Signal Transduction and Targeted Therapy最新文献

The vaginal microbiome is critical for the reproductive health of women, yet the differential impacts exerted by the host and by ambient environmental variables on the vaginal microbiome remain largely unknown. Here, we conducted a comprehensive cross-sectional study of the relationships between the vaginal microbiome and 81 matched host and environmental variables across 6755 Chinese women. By 16S rRNA sequencing, we identified four core vaginal microbiota with a prevalence of over 90% and a total median abundance of 98.8%. Twenty-four variables, including physiology, lifestyle behaviors, gynecologic history, social and environmental information, were found associated with the microbiome composition, of which bacterial vaginosis (BV) showed the largest effect size. Age was among the strongest explanatory variables and the vaginal microbiome dynamically succeeded with increasing age, especially with a composition turning point at the age of 45. Our mediation analyses indicated that the effects of age on the microbiome could be mediated by variables such as parity number and lifestyles. We further classified the vaginal microbiomes of the population into 13 “Vagitypes”. Women with Lactobacillus iners- and Lactobacillus jensenii-dominated Vagitypes had significantly higher live birth rate than those with Vagitype dominated by Fannyhessea vaginae (53.40%, 59.09% vs 21.43%; OR [95% CI]: 3.62 [1.12–14.87], 5.39 [1.27–27.36]; P = 0.031, P = 0.021). This study provides a comprehensive overview of the associations between identified variables and the vaginal microbiome, representing an important step toward understanding of environment-microbe-host interactions.

Breast cancer, characterized by unique epidemiological patterns and significant heterogeneity, remains one of the leading causes of malignancy-related deaths in women. The increasingly nuanced molecular subtypes of breast cancer have enhanced the comprehension and precision treatment of this disease. The mechanisms of tumorigenesis and progression of breast cancer have been central to scientific research, with investigations spanning various perspectives such as tumor stemness, intra-tumoral microbiota, and circadian rhythms. Technological advancements, particularly those integrated with artificial intelligence, have significantly improved the accuracy of breast cancer detection and diagnosis. The emergence of novel therapeutic concepts and drugs represents a paradigm shift towards personalized medicine. Evidence suggests that optimal diagnosis and treatment models tailored to individual patient risk and expected subtypes are crucial, supporting the era of precision oncology for breast cancer. Despite the rapid advancements in oncology and the increasing emphasis on the clinical precision treatment of breast cancer, a comprehensive update and summary of the panoramic knowledge related to this disease are needed. In this review, we provide a thorough overview of the global status of breast cancer, including its epidemiology, risk factors, pathophysiology, and molecular subtyping. Additionally, we elaborate on the latest research into mechanisms contributing to breast cancer progression, emerging treatment strategies, and long-term patient management. This review offers valuable insights into the latest advancements in Breast Cancer Research, thereby facilitating future progress in both basic research and clinical application.

Chemo-immunotherapy is the current first-line treatment for patients with extensive-stage small cell lung cancer (ES-SCLC), but survival benefits are modest. We aimed to evaluate the safety, antitumor activity and biomarkers of first-line camrelizumab and apatinib plus chemotherapy in untreated ES-SCLC patients. In this single-arm trial (ClinicalTrials.gov NCT05001412), eligible patients received 2 cycles of etoposide and carboplatin (EC) as induction treatment followed by 2–4 cycles of camrelizumab, apatinib plus EC, then maintenance camrelizumab plus apatinib. Primary endpoint was safety. Secondary endpoints included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Targeted sequencing and whole transcriptome sequencing were performed to explore biomarkers. All enrolled 40 patients were treated and analyzed for safety. During the entire treatment, treatment-emergent adverse events (TEAEs) occurred in 40 patients (100%), and 30 (75.0%) were grade ≥3. The most common grade ≥3 TEAEs were neutropenia (35.0%), anemia (15.0%) and increased alanine aminotransferase (15.0%). No treatment-related deaths occurred. Among 36 evaluable patients, ORR was 88.9% (95% CI: 73.9%–96.9%), median PFS was 7.3 months (95% CI: 6.6–9.2) and median OS was 17.3 months (11.8-not reached). Mutations in RB1, high levels of tumor mutation burden, natural killer cells, and interferons, and low levels of cancer-associated fibroblasts, correlated with prolonged PFS. Induction chemotherapy followed by camrelizumab, apatinib plus EC demonstrated acceptable safety and promising antitumor activity in untreated ES-SCLC patients. The identified biomarkers need further validation.

Trial Registration ClinicalTrials.gov Identifier: NCT05001412.

Dear Editor,

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention. Mitochondrial malate dehydrogenase (MDH2), an enzyme in the TCA cycle, was identified as an anti-aging target through activity-based protein profiling in present study. The expression level of MDH2 was positively correlated with the cellular senescence in Mdh2 knockdown or overexpression fibroblasts. Glibenclamide (Gli), a classic anti-glycemic drug, was found to inhibit the activity of MDH2 and relieve fibroblast senescence in an MDH2-dependent manner. The anti-aging effects of Gli were also further validated in vivo, as it extended the lifespan and reduced the frailty index of naturally aged mice. Liver specific Mdh2 knockdown eliminated Gli’s beneficial effects in naturally aged mice, reducing p16^INK4a expression and hepatic fibrosis. Mechanistically, MDH2 inhibition or knockdown disrupted central carbon metabolism, then enhanced the methionine cycle flux, and subsequently promoted histone methylation. Notably, the tri-methylation of H3K27, identified as a crucial methylation site in reversing cellular senescence, was significantly elevated in hepatic tissues of naturally aged mice with Mdh2 knockdown. Taken together, these findings reveal that MDH2 inhibition or knockdown delays the aging process through metabolic-epigenetic regulation. Our research not only identified MDH2 as a potential therapeutic target and Gli as a lead compound for anti-aging drug development, but also shed light on the intricate interplay of metabolism and epigenetic modifications in aging.

This phase III trial aimed to compare ARX788, a site-specific, construct-homogeneous antibody-drug conjugate, with lapatinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) who had progressed on one line of trastuzumab based regimen. Eligible patients were randomized (1:1) to receive ARX788 (1.5 mg/kg, IV, Q3W) or lapatinib plus capecitabine (LC: lapatinib 1250 mg QD; capecitabine 1000 mg/m² BID, days 1–14, Q3W) and stratified by prior chemotherapy lines (0-1 versus >1) and visceral metastasis (yes versus no). The primary outcome was progression-free survival (PFS) assessed by a blinded independent central review (BICR). A total of 441 patients were randomly assigned to receive either ARX788 (n = 221) or LC (n = 220). The median PFS was 11.3 (95% confidence interval [CI], 8.4–13.8) months with ARX788 compared with 8.2 (95% CI, 6.9–8.7) months with LC, as per BICR (hazard ratio [HR] 0.64, p = 0.0006). Frequencies of treatment-related adverse events (TRAEs) of any grade were 98.6% and 99.1% for ARX788 and LC, respectively. Grade ≥3 TRAEs were 41.4% and 40.0%, respectively, the most common adverse events were blurred vision (12.3%), dry eye (9.1%), keratopathy (5.9%), and interstitial lung disease (ILD, 5.9%) with ARX788; hand-foot syndrome (18.1%) and hypokalemia (5.1%) with LC; all the hematological and gastrointestinal events of grade ≥3 with ARX788 were less than 3%. Six treatment-related deaths occurred, with three cases possibly related to ILD. ARX788 significantly improved PFS compared with LC in patients with HER2-positive ABC with a distinct toxicity profile, supporting it as a potential treatment option.

Aggressive tumors pose ultra-challenges to drug resistance. Anti-cancer treatments are often unsuccessful, and single-cell technologies to rein drug resistance mechanisms are still fruitless. The National Cancer Institute defines aggressive cancers at the tissue level, describing them as those that spread rapidly, despite severe treatment. At the molecular, foundational level, the quantitative biophysics discipline defines aggressive cancers as harboring a large number of (overexpressed, or mutated) crucial signaling proteins in major proliferation pathways populating their active conformations, primed for their signal transduction roles. This comprehensive review explores highly aggressive cancers on the foundational and cell signaling levels, focusing on the differences between highly aggressive cancers and the more treatable ones. It showcases aggressive tumors as harboring massive, cancer-promoting, catalysis-primed oncogenic proteins, especially through certain overexpression scenarios, as predisposed aggressive tumor candidates. Our examples narrate strong activation of ERK1/2, and other oncogenic proteins, through malfunctioning chromatin and crosslinked signaling, and how they activate multiple proliferation pathways. They show the increased cancer heterogeneity, plasticity, and drug resistance. Our review formulates the principles underlying cancer aggressiveness on the molecular level, discusses scenarios, and describes drug regimen (single drugs and drug combinations) for PDAC, NSCLC, CRC, HCC, breast and prostate cancers, glioblastoma, neuroblastoma, and leukemia as examples. All show overexpression scenarios of master transcription factors, transcription factors with gene fusions, copy number alterations, dysregulation of the epigenetic codes and epithelial-to-mesenchymal transitions in aggressive tumors, as well as high mutation loads of vital upstream signaling regulators, such as EGFR, c-MET, and K-Ras, befitting these principles.

Aberrant RNA alternative splicing in cancer generates varied novel isoforms and protein variants that facilitate cancer progression. Here, we employed the advanced long-read full-length transcriptome sequencing on gallbladder normal tissues, tumors, and cell lines to establish a comprehensive full-length gallbladder transcriptomic atlas. It is of note that receptor tyrosine kinases were one of the most dynamic components with highly variable transcript, with Erb-B2 receptor tyrosine kinase 2 (ERBB2) as a prime representative. A novel transcript, designated ERBB2 i14e, was identified for encoding a novel functional protein, and its protein expression was elevated in gallbladder cancer and strongly associated with worse prognosis. With the regulation of splicing factors ESRP1/2, ERBB2 i14e was alternatively spliced from intron 14 and the encoded i14e peptide was proved to facilitate the interaction with ERBB3 and downstream signaling activation of AKT. ERBB2 i14e was inducible and its expression attenuated anti-ERBB2 treatment efficacy in tumor xenografts. Further studies with patient derived xenografts models validated that ERBB2 i14e blockage with antisense oligonucleotide enhanced the tumor sensitivity to trastuzumab and its drug conjugates. Overall, this study provides a gallbladder specific long-read transcriptome profile and discovers a novel mechanism of trastuzumab resistance, thus ultimately devising strategies to improve trastuzumab therapy.