially confirmed the comparability of general patient information between groups A and B. Notably, the abnormal detection rate in group A was significantly higher than in group B (P < 0.01). In terms of endoscopic findings, the anal fistula group (group A) exhibited higher rates of detecting bowel inflammation, inflammatory bowel disease, and polyps compared to the non-anal fistula group (group B) (P < 0.05). The distribution of inflammation locations indicated higher detection rates in the terminal ileum, ileocecal region, and ascending colon for group A compared to group B (P < 0.05). Although the incidence of IBD in group A was higher than in group B, this difference did not reach statistical significance (P > 0.05). Subsequently, the analysis of the subgroup (groups A and C) revealed a significant disparity in intestinal endoscopic detection rates (P < 0.01) and statistically significant differences in detecting IBD (P < 0.05) and Crohn's disease (P < 0.05) between the two anal fistula subgroups. CONCLUSIONS: The findings of this study underscore the substantial clinical value of preoperative colonoscopy in the comprehensive evaluation of patients with anal fistula. Preoperative colonoscopy aids in ruling out localized perianal lesions caused by underlying inflammatory bowel disease, thereby mitigating the likelihood of missed diagnoses and enhancing treatment outcomes. This research highlights the importance of incorporating preoperative colonoscopy as a valuable diagnostic tool in managing anal fistula patients.

Immune response to foreign materials in spinal fusion surgery.

Spinal fusion surgery is a common procedure used to stabilize the spine and treat back pain. The procedure involves the use of foreign materials such as screws, rods, or cages, which can trigger a foreign body reaction, an immune response that involves the activation of immune cells such as macrophages and lymphocytes. The foreign body reaction can impact the success of spinal fusion, as it can interfere with bone growth and fusion. This review article provides an overview of the cellular and molecular events in the foreign body reaction, the impact of the immune response on spinal fusion, and strategies to minimize its impact. By carefully considering the use of foreign materials and optimizing surgical techniques, the impact of the foreign body reaction can be reduced, leading to better outcomes for patients.

Prognostic relevance of tumor­infiltrating lymphocytes in residual tumor tissue from patients with triple­negative breast cancer following neoadjuvant chemotherapy: A systematic review and meta­analysis.

Further adjuvant chemotherapy treatment can provide benefits to certain patients with triple-negative breast cancer (TNBC) that fail to achieve pathological complete response (pCR) after the administration of a neoadjuvant chemotherapy (NAC) regimen. However, biomarkers suitable for identifying patients likely to experience poor prognostic outcomes after undergoing additional adjuvant chemotherapy are currently lacking. Accordingly, the present meta-analysis was conducted to explore the relationship between tumor-infiltrating lymphocytes (TILs) or TIL subtypes (CD4+ or CD8+) in residual tumor (RT) tissue following NAC and TNBC patient prognosis. Relevant studies published through March 2023 were identified in Pubmed, The Cochrane Library, Embase and Web of Science databases. After excluding irrelevant studies, data were extracted from the remaining reports, while study quality was analyzed with the Newcastle-Ottawa Scale. Subsequent analyses were performed with Stata 14.0 and Review Manager 5.3. In total, seven relevant studies incorporating 1,202 patients were identified, all of which were retrospective cohort studies. Pooled analyses demonstrated that those patients exhibiting higher levels of RT TIL infiltration following NAC exhibited significantly improved recurrence-free, metastasis-free and event-free survival (RFS/MFS/EFS) compared with patients with lower RT TIL infiltration levels, together with an improved distant recurrence-free interval (DRFI) [hazard ratio (HR)=0.52; 95% confidence interval (CI)=0.39-0.69; P<0.00001]. In addition, patients exhibiting high RT TIL infiltration exhibited improved overall survival (OS) and breast cancer-specific survival (BCSS; HR=0.49; 95% CI=0.38-0.65; P<0.00001). Additional subgroup analyses revealed that patients with higher TIL infiltration levels or TIL subtype (CD4+ or CD8+) infiltration exhibited improved RFS/MFS/EFS/DRFI as compared with patients with lower levels of overall TIL or TIL subtype (CD4+ or CD8+) infiltration in RT tissue (HR=0.35, 95% CI=0.20-0.59, P<0.0001; HR=0.49, 95% CI=0.33-0.71, P=0.0002). Consistently, the OS/BCSS of patients exhibiting high levels of overall TIL or TIL subtype (CD4+ or CD8+) infiltration was increased compared with patients with lower levels of such infiltration (HR=0.33, 95% CI=0.19-0.59, P=0.0002; HR=0.55, 95% CI=0.41-0.76, P=0.0002). These data thus demonstrate that levels of overall TIL infiltration or infiltration by CD4+ or CD8+ TILs in RT following NAC can be used as a biomarker to reliably predict prognostic outcomes in patients with TNBC, in addition to highlighting possible targets that may guide the further immunotherapeutic management of these patients.

Associations between Differential Aging and Lifestyle, Environment, Current, and Future Health Conditions: Findings from Canadian Longitudinal Study on Aging.

INTRODUCTION: An aging population will bring a pressing challenge for the healthcare system. Insights into promoting healthy longevity can be gained by quantifying the biological aging process and understanding the roles of modifiable lifestyle and environmental factors, and chronic disease conditions. METHODS: We developed a biological age (BioAge) index by applying multiple state-of-art machine learning models based on easily accessible blood test data from the Canadian Longitudinal Study of Aging (CLSA). The BioAge gap, which is the difference between BioAge index and chronological age, was used to quantify the differential aging, i.e., the difference between biological and chronological age, of the CLSA participants. We further investigated the associations between the BioAge gap and lifestyle, environmental factors, and current and future health conditions. RESULTS: BioAge gap had strong associations with existing adverse health conditions (e.g., cancers, cardiovascular diseases, diabetes, and kidney diseases) and future disease onset (e.g., Parkinson's disease, diabetes, and kidney diseases). We identified that frequent consumption of processed meat, pork, beef, and chicken, poor outcomes in nutritional risk screening, cigarette smoking, exposure to passive smoking are associated with positive BioAge gap ("older" BioAge than expected). We also identified several modifiable factors, including eating fruits, legumes, vegetables, related to negative BioAge gap ("younger" BioAge than expected). CONCLUSIONS: Our study shows that a BioAge index based on easily accessible blood tests has the potential to quantify the differential biological aging process that can be associated with current and future adverse health events. The identified risk and protective factors for differential aging indicated by BioAge gap are informative for future research and guidelines to promote healthy longevity.

Sijunzi Tang improves gefitinib resistance by regulating glutamine metabolism.

Lung cancer is a major health concern and significant barrier to human well-being and social development. Although targeted therapy has shown remarkable progress in the treatment of lung cancer, the emergence of drug resistance has limited its clinical efficacy. Sijunzi Tang (SJZ) is a classical Chinese herbal formula known for tonifying qi and nourishing the lungs, has been recognized for its potential in lung cancer management. However, the underlying mechanism of its combined use with anti-cancer drugs remains unclear. Here, we investigated the anti-lung cancer efficacy and underlying mechanisms of the combination of gefitinib and SJZ in gefitinib-resistant human lung adenocarcinoma cells (PC-9/GR). We conducted in vitro and in vivo experiments using histopathology and targeted metabolomics approaches. Our results demonstrated that the combination of SJZ and gefitinib exhibited synergistic effects on tumor growth inhibition in PC-9/GR-bearing nude mice. Notably, the co-administration of SJZ and gefitinib synergistically promoted tumor cell apoptosis, potentially through the regulation of BAX and BCL-2 expression. Immunohistochemistry and western blot analysis found down-regulation of GLS, GS, and SLC1A5 expression in the co-administration group compared to the control and the individual treatment groups. Targeted metabolomics revealed significant alterations in the plasma glutamine metabolic markers glutamine, alanine, succinate, glutamate, and pyruvate. Of the glutamine metabolism markers measured in tumor tissues, glutamine and pyruvate demonstrated significant differences across the treatment groups. These findings suggest that administration of SJZ improves gefitinib resistance in the treatment of lung cancer without toxic effects. Moreover, SJZ may affect glutamine metabolism by regulating key targets involved in glutamine metabolism (SLC1A5, GLS, and GS) and modulating the levels of related metabolic markers, ultimately reducing gefitinib resistance.

Potential prognostic and therapeutic value of ANXA8 in renal cell carcinoma: based on the comprehensive analysis of annexins family.

BACKGROUND: Annexins are a family of proteins involved in a wide variety of cellular processes such as inflammation, proliferation, differentiation, apoptosis, migration and membrane repair. However, the role of most Annexins in renal cell carcinoma (RCC) remained unclear. METHODS: The differentially expressed Annexins in RCC compared with normal controls were screened applying the TCGA database. The correlation of differentially expressed Annexins with clinical stages, grades and overall survival was analyzed to explore the clinical significance of Annexins in RCC. Then ANXA8 was selected and further stained in the discover and validation RCC cohort. The correlation of ANXA8 expression with clinical parameter was verified at the protein level. To explore the potential function of ANXA8, ANXA8 was knockdown in the RCC cell line and further analyzed using transcriptome and bioinformatic analysis. RESULTS: mRNA expression of ANXA1, ANXA2R, ANXA4, ANXA8, ANXA8L1 and ANXA13 were significantly upregulated in RCC compared with normal kidney tissues. In contrast, ANXA3 and ANXA9 mRNA expression was significantly downregulated. Higher expression of ANXA2R, ANXA8 and ANXA8L1 were correlated with worse overall survival, while lower expression of ANXA3, ANXA9 and ANXA13 were associated with worse clinical outcomes in RCC patients. We further demonstrated that ANXA8 expression was significantly increased in RCC compared with normal renal tissues at the protein level. And higher protein expression of ANXA8 was associated with higher clinical grades. Through the bioinformatics analysis and cell cycle analysis, we found knockdown of ANXA8 mainly influenced the cell cycle and DNA replication. The top ten hub genes consist of CDC6, CDK2, CHEK1, CCNB1, ORC1, CHEK2, MCM7, CDK1, PCNA and MCM3. CONCLUSIONS: Multiple members of Annexins were abnormally expressed and associated with the prognosis of RCC. The expression of ANXA8 was significantly increased in RCC and associated with poor prognosis. ANXA8 might influence the cell cycle and could be a potential biomarker and therapeutic target for RCC.

The recent progress of endocrine therapy-induced osteoporosis in estrogen-positive breast cancer therapy.

Breast cancer is a significant global health concern, and the discovery of endocrine therapy has played a crucial role in the treatment of estrogen-positive breast cancer. However, these therapies are often associated with osteoporosis-related adverse events, which increase the risk of fractures in breast cancer patients and can result in limited mobility and reduced quality of life. Previous studies have shown that osteoporosis is essential side effects of the breast cancer therapy, although the exact mechanisms remain mostly unclear. Current clinical treatments, such as bisphosphonates, cause side effects and may impact the therapeutic response to endocrine drugs. In this review, we explore the likelihood of endocrine therapy-induced osteoporosis in estrogen-positive breast cancer therapy and discuss the involved mechanisms as well as the therapeutic potential of drugs and drug combination strategies.