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BackgroundThe first-line treatment for advanced hepatocellular carcinoma has evolved significantly. This study aimed to identify the most beneficial regimen.MethodsA systematic search was conducted from July 2012 to August 2024 across the following four databases: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. This search focused on phase III prospective randomized controlled trials that compared first-line treatment for advanced hepatocellular carcinoma.ResultsSeventeen studies involving 10322 patients were included in this network meta-analysis. Of the studies we included, twelve studies were global multicenter clinical studies, four were initiated in China, and one was initiated in Korea. The results of our statistical analysis suggest that Hepatic artery infusion chemotherapy with oxaliplatin plus fluorouracil (HAIC-FO) demonstrated significant overall survival (OS) benefits compared with most treatments, including various immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). In terms of OS, HAIC had shown similar efficacy with sorafenib plus FOLFOX (HR, 0.88; 95% CI: 0.37-2.09) and transcatheter arterial chemoembolization (TACE) combined with lenvatinib (HR, 0.69; 95% CI: 0.30-1.56). Notably, immune-related treatments, such as ICIs combined with anti-VEGF therapies, also showed improved OS compared with anti-VEGF-TKIs alone. In terms of progression-free survival (PFS), HAIC-FO outperformed anti-VEGF-TKI monotherapy, ICI monotherapy, and several ICI combinations. However, it was not superior to lenvatinib plus TACE or lenvatinib plus pembrolizumab. Based on the Surface Under the Cumulative Ranking Curve (SUCRA) values, HAIC-FO was ranked the most effective in terms of OS (SUCRA = 0.961) and objective response rate (ORR) (SUCRA = 0.971). The results of the subgroup analysis suggested that HAIC-FO achieved the best OS benefit in the macrovascular invasion (MVI) and extrahepatic spread (EHS) subgroup (SUCRA = 0.99) and that tremelimumab combined with durvalumab achieved the best OS benefit in the Asian subgroup (SUCRA = 0.88).ConclusionThis systematic review and network meta-analysis suggest that HAIC-based therapies may become a potential first-line treatment option for advanced HCC, especially for patients in Mainland China with MVI and EHS. Additionally, immune-related treatments may be more suitable for Asian populations.

In the quest to address the critical shortage of donor organs for transplantation, xenotransplantation stands out as a promising solution, offering a more abundant supply of donor organs. Yet, its widespread clinical adoption remains hindered by significant challenges, chief among them being immunological rejection. Central to this issue is the role of the complement system, an essential component of innate immunity that frequently triggers acute and chronic rejection through hyperacute immune responses. Such responses can rapidly lead to transplant embolism, compromising the function of the transplanted organ and ultimately causing graft failure. This review delves into three key areas of xenotransplantation research. It begins by examining the mechanisms through which xenotransplantation activates both the classical and alternative complement pathways. It then assesses the current landscape of xenotransplantation from donor pigs, with a particular emphasis on the innovative strides made in genetically engineering pigs to evade complement system activation. These modifications are critical in mitigating the discordance between pig endogenous retroviruses and human immune molecules. Additionally, the review discusses pharmacological interventions designed to support transplantation. By exploring the intricate relationship between the complement system and xenotransplantation, this retrospective analysis not only underscores the scientific and clinical importance of this field but also sheds light on the potential pathways to overcoming one of the major barriers to the success of xenografts. As such, the insights offered here hold significant promise for advancing xenotransplantation from a research concept to a viable clinical reality.

Purpose: The combination of near-infrared (NIR) and positron emission tomography (PET) imaging presents an opportunity to utilize the benefits of dual-modality imaging for tumor visualization. Based on the observation that fibroblast activation protein (FAP) is upregulated in cancer-associated fibroblasts (CAFs) infiltrating all solid tumors, including head and neck squamous cell carcinoma (HNSCC), we developed the novel PET/NIR probe [68Ga]Ga-FAP-2286-ICG. Preclinically, the specificity, biodistribution and diagnostic properties were evaluated.Methods: Cell uptake assays were completed with the U87MG cell to evaluate the specificity of the [68Ga]Ga-FAP-2286-ICG. The tumor-targeting efficiency, biodistribution and optimal imaging time window of the [68Ga]Ga-FAP-2286-ICG were studied in mice bearing U87MG xenografts. HNSCC tumor-bearing mice were used to evaluate the feasibility of [68Ga]Ga-FAP-2286-ICG for tumor localization and guided surgical resection of HNSCC tumors.Results: The in vitro experiments confirmed that [68Ga]Ga-FAP-2286-ICG showed good stability, specific targeting of the probe to FAP, and the durable retention effect in high-expressing FAP tumors U87MG cell. Good imaging properties such as good tumor uptake, high tumor-to-background ratios (5.44 ± 0.74) and specificity, and tumor contouring were confirmed in studies with mice bearing the U87MG xenograft. PET/CT imaging of the probe in head and neck cancer-bearing mice demonstrated specific uptake of the probe in the tumor with a clear background. Fluorescence imaging further validated the value of the probe in guiding surgical resection and achieving precise removal of the tumor and residual lesions.Conclusion: In a preclinical model, these attractive [68Ga]Ga-FAP-2286-ICG PET/NIR imaging acquired in head and neck cancer make it a promising FAP-targeted multimodal probe for clinical translation.

Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies (HEMT), including elexacaftor-tezacaftor-ivacaftor, correct the underlying molecular defect causing CF. HEMT decreases general symptom burden by improving clinical metrics and quality of life for most people with CF (PwCF) with eligible CFTR variants. This has resulted in more pregnancies in women living with CF. All HEMT are known to be able pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of HEMT in young rats demonstrated infant cataracts, and case reports have reported the presence of congenital cataracts in early life exposure to HEMT. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of healthy and abnormal lens development in the context of HEMT exposure during pregnancy and breastfeeding, and raises questions that remain unanswered.

Chlamydia trachomatis, one species of Chlamydia spp., has the greatest impact on human health and is the main cause of bacterial sexually transmitted diseases and preventable blindness among all Chamydia spp. species. The obligate intracellular parasitism and unique biphasic developmental cycle of C. trachomatis are the main barriers for the development of tools of genetic manipulation. The past decade has witnessed significant gains in genetic manipulation of C. trachomatis, including chemical mutagenesis, group II intron-based targeted gene knockout, fluorescence-reported allelic exchange mutagenesis (FRAEM), CRISPR interference (CRISPRi) and the recently developed transposon mutagenesis. In this review, we discuss the current status of genetic manipulations of C. trachomatis and highlights new challenges in the nascent field of Chlamydia genetics.

BackgroundSentinel lymph node (SLN) biopsy has been widely recognized as an excellent surgical and staging procedure for early-stage breast cancer, and its development has greatly improved the detection of micrometastases. However, the axillary treatment of micrometastasis has been the subject of much debate.MethodsWe identified 427,131 women diagnosed with breast cancer from 2010 to 2018 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients whose nodal status was micrometastases (pTxN1miM0) were classified into two groups: the SLNB only group and SLNB with complete ALND group, and we used these classifications to carry out propensity-score matching (PSM) analysis. The primary and secondary endpoints were OS and BCSS, respectively. We then implemented the Kaplan-Meier method and Cox proportional hazard model and used Fine and Gray competitive risk regression to identify factors associated with the risk of all-cause mortality.ResultsAfter the PSM, 1,833 pairs were included in total. The SLNB with complete ALND showed no significant difference in OS (HR=1.04, 95% CI: 0.84-1.28, P=0.73) or BCSS (HR= 1.03, 95% CI: 0.79-1.35, P=0.82) compared to the SLNB only group, and axillary treatment was not associated with breast cancer-specific death (BCSD) (HR=1.13, 95% CI: 0.86-1.48, P=0.400) or other cause-specific death (OCSD) (HR=0.98, 95% CI:0.70-1.38, P=0.920). There was no statistically significant difference in the cumulative incidence of BCSD (Grey’s test, P=0.819) or OCSD (Grey’s test, P=0.788) for between the two groups either. For different molecular subtypes, patients in the SLNB only group showed no statistically significant differences from those in the SLNB with complete ALND group with Luminal A (HR=1.00, 95% CI:0.76-1.32, P=0.98) or Luminal B (HR=0.82, 95% CI:0.42-1.62, P=0.55) but similar OS to HER2-enriched (HR=1.58, 95% CI:0.81-3.07, P=0.19) or triple negative breast cancers (HR=1.18, 95% CI:0.76-1.81, P=0.46).ConclusionsOur results suggest that in early breast cancer patients with micrometastasis, complete ALND does not seem to be required and that SLNB suffices to control locoregional and distant disease, with no significant adverse effects on survival compared to complete ALND.

BackgroundBronchopulmonary dysplasia (BPD) is the most common neonatal chronic lung disease. However, its exact molecular pathogenesis is not understood. We aimed to identify relevant gene modules that may play crucial roles in the occurrence and development of BPD by weighted gene co-expression network analysis (WGCNA).MethodsWe used RNA-Seq data of BPD and healthy control rats from our previous studies, wherein data from 30 samples was collected at days 1, 3, 7, 10, and 14. Data for preprocessing analysis included 17,613 differentially expressed genes (DEGs) with false discovery rate

Transarterial embolization (TAE) is a personalized technology that offers precise delivery of chemotherapeutic drugs or selective internal radiation therapy for hepatocellular carcinoma (HCC). Beta-emitting radionuclide embolisms for TAE (β-based TARE) are commonly used in the clinic via inducing biochemical lethality on tumor cells, while alpha-emitting radionuclides-based embolisms for TAE (α-based TARE) are still under study. The feeding artery plays a key role in tumor growth, metastasis, and recurrence. In this research, the auricular central arteries (ACAs) of rabbits were embolized with silk fibroin-based microspheres (SFMs) or SFMs integrated with α (Ra-223) or β (I-131) radionuclides to investigate the influence on vessels. TARE-induced tissue necrosis and the following neovascularization were measured by pathological analysis and 68Ga-DOTA-RGD PET/CT. The results showed that, compared to I-131, Ra-223 enhanced the growth inhibition of human hepatoma cells Huh-7 and induced more DNA double-strand breaks in vascular smooth muscle cells. Unlike β-based TARE, which mainly led to extensive necrosis of surrounding tissues, α-based TARE induced irreversible necrosis of a limited area adjacent to the embolized vessels. RGD PET revealed the inhibition on neovascularization in α-based TARE (SUVmax = 0.053 ± 0.004) when compared with normal group (SUVmax = 0.099 ± 0.036), the SFMs-lipiodol group (SUVmax = 0.240 ± 0.040), and β-based TARE (SUVmax = 0.141 ± 0.026), owing to the avoidance of the embolism-induced neovascularization. In conclusion, α-based TARE provided a promising strategy for HCC treatments via destroying the embolized vessels and inhibiting neovascularization.

Abstract Objective: Breast cancer (BC) is becoming the leading cause of cancer-related death in women all over the word. Identification of diagnostic biomarkers for early detection of BC is one of the most effective ways to reduce the mortality.Methods: Plasma samples from BC patients (n = 120) and normal controls (n = 50) were collected to determine the differentially expressed circulating miRNAs in BC patients. Binary logistic regression was applied to develop miRNA diagnostic models. Receiver operating characteristic (ROC) curves were applied to calculate the area under the curve (AUC). MMTV-PYMT mammary tumor mice were used to validate the expression change of those circulating miRNAs. Plasma samples from patients with other tumor types were collected to determine the specificity of the model in diagnosis of BC.Results: In the screening phase, 5 circulating miRNAs (miR-16, miR-17, miR-19b, miR-27a, and miR-106a) were identified as the most significantly upregulated miRNAs in plasma of BC patients. In consistence, the 5 miRNAs showed upregulation in the circulation of additional 80 BC patients in a tumor stage-dependent manner. Application of a tumor-burden mice model further confirmed upregulation of the 5 miRNAs in circulation. Based on these data, five models with diagnostic potential of BC were developed. Among the 5 miRNAs, miR-19b ranked at the top position with the highest specificity and the biggest contribution. In combination with miR-16 and miR-106a, a miR-19b-based 3-circulating miRNA model was selected as the best for further validation. Taken the samples together, the model showed 92% of sensitivity and 90% of specificity in diagnosis of BC. In addition, three other tumor types including prostate cancer, thyroid cancer and colorectal cancer further verified the specificity of the BC diagnostic model. Conclusion: The current study developed a miR-19b-based 3-miRNA model holding potential for diagnosis of BC using blood samples.

The worldwide incidence of head and neck cancer (HNC) exceeds half a million cases annually, and up to half of the patients with HNC present with advanced disease. Surgical resection remains the mainstay of treatment for many HNCs, although radiation therapy, chemotherapy, targeted therapy, and immunotherapy might contribute to individual patient’s treatment plan. Irrespective of which modality is chosen, disease prognosis remains suboptimal, especially for higher staging tumors. Cold atmospheric plasma (CAP) has recently demonstrated a substantial anti-tumor effect. After a thorough literature search, we provide a comprehensive review depicting the oncological potential of CAP in HNC treatment. We discovered that CAP applies to almost all categories of HNC, including upper aerodigestive tract cancers, head and neck glandular cancers and skin cancers. In addition, CAP is truly versatile, as it can be applied not only directly for superficial or luminal tumors but also indirectly for deep solid organ tumors. Most importantly, CAP can work collaboratively with existing clinical oncotherapies with synergistic effect. After our attempts to elaborate the conceivable molecular mechanism of CAP’s anti-neoplastic effect for HNC, we provide a brief synopsis of recent clinical and preclinical trials emphasizing CAP’s applicability in head and neck oncology. In conclusion, we have enunciated our vision of plasma oncology using CAP for near future HNC treatment.

In this study, we use numerical methods to study the acoustic streaming effect of the acoustic black hole (ABH). Firstly, we build an ABH model to study the acoustic streaming effect. By deriving the waves equations and solving the Navier–Stokes equations, we obtain the flow field, sound field, and temperature field under the acoustic excitation. Secondly, the simulation result reveals the mechanism of acoustic streaming effects on the sound transmission characteristics of cavity ABH. The numerical results show that the abrupt decrease in the sound pressure is caused by the great changes in the velocity gradient caused by the catastrophe of cross section. The energy of the sound waves can also be dissipated by the thermal viscous layer at low frequencies. Finally, based on the acoustic streaming effects of the acoustic medium in the ABH, we propose feasible methods to enhance the sound insulation. Increasing the cross section of the cavity in ABH can get a better sound insulation effect at high frequencies, and decreasing the cross section can improve Sound Transmission Loss (STL). Through optimization, STL can reach more than 25 dB at low frequencies.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory complication commonly seen in premature infants. Following continuous advances in neonatal intensive care diagnosis and treatment technology, an increasing number of premature babies are being treated successfully. Despite these remarkable improvements, there has been no significant decline in the incidence of BPD; in fact, its incidence has increased as more extremely preterm infants survive. Therefore, in view of the impact of BPD on the physical and mental health of children and the increased familial and social burden on these children, early prevention of BPD is emphasized. In recent decades, the clinical application of caffeine in treating primary apnea in premature infants was shown not only to stimulate the respiratory center but also to confer obvious protection to the nervous and respiratory systems. Numerous clinical cross-sectional and longitudinal studies have shown that caffeine plays a significant role in the prevention and treatment of BPD, but there is a lack of overall understanding of its potential molecular mechanisms. In this review, we summarize the possible molecular mechanisms of caffeine in the prevention or treatment of BPD, aiming to better guide its clinical application.

Programmed cell death protein 1 (PD-1) expression is considered a prognostic marker of tumor response to the immuno-blocking therapy. In this study, nivolumab was conjugated with diethylenetriamine pentaacetate (DTPA) via condensation reaction between amidogen and p-SCN-Bn-DTPA, which provided labeling sites for 99mTc4+ or Gd3+ ions. SPECT and magnetic resonance T1 weighted imaging (T1WI) analyses were performed on mouse models of colorectal carcinoma expressing humanized PD-1 antigen. Furthermore, PD-1 expression in intestinal tracks was assessed by immunohistochemistry, and then compared with the imageological findings. Nivolumab-DTPA was synthesized with varying molar ratios and was labeled with Gd or 99mTc with a chemical purity of 96.28 ± 1.16% and good stability. In SPECT images, lesions with high 99mTc-DTPA-nivolumab uptake and relatively clear background were shown at 6 h. Thereafter, the suspected intestinal thickening in Gd-free T1WI was observed at 2 h after the addition of Gd-DTPA-nivolumab. Notably, the results of both SPECT and T1WI analyses were consistent with the postmortem examination and immunohistochemistry results (for linear correlation with target to non-target ratios, R2 = 0.8038, p < 0.05). In conclusion, nivolumab-DTPA could act as a probe precursor for identifying PD-1-positive lesions, not only through integrating the advantages of immunohistochemistry and molecular imaging but also by providing a noninvasive method for monitoring systemic changes.

Background: Remote ischemic pre-conditioning (RIPC) alleviated the myocardial ischemia-reperfusion injury, yet the underlying mechanisms remain to be fully elucidated, especially at the late phase. Searching a key component as a transfer carrier may provide a novel insight into RIPC-mediated cardioprotection in the condition of myocardial ischemia-reperfusion.Objective: To investigate the cardioprotective effect of plasma exosomes at the late phase of RIPC and its potential signaling pathways involved.Methods and Results: Exosomes were isolated from the plasma of rats 48 h after the RIPC or control protocol. Although the total plasma exosomes level had no significant change at the late phase of RIPC (RIPC-exosome) compared with the control exosomes (Control-exosome), the RIPC-exosome afforded remarkable protection against myocardial ischemia-reperfusion (MI/R) injury in rats and hypoxia-reoxygenation (H/R) injury in cells. The miRNA array revealed significant enrichment of miR-126a-3p in RIPC-exosome. Importantly, both miR-126a-3p inhibitor and antagonist significantly blunted the cardioprotection of RIPC-exosome in H/R cells and MI/R rats, respectively, while miR-126a-3p mimic and agomir showed significant cardioprotection against H/R injury in cells and MI/R injury in rats. Mechanistically, RIPC-exosome, especially exosomal miR-126a-3p, activated the reperfusion injury salvage kinase (RISK) pathway by enhancing the phosphorylation of Akt and Erk1/2, and simultaneously inhibited Caspase-3 mediated apoptotic signaling.Conclusions: Our findings reveal a novel myocardial protective mechanism that plasma exosomes at the late phase of RIPC attenuate myocardial ischemia-reperfusion injury via exosomal miR-126a-3p.

BackgroundGastric cancer (GC) still represents the third leading cause of cancer-related death worldwide. Peritoneal relapse (PR) is the most frequent metastasis occurring among patients with advanced gastric cancer. Increasingly more evidence have clarified the tumor immune microenvironment (TIME) may predict survival and have clinical significance in GC. However, tumor-transcriptomics based immune signatures derived from immune profiling have not been established for predicting the peritoneal recurrence of the advanced GC.MethodsIn this study, we depict the immune landscape of GC by using transcriptome profiling and clinical characteristics retrieved from GSE62254 of Gene Expression Omnibus (GEO). Immune cell infiltration score was evaluated via single-sample gene set enrichment (ssGSEA) analysis algorithm. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to select the valuable immune cells and construct the final model for the prediction of PR. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to check the accuracy of PRIs. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore the molecular pathways associated with PRIs.ResultsA peritoneal recurrence related immune score (PRIs) with 10 immune cells was constructed. Compared to the low-PRIs group, the high-PRIs group had a greater risk. The upregulation of the focal adhesion signaling was observed in the high-PRIs subtype by GSEA and KEGG. Multivariate analysis found that both in the internal training cohort and the internal validation cohort, PRIs was a stable and independent predictor for PR. A nomogram that integrated clinicopathological features and PRIs to predict peritoneal relapse was constructed. Subgroup analysis indicated that the PRIs could obviously distinguish peritoneal recurrence in different molecular subtypes, pathological stages and Lauren subtypes, in which PRIs of Epithelial-Mesenchymal Transitions (EMT) subtype, III-IV stage and diffuse subtype are higher respectively.ConclusionOverall, we performed a comprehensive evaluation of the immune landscape of GC and constructed a predictive PR model based on the immune cell infiltration. The PRIs represents novel promising feature of predicting peritoneal recurrence of GC and sheds light on the improvement of the personalized management of GC patients after surgery.

Cancer stem cells (CSCs) contribute to the cancer initiation, metastasis and drug resistance in non-small cell lung cancer (NSCLC). Herein, we identified a miR-221/222 cluster as a novel regulator of CSCs in NSCLC. Targeted overexpression or knockdown of miR-221/222 in NSCLC cells revealed the essential roles of miR-221/222 in regulation of lung cancer cell proliferation, mammosphere formation, subpopulation of CD133+ CSCs and the expression of stemness genes including OCT4, NANOG and h-TERT. The in vivo animal study showed that overexpression of miR-221/222 significantly enhanced the capacity of lung cancer cells to develop tumor and grow faster, indicating the importance of miR-221/222 in tumorigenesis and tumor growth. Mechanistically, Reck was found to be a key direct target gene of miR-221/222 in NSCLC. Overexpression of miR-221/222 significantly suppressed Reck expression, activated Notch1 signaling and increased the level of NICD. As an activated form of Notch1, NICD leads to enhanced stemness in NSCLC cells. In addition, knockdown of Reck by siRNA not only mimicked miR-221/222 effects, but also demonstrated involvement of Reck in the miR-221/222-induced activation of Notch1 signaling, verifying the essential roles of the miR-221/222-Reck-Notch1 axis in regulating stemness of NSCLC cells. These findings uncover a novel mechanism by which lung CSCs are significantly manipulated by miR-221/222, and provide a potential therapeutic target for the treatment of NSCLC.

Primary liver tumor with hepatocellular carcinoma accounting for 75–80% of all such tumors, is one of the global leading causes of cancer-related death, especially in cirrhotic patients. Liver tumors are highly hypervascularized via the hepatic artery, while normal liver tissues are mainly supplied by the portal vein; consequently, intra-arterially delivered treatment, which includes transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), is deemed as a palliative treatment. With the development of nuclear technology and radiochemistry, TARE has become an alternative for patients with hepatic cancer, especially for patients who failed other therapies, or for patients who need tumor downstaging treatment. In practice, some radionuclides have suitable physicochemical characteristics to act as radioactive embolism agents. Among them, 90Y emits β rays only and is suitable for bremsstrahlung single photon emission computed tomography (BS SPECT) and positron emission tomography (PET); meanwhile, some others, such as 131I, 153Sm, 166Ho, 177Lu, 186Re, and 188Re, emit both β and γ rays, enabling embolism beads to play a role in both therapy and single photon emission computed tomography (SPECT) imaging. During TARE, concomitant imaging provide additive diagnostic information and help to guide the course of liver cancer treatment. Therefore, we review the theranostic radionuclides that have been used or could potentially be used in TARE for liver cancer and focus on the clinical benefits of diagnostic applications, including real-time monitoring of embolism beads, evaluating irradiation dose, predicting therapy effects, and corresponding adjustments to TARE.

Cisplatin has been widely used in the treatment of a various types of cancers including triple-negative breast cancer (TNBC) by damaging DNA and inducing apoptosis. However, its anti-cancer effects are often limited due to chemo-resistance, which is one of the main reasons causing cancer relapse and metastasis. To overcome resistance, cisplatin is often used in combination with other drugs or molecules. Our study found that the targeted inhibition of miR-221/222 in MDA-MB-231 cells promoted cisplatin-induced cell apoptosis, and increased the cell sensitivity to cisplatin in vitro. Much higher expression levels of miR-221/222 were detected in the cisplatin-resistant MDA-MB-231 cells and in cisplatin-resistant breast cancer patients. The combination chemotherapy of cisplatin with anti-miR-221/222 showed much higher efficiency in suppressing tumor growth in the mice transplanted with MDA-MB-231 cells. In addition, anti-miR-221 and anti-miR-222 showed synergetic effects on improving sensitivity to cisplatin in MDA-MB-231 cells. Suppression of SOCS1-STAT3-Bcl-2 pathway and activation of p53-Pten signaling both contribute to anti-miR-221/222-induced sensitivity to cisplatin in MDA-MB-231 cells. These findings suggest the potential of a novel approach for the combination chemotherapy of cisplatin with small non-coding RNA in treatment of human TNBC.

Tumor cells reside in a highly complex and heterogeneous tumor microenvironment (TME), which is composed of a myriad of genetically stable non-cancer cells, including fibroblasts, immune cells, endothelial cells, and epithelial cells, and a tumor-specific extracellular matrix (ECM). Cancer-associated fibroblasts (CAFs), as an abundant and active stromal cell population in the TME, function as the signaling center and remodeling machine to aid the creation of a desmoplastic tumor niche. Although there is no denial that the TME and CAFs may have anti-tumor effects as well, a great deal of findings reported in recent years have convincingly revealed the tumor-promoting effects of CAFs and CAF-derived ECM proteins, enzymes, chemical factors and other downstream effectors. While there is growing enthusiasm for the development of CAF-targeting therapies, a better understanding of the complexities of CAF-ECM and CAF-cancer cell interactions is necessary before novel therapeutic strategies targeting the malignant tumor “soil” can be successfully implemented in the clinic.

PurposeThis study aimed to introduce a new modified en-bloc resection method and evaluate its feasibility and safety in endoscopic thyroid surgery via bilateral areolar approach (BAA).MethodsPapillary thyroid carcinoma (PTC) patients who underwent lobectomy and ipsilateral central node dissection (CND) via the BAA approach were retrospectively reviewed. Their clinical characteristics and outcomes were evaluated, including operative duration, lymph node yield (LNY), surgical complications, recurrence rate, and metastasis rate, over a ten-year follow-up period. Simultaneous lobectomy and CND were performed in the modified en-bloc group, whereas lobectomy was performed first, followed by CND in the conventional group.ResultsThe study included 108 patients in the modified en-bloc group and 213 in the conventional group. There were no significant differences in gender, age, tumor locations, tumor dominant nodule size, or the incidence of concomitant Hashimoto thyroiditis when comparing clinicopathologic characteristics. The comparison of operative duration (P = 0.14), blood loss (P = 0.13), postoperative hospital stay (P = 0.58), incidence of transient vocal cord paralysis (P = 0.90) and hypocalcemia (P = 0.60) did not show any differences. The mean LNY achieved in the central compartment of the modified en-bloc group (7.5 ± 4.5) was significantly higher than that in the conventional group (5.6 ± 3.6). Two patients in the modified en-bloc group and two in the conventional group experienced metastasis after surgery during the ten-year follow-up (1.8% vs. 0.9%, P = 0.60). The learning curve analysis showed a significant decrease in operative duration after the 25-35th cases for modified en-bloc resection.ConclusionsThe modified en-bloc resection method in endoscopic thyroid surgery via BAA is a technically feasible and safe procedure with excellent cosmetic outcomes for selective PTC patients.

We investigated the optimum co-culture ratio with the highest biological nitrogen removal rate, revealing that chemical oxygen demand, total nitrogen (TN), and ammoniacal nitrogen (NH3-N) removal was increased in the Chlorella pyrenoidosa and Yarrowia lipolytica co-culture system at a 3:1 ratio. Compared with the control, TN and NH3-N content in the co-incubated system was decreased within 2–6 days. We investigated mRNA/microRNA (miRNA) expression in the C. pyrenoidosa and Y. lipolytica co-culture after 3 and 5 days, identifying 9885 and 3976 differentially expressed genes (DEGs), respectively. Sixty-five DEGs were associated with Y. lipolytica nitrogen, amino acid, photosynthetic, and carbon metabolism after 3 days. Eleven differentially expressed miRNAs were discovered after 3 days, of which two were differentially expressed and their target mRNA expressions negatively correlated with each other. One of these miRNAs regulates gene expression of cysteine dioxygenase, hypothetical protein, and histone-lysine N-methyltransferase SETD1, thereby reducing amino acid metabolic capacity; the other miRNA may promote upregulation of genes encoding the ATP-binding cassette, subfamily C (CFTR/MRP), member 10 (ABCC10), thereby promoting nitrogen and carbon transport in C. pyrenoidosa. These miRNAs may further contribute to the activation of target mRNAs. miRNA/mRNA expression profiles confirmed the synergistic effects of a co-culture system on pollutant disposal.

Non-infectious chronic diseases, especially inflammatory bowel diseases (IBDs), hypertension, and diabetes mellitus, are characterized by a prolonged and multisystemic course, and their incidence increases annually, usually causing serious economic burden and psychological stress for patients. Therefore, these diseases deserve scientific and consistent disease management. In addition, the lack of a comprehensive “early disease clues tracking—personalized treatment system—follow-up” model in hospitals also exacerbates this dilemma. Based on these facts, we propose an individualized prediction management system for IBDs based on chronic diseases, focusing on the established IBDs-related prediction models and summarizing their advantages and disadvantages. We call on researchers to pay attention to the integration of models with clinical practice and the continuous correction of models to achieve truly individualized medical treatment for chronic diseases, thus providing substantial value for the rapid diagnosis and adequate treatment of chronic diseases such as IBDs, which follow the “relapse-remission” disease model, and realizing long-term drug use and precise disease management for patients. The goal is to achieve a new level of chronic disease management by scientifically improving long-term medication, precise disease management, and individualized medical treatment, effectively prolonging the remission period and reducing morbidity and disability rates.

BackgroundAmmonia oxidizing bacteria (AOB) in soil are of great biological importance as they regulate the cycling of N in agroecosystems. Plants are known to harbor AOB but how they occupy the plant is an unresolved question.MethodsMetabarcoding studies were carried out using Illumina MiSeq sequencing to test the potential of seed vectored AOB exchange between plants and soil.Results and discussionWe found 27 sequences associated with AOB strains belonging to the genera Nitrosospira, Nitrosovibrio, and Nitrosomonas inhabiting Elymus nutans seeds collected from four geographically distanced alpine meadows. Nitrosospira multiformis was the most dominant across the four locations. The AOB community in E. nutans seeds was compared with that of the leaves, roots and soil in one location. Soil and seeds harbored a rich but dissimilar AOB community, and Nitrosospira sp. PJA1, Nitrosospira sp. Nsp17 and Nitrosovibrio sp. RY3C were present in all plant parts and soils. When E. nutans seeds were germinated in sterilized growth medium under greenhouse conditions, the AOB in seeds later appeared in leaves, roots and growth medium, and contributed to nitrification. Testing the AOB community of the second-generation seeds confirmed vertical transmission, but low richness was observed.ConclusionThese results suggest seed vectored AOB may play a critical role in N cycle.

Immune checkpoint inhibitors (ICIs) significantly improve the survival of patients with non-small-cell lung cancer (NSCLC), but only some patients obtain clinical benefits. Predictive biomarkers for ICIs can accurately identify people who will benefit from immunotherapy. Lipid metabolism signaling plays a key role in the tumor microenvironment (TME) and immunotherapy. Hence, we aimed to explore the association between the mutation status of the lipid metabolism pathway and the prognosis of patients with NSCLC treated with ICIs. We downloaded the mutation data and clinical data of a cohort of patients with NSCLC who received ICIs. Univariate and multivariate Cox regression models were used to analyze the association between the mutation status of the lipid metabolism signaling and the prognosis of NSCLC receiving ICIs. Additionally, The Cancer Genome Atlas (TCGA)–NSCLC cohort was used to explore the relationships between the different mutation statuses of lipid metabolism pathways and the TME. Additionally, we found that patients with high numbers of mutations in the lipid metabolism pathway had significantly enriched macrophages (M0- and M1-type), CD4 + T cells (activated memory), CD8 + T cells, Tfh cells and gamma delta T cells, significantly increased expression of inflammatory genes [interferon-γ (IFNG), CD8A, GZMA, GZMB, CXCL9, and CXCL10] and enhanced immunogenic factors [neoantigen loads (NALs), tumor mutation burden (TMB), and DNA damage repair pathways]. In the local-NSCLC cohort, we found that the group with a high number of mutations had a significantly higher tumor mutation burden (TMB) and PD-L1 expression. High mutation status in the lipid metabolism pathway is associated with significantly prolonged progression-free survival (PFS) in NSCLC, indicating that this marker can be used as a predictive indicator for patients with NSCLC receiving ICIs.

Chimeric antigen receptor (CAR) technology has revolutionized cancer treatment, particularly in malignant hematological tumors. Currently, the BCMA-targeted second-generation CAR-T cells have showed impressive efficacy in the treatment of refractory/relapsed multiple myeloma (R/R MM), but up to 50% relapse remains to be addressed urgently. Here we constructed the BCMA-targeted fourth-generation CAR-T cells expressing IL-7 and CCL19 (i.e., BCMA-7 × 19 CAR-T cells), and demonstrated that BCMA-7 × 19 CAR-T cells exhibited superior expansion, differentiation, migration and cytotoxicity. Furthermore, we have been carrying out the first-in-human clinical trial for therapy of R/R MM by use of BCMA-7 × 19 CAR-T cells (ClinicalTrials.gov Identifier: NCT03778346), which preliminarily showed promising safety and efficacy in first two enrolled patients. The two patients achieved a CR and VGPR with Grade 1 cytokine release syndrome only 1 month after one dose of CAR-T cell infusion, and the responses lasted more than 12-month. Taken together, BCMA-7 × 19 CAR-T cells were safe and effective against refractory/relapsed multiple myeloma and thus warranted further clinical study.

Tumor necrosis factor receptor-associated factor (TRAF) proteins are a family of signaling molecules that function downstream of multiple receptor signaling pathways, and they play a pivotal role in the regulation of intracellular biological progresses. These TRAF-dependent signaling pathways and physiological functions have been involved in the occurrence and progression of ischemia-reperfusion injury (IRI), which is a common pathophysiological process that occurs in a wide variety of clinical events, including ischemic shock, organ transplantation, and thrombolytic therapy, resulting in a poor prognosis and high mortality. IRI occurs in multiple organs, including liver, kidney, heart, lung, brain, intestine, and retina. In recent years, mounting compelling evidence has confirmed that the genetic alterations of TRAFs can cause subversive phenotype changes during IRI of those organs. In this review, based on current knowledge, we summarized and analyzed the regulatory effect of TRAFs on the IRI of various organs, providing clear direction and a firm theoretical basis for the development of treatment strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in IRI-related diseases.

Background and aims: The next-generation sequencing technologies and their related assessments of circulating tumor DNA in both glioma and metastatic brain tumors remain largely limited.Methods: Based largely on a protocol approved by the institutional review board at Peking University International Hospital, the current retrospective, single-center study was conducted. Genomic DNA was extracted from blood samples or tumor tissues. With the application of NextSeq 500 instrument (Illumina), Sequencing was performed with an average coverage of 550-fold. Paired-end sequencing was employed utilized with an attempt to achieve improved sensitivity of duplicate detection and therefore to increase the detection reliability of possible fusions.Results: A total of 28 patients (21 men and 7 women) with brain tumors in the present study were involved in the study. The patients enrolled were assigned into two groups, including glioma group (n = 21) and metastatic brain tumor group (n = 7). The mean age of metastatic brain tumor group (59.86 ± 8.85 y), (43.65 ± 13.05 y) reported significantly higher results in comparison to that of glioma group (45.3 ± 12.3 years) (P < 0.05). The mutant genes in metastatic brain tumor group included ALK, MDM2, ATM, BRCA1, FGFR1, MDM4 and KRAS; however, there were no glioma-related mutant genes including MGMT, IDH1, IDH2, 1p/19q, and BRAF et al. Interesteringly, only two patient (28.3%) was detected blood ctDNA in metastatic brain tumor group; In contrast, blood ctDNA was found in ten glioma patients (47.6%) including 1p/19q, MDM2, ERBB2, IDH1, CDKN2A, CDK4, PDGFRA, CCNE1, MET. The characterizations of IDH mutations in the glioma included IDH1 mutation (p.R132H) and IDH2 mutation (p.R172K). The mutation rate of IDH in tumor tissues was 37.06 ± 8.32%, which was significantly higher than blood samples (P < 0.05).Conclusion: The present study demonstrated that the mutant genes among glioma and metastatic brain tumors are shown to be different. Moreover, the ctDNAs in the metastatic brain tumors included ALK and MDM2, and glioma-related ctDNAs included 1p/19q and MDM2 followed by frequencies of ERBB2, IDH1, CDKN2A, CDK4, PDGFRA, CCNE1, MET. These ctDNAs might be biomarkers and therapeutic responders in brain tumor.