Circulating tumor DNA: from discovery to clinical application in breast cancer.

Breast cancer (BC) stands out as the cancer with the highest incidence of morbidity and mortality among women worldwide, and its incidence rate is currently trending upwards. Improving the efficiency of breast cancer diagnosis and treatment is crucial, as it can effectively reduce the disease burden. Circulating tumor DNA (ctDNA) originates from the release of tumor cells and plays a pivotal role in the occurrence, development, and metastasis of breast cancer. In recent years, the widespread application of high-throughput analytical technology has made ctDNA a promising biomarker for early cancer detection, monitoring minimal residual disease, early recurrence monitoring, and predicting treatment outcomes. ctDNA-based approaches can effectively compensate for the shortcomings of traditional screening and monitoring methods, which fail to provide real-time information and prospective guidance for breast cancer diagnosis and treatment. This review summarizes the applications of ctDNA in various aspects of breast cancer, including screening, diagnosis, prognosis, treatment, and follow-up. It highlights the current research status in this field and emphasizes the potential for future large-scale clinical applications of ctDNA-based approaches.

Appropriate thromboprophylaxis strategy for COVID-19 patients on dosage, antiplatelet therapy, outpatient and post-discharge prophylaxis: a meta-analysis of randomized controlled trials.

BACKGROUND: There was controversy surrounding the optimal thromboprophylaxis strategy for COVID-19 patients. This included debates on the dosage of anticoagulants for thromboembolism prophylaxis, the requirement for additional antiplatelet therapy, and the necessity of prophylaxis for outpatients and post-discharge. To explore this, we performed a meta-analysis of randomized controlled trials. METHODS: PubMed, Cochrane Library, Embase, and Web of Science were last searched on 26 July 2023 for studies comparing the effect of different dose of anticoagulation, additional antiplatelet and post-discharge prophylaxis for COVID-19 patients. The results of eligible studies were analyzed in terms of thromboembolism events, major bleeding and all-cause mortality during follow-up. RESULTS: Our study included a total of 25 randomized controlled trials, involving 17,911 patients. Our results revealed that, compared to prophylactic dose, therapeutic dose showed lower thrombotic risk (RR, 0.66; 95%CI, 0.45 to 0.96) but had similar major bleeding risk for critically ill patients with COVID-19. On the other hand, intermediate dose and prophylactic dose demonstrated similar thromboembolism risk and major bleeding risk. For non-critically ill patients with COVID-19, therapeutic dose of anticoagulants was associated with lower thrombotic risk (RR, 0.50; 95%CI 0.34 to 0.72) but, at the same time, increased the risk of major bleeding (RR, 2.01; 95%CI 1.22 to 3.33). However, intermediate dose showed lower thromboembolism risk (RR, 0.38; 95%CI 0.21 to 0.69) while maintaining a similar major bleeding risk. In critically ill patients, additional antiplatelet therapy showed similar thromboembolism, major bleeding risk, and mortality when compared to no treatment. For outpatients, additional prophylactic anticoagulation showed similar thromboembolism, major bleeding risk, and mortality when compared to no treatment. For post-discharge patients, post-discharge prophylaxis reduced thromboembolism risk (RR, 0.49; 95%CI 0.31 to 0.76) but increased major bleeding risk (RR, 2.63; 95%CI, 1.13 to 6.14). CONCLUSION: For non-critically ill patients, therapeutic dose prophylactic anticoagulation significantly reduced venous thromboembolism but increases major bleeding risk. Intermediate dose effectively lowered venous thromboembolism without raising major bleeding risk. The optimal dose and need for additional antiplatelet therapy in critically ill patients, as well as the necessity of prophylactic anticoagulation in outpatient and post-discharge patients, required further investigation and confirmation through rigorous evidence studies.

Similar outcomes between arthroscopic capsular release and manipulation under anaesthesia for frozen shoulder: A meta-analysis.

To compared the arthroscopic capsular release (ACR) with manipulation under anaesthesia (MUA) for the surgical treatment of frozen shoulder (FS) based on postoperative outcomes and complications. PubMed, Cochrane Library, Embase, and Web of Science were searched on October 2, 2023 to retrieve eligible studies that compared ACR with MUA in terms of clinical outcomes (pain visual analogue scale, external rotation, forward flexion and adverse events) for patients with FS. Mean differences (MD) were calculated for continuous outcomes and odds ratios (OR) were calculated for dichotomous outcomes. Six papers, including 5 clinical studies (a total of 690 shoulders), were included in the final meta-analysis. The forward flexion was found to be larger in the ACR group at 3 months (MD, 2.73; 95%CI, 0.42-5.04; I2 = 44%; P = 0.02) and 6 months (MD, 2.36; 95%CI, 1.29-3.44; I2 = 0%; P < 0.0001). Except for this, ACR was comparable with MUA in terms of pain visual analogue scale at 3, 6 and 12 months (p = 0.25, p = 0.11, p = 0.28, respectively), external rotation at 3, 6 and 12 months (p = 0.15, p = 0.52, p = 0.23, respectively), and forward flexion at 12 months (p = 0.08). There were no differences in complication rates between the two groups (OR, 0.82; 95%CI, 0.47-1.44; I2 = 0%; P = 0.50). In comparison with MUA, ACR demonstrated better outcomes for forward flexion at 3 and 6 months, while there were no significant differences between ACR and MUA in terms of pain visual analogue scale, external rotation and adverse events.

Long-term effects of exercise therapy versus arthroscopic partial meniscectomy for degenerative meniscal tear: A meta-analysis of randomized controlled trials.

BACKGROUND: Degenerative meniscal tear (DMT) is common in the elderly population. However, there has been controversy over the treatment of DMT regarding whether to adopt arthroscopic partial meniscectomy (APM) or exercise therapy (ET). In order to compare the long-term outcomes between the two treatment methods, we conducted a meta-analysis of randomized controlled trials (RCTs) with long-term follow-up. METHODS: PubMed, Cochrane Library, Embase, and Web of Science were last searched on 16 April 2023 for studies on DMT that compared the clinical outcomes between APM and ET. The subjective outcomes of the comparison include the Knee Injury and Osteoarthritis Outcome Score (KOOS), which consists of five sub-scales: pain, symptoms, activities of daily living (ADL), sport and recreation (Sport/recreation), and quality of life (QOL). The objective outcome includes knee osteoarthritis progression. RESULTS: We identified 6 potentially eligible trials, including 1078 participants, from the literature search. ET showed a lower risk of knee osteoarthritis progression than APM (RR, 1·27; 95%CI 1·05 to 1·53). There were no statistically significant differences in the KOOS-pain, KOOS-symptoms, KOOS-ADL, KOOS-Sport/recreation, and KOOS-QOL between the two treatment methods. CONCLUSION: For the treatment of DMT, ET showed a lower risk of knee osteoarthritis progression than APM. ET and APM had comparable effects on subjective outcomes including pain management and knee function. Therefore, it is not recommended to use APM but rather recommended to use ET for treating APM.

Preferences in anterior cruciate ligament reconstruction: A survey among orthopedic surgeons in China.

The purpose of this study was to reveal the current trends and preferences of Chinese orthopedic surgeons regarding anterior cruciate ligament (ACL) reconstruction through a nationwide web-based survey conducted in China. The survey questionnaire was distributed via WeChat to the chairmen of provincial orthopedic and sports medicine organizing committees in China, who then shared it in their respective WeChat workgroups. The questionnaire consisted of 52 multiple-choice questions covering 8 sections. Data collection was implemented by Questionnaire Star. A total of 812 valid questionnaires were returned: 94.21% of the respondents preferred single-bundle reconstruction of ACL, while 61.70% preferred autogenous semitendinosus plus gracilis reconstruction; 76.35% of the respondents preferred establishing the femoral tunnel first, while 47.29% preferred establishing the femoral tunnel through a medial auxiliary approach; and 85.10% of the respondents recommended patients to undergo surgery within 3 months after ligament injury. Besides, the vast majority of respondents chose to retain the ligamentous remnant bundle (92.98%) and recommended routine use of knee braces postoperatively (94.09%). It is recommended to perform arthroscopic single-bundle ACL reconstruction with the remnant preserving technique using a hamstring autograft within 3 months of ACL rupture, with support of postoperative functional braces.

Evidence of Coal Biodegradation from Coalbed-Produced Water - A Case Study of Dafosi Gas Field, Ordos Basin, China.

Bioconversion of coal to methane occurs in the coalbed aquifer environment. To investigate the evidence of coal biodegradation from coalbed-produced water, we collected six field water samples from the Dafosi gas field and prepared one laboratory-simulated water sample and one indoor anaerobic microbial degradation sample with the highest compound concentration as the two reference standards. Gas chromatography-mass spectrometry was used to detect the organic compound type, concentration, and differences in the biomarker compound sensitivity. Results indicate that extracted organic matter from coalbed-produced water samples can be evidence of biodegradation. Variations in range compounds (such as n-alkanes, tri- and pentacyclic terpenes, and steranes) and their sensitivity confirmed active microbial degradation in the studied area. A positive correlation between the n-alkanes content in the coalbed-produced water and the stable carbon isotope value of methane further verifies that the n-alkanes are primary substrates for maintaining microbial activity. Therefore, evidence including n-alkanes, tri- and pentacyclic terpenes, steranes, unresolved complex mixtures, and stable carbon isotope composition of methane contribute to biogenic methane generation in situ. Our limited data suggest that managing soluble organic matter in the coalbed-produced water may provide a viable route for coal biodegradation since most microorganisms survive within the coal seam water.

Regulation and clinical potential of telomerase reverse transcriptase (TERT/hTERT) in breast cancer.

Telomerase reverse transcriptase (TERT/hTERT) serves as the pivotal catalytic subunit of telomerase, a crucial enzyme responsible for telomere maintenance and human genome stability. The high activation of hTERT, observed in over 90% of tumors, plays a significant role in tumor initiation and progression. An in-depth exploration of hTERT activation mechanisms in cancer holds promise for advancing our understanding of the disease and developing more effective treatment strategies. In breast cancer, the expression of hTERT is regulated by epigenetic, transcriptional, post-translational modification mechanisms and DNA variation. Besides its canonical function in telomere maintenance, hTERT exerts non-canonical roles that contribute to disease progression through telomerase-independent mechanisms. This comprehensive review summarizes the regulatory mechanisms governing hTERT in breast cancer and elucidates the functional implications of its activation. Given the overexpression of hTERT in most breast cancer cells, the detection of hTERT and its associated molecules are potential for enhancing early screening and prognostic evaluation of breast cancer. Although still in its early stages, therapeutic approaches targeting hTERT and its regulatory molecules show promise as viable strategies for breast cancer treatment. These methods are also discussed in this paper. Video Abstract.

The role of aspirin versus low-molecular-weight heparin for venous thromboembolism prophylaxis after total knee arthroplasty: a meta-analysis of randomized controlled trials.

BACKGROUND: There is a debate over the use of aspirin after total knee arthroplasty (TKA) for venous thromboembolism (VTE) prophylaxis. To evaluate the clinical effectiveness and safety of aspirin after TKA, the authors performed a meta-analysis of randomized controlled trials that compared aspirin with low-molecular-weight heparin (LMWH). METHODS: PubMed, Cochrane Library, Embase, and Web of Science were last searched on 31 January 2023 for studies comparing the effect of VTE prophylaxis between aspirin and LMWH. The results of eligible studies were analyzed in terms of VTE, deep venous thrombosis, pulmonary embolism, and bleeding complications rates. RESULTS: Six randomized controlled trials including 6772 patients met the inclusion criteria. LMWH showed a statistically significant reduction in the overall VTE rate (RR 1.46, 95% CI: 1.16-1.84). No significant differences in deep venous thrombosis, pulmonary embolism, and bleeding complications rates were found between aspirin and LMWH. CONCLUSION: Compared with LMWH, aspirin presents a higher risk of VTE after TKA. In terms of safety, aspirin and LMWH show comparable outcomes. The results do not support the role of aspirin role as an anticoagulant for preventing VTE after TKA.

TME-triggered copper-coordinated engineered programmable nanogenerators for on-demand cascade-amplifying oxidative stress.

Although oxidative stress-based antitumor modality derived from reactive oxygen species (ROS) storm has attracted considerable attention in copper-based nanomaterials, its efficiency is still weakened by the insufficient hydrogen peroxide (H2O2) and overexpressed glutathione (GSH) in a tumor microenvironment (TME). In view of this, we designed an engineered programmable spike-like nanogenerator via the coordination-driven co-assembly of Evans Blue (EB), copper ions (CuII), and 5-hydroxy-p-naphthoquinone (HND). For programmable nanogenerators, the introduction of EB as a stabilizer-like component can not only adjust its morphology but also achieve its visual tracking. Interestingly, such programmable nanogenerators can be efficiently enriched in tumor regions and then internalized into tumor cells due to ECH with spike-like morphology. Notably, once the nanogenerator is disintegrated and burst to release the drug upon acidic lysosome and endogenous GSH triggering, the released HND can not only efficiently amplify endogenous H2O2 by intracellular oxidoreductases but also down-regulate the peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin 1) activity. In addition, the released CuII ions can efficiently catalyze the degradation of the endogenous H2O2 to amplify hydroxyl radicals (˙OH) and down-regulate the overexpressed GSH to reduce ˙OH elimination for on-demand cascade-amplifying oxidative stress. Importantly, such programmable nanogenerators show an excellent antitumor effect via down-regulating the Pin 1 activity and cascade-amplifying oxidative stress. In this study, we propose a spatiotemporally programmable cascade nanogenerator for oxidative stress-based antitumor therapy.

Platinum-Coordinated Engineered Nanoreactors with O2 Self-Amplificationand On-Demand Cascade Chemo-Drug Synthesis for Self-Reinforcing Hypoxic Oncotherapy.

How to efficiently synthesize toxic chemo-drugs in the hypoxia tumor microenvironment still faces a huge challenge. Herein, we have tailored engineered vehicle-free nanoreactors by coordination-driven co-assembly of photosensitizer indocyanine green (ICG), transition metal platinum (Pt), and nontoxic 1,5-dihydroxynaphthalene (DHN) to self-amplify O2 and cascade chemo-drug synthesis in tumor cells for self-reinforcing hypoxic oncotherapy. Once vehicle-free nanoreactors are internalized into tumor cells, they show a serious instability that results in rapid disassembly and on-demand drug release under the stimuli of acidic lysosome and laser radiation. Notably, the released Pt can efficiently decompose the endogenous hydrogen peroxide (H2O2) into O2 to alleviate tumor hypoxia, which is conducive to enhancing the photodynamic therapy (PDT) efficiency of the released ICG. Complementarily, a large amount of the 1O2 generated by PDT can efficiently oxidize the released nontoxic DHN into the highly toxic chemo-drug juglone. Therefore, such vehicle-free nanoreactors can achieve intracellular on-demand cascade chemo-drug synthesis and self-reinforce photo-chemotherapeutic efficacy on the hypoxic tumor. On the whole, such a simple, flexible, efficient, and nontoxic therapeutic strategy will broaden the study of on-demand chemo-drug synthesis and hypoxic oncotherapy.

Long-term survival of patients with intracranial metastases from thyroid cancer presenting with seizures: a case report and literature review.

Background: Thyroid cancer has low incidence and mortality. While metastatic cancer is the most common type of intracranial cancer, patients with intracranial metastases from thyroid cancer very rarely present with seizures. Here, we describe a case study and review the neurological symptoms and histopathology of intracranial metastases from thyroid cancer. Case Description: A 38-year-old woman was diagnosed with intracranial metastases from papillary thyroid cancer, with the chief symptom being generalized seizures. The bilateral frontal masses were completely resected in 2 operations, after which the patient was treated with whole-brain radiotherapy and tyrosine kinase inhibitors (TKIs). It has now been over 13 years since thyroid cancer resection and 51 months since she was diagnosed with intracranial metastases from papillary thyroid cancer. The long-term survival might be due to the effective and prompt treatment. Through literature review, we found the incidence of intracranial metastases from different subtypes of thyroid cancer to be inconsistent with epidemiological findings in thyroid cancer. Conclusions: Intracranial metastases of thyroid cancer should be considered when the patient has a history of thyroid cancer with seizures. A combination of surgery, radiation therapy, and TKI drugs may prolong survival.

Antiovarian cancer mechanism of esculetin: inducing G0/G1 arrest and apoptosis via JAK2/STAT3 signalling pathway.

OBJECTIVES: Esculetin is a coumarin derivative, which is extracted from the dried barks of fraxinus chinensis Roxb. Although it is reported esculetin possesses multiple pharmacological activities, its associated regulatory mechanism on ovarian cancer isn't well investigated. METHODS: Cytotoxicity is evaluated by MTT, clonogenic and living/dead cells staining assays. Migration and invasion effects are investigated by wound healing, and transwell assays. The effect of cell cycle and apoptosis are analyzed by flow cytometry and western blotting. Mitochondrial membrane potential and intracellular reactive oxygen species (ROS) is assessed by fluorescence microscope. Analysis of animal experiments are carried out by various pathological section assays. KEY FINDINGS: Esculetin exerts an anti- ovarian cancer effect. It is found that apoptosis induction is promoted by the accumulation of excessive ROS and inhibition of JAK2/STAT3 signalling pathway. In addition, exposure to esculetin leads to the cell viability reduction, migration and invasion capability decrease and G0/G1 phase cell cycle arrest induced by down-regulating downstream targets of STAT3. In vivo experimental results also indicate esculetin can inhibit tumour growth of mice. CONCLUSIONS: Our study provides some strong evidences to support esculetin as a potential anti-cancer agent in ovarian cancer.