Efficacy and safety of camrelizumab plus apatinib in patients with advanced esophageal squamous cell carcinoma previously treated with immune checkpoint inhibitors (CAP 02 Re-challenge): A single-arm, phase II study.

BACKGROUND: With the increasing use of immune checkpoint inhibitors (ICIs) in advanced esophageal squamous cell carcinoma (ESCC), there remains an unmet need for options to address disease progression after prior ICIs. This single-arm phase II study evaluated the efficacy and safety of re-challenge with camrelizumab plus apatinib in patients with advanced ESCC who were previously treated with ICIs. METHODS: This study enrolled patients aged 18-75 years with unresectable locally advanced, locally recurrent, or distant metastatic ESCC who received prior ICIs. Patients received intravenous camrelizumab 200 mg every 2 weeks and oral apatinib 250 mg daily until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was the investigator-assessed confirmed objective response rate (ORR). RESULTS: Between September 1, 2021 and March 29, 2023, 49 eligible patients were enrolled and received treatment. Among the 49 patients, the confirmed ORR was 10.2 % (95 % CI 3.4-22.2), the disease control rate (DCR) was 69.4 % (54.6-81.7), the median progression-free survival (PFS) was 4.6 months (95 % CI 3.8-6.5) and overall survival (OS) was 7.5 months (5.5-13.6). Grade ≥ 3 treatment-related adverse events occurred in 17 patients (34.7 %). No treatment-related deaths occurred. CONCLUSIONS: This study showed that the confirmed ORR was modest and did not reach clinically meaningful improvement for patients with ESCC who were previously treated with ICIs, with a manageable safety profile.

Chimeric peptide-engineered immunostimulant for endoplasmic reticulum targeted photodynamic immunotherapy against metastatic tumor.

The combination of therapy-induced immunogenic cell death (ICD) and immune checkpoint blockade can provide a mutually reinforced strategy to reverse the poor immunogenicity and immune escape behavior of tumors. In this work, a chimeric peptide-engineered immunostimulant (ER-PPB) is fabricated for endoplasmic reticulum (ER)-targeted photodynamic immunotherapy against metastatic tumors. Among which, the amphiphilic chimeric peptide (ER-PP) is composed of ER-targeting peptide FFKDEL, hydrophilic PEG8 linker and photosensitizer protoporphyrin IX (PpIX), which could be assembled with a PD-1/PD-L1 blocker (BMS-1) to prepare ER-PPB. After passively targeting at tumor tissues, ER-PPB will selectively accumulate in the ER. Next, the localized PDT of ER-PPB will produce a lot of ROS to destroy the primary tumor cells, while increasing the ER stress to initiate a robust ICD cascade. Moreover, the concomitant delivery of BMS-1 can impede the immune escape of tumor cells through PD-1/PD-L1 blockade, thus synergistically activating the immune system to combat metastatic tumors. In vitro and in vivo results demonstrate the robust immune activation and metastatic tumor inhibition characteristics of ER-PPB, which may offer a promising strategy for spatiotemporally controlled metastatic tumor therapy.

How the perfectionistic climate of a sports team predicts the athletic performance of elite athletes: a case study of the CUBAL women's basketball team.

Objective: In competitive sports, understanding how the perfectionistic climate within teams influences the performance of elite female athletes can provide valuable insights for enhancing coaching practice and athletic achievement. Based on the cognitive appraisal theory of stress, this study constructs a dual-path model using stressors and coping strategies as mediators, referred to as the Perfectionistic Climate on Athletic Performance model (PCPM). The study explores the predictive role of the perfectionistic climate within sports teams on the athletic performance of elite female basketball players. Methods: The empirical study the relationships among the variables in the model using a sample of 125 core players from the top-level women's basketball teams in the 24th CUBAL24 tournament in 2022. A Structural Equation Modeling (SEM) analysis was conducted using AMOS 20.0, primarily employing the bias-corrected Bootstrap method to test the dual-path model. Results: The findings reveal double-edged paths towards a perfectionistic climate on athletic performance. In the positive pathway, a perfectionistic climate can positively predict athletic performance through challenge-related sources of stress and positive coping strategies. In the negative pathway, a perfectionistic climate can negatively predict athletic performance through threat-related sources of stress and negative coping strategies. Conclusion: Coaches need to pay attention to athletes' cognitive evaluations of the perfectionistic climate as a source of pressure. By setting challenging goals, coaches can guide athletes to view the perfectionistic climate of the sports team as a source of challenging pressure, thus unleashing their potential. Coaches should actively guide athletes in coping with the pressure brought about by the perfectionistic climate, enhancing their ability to handle stress. This will enable athletes to better adapt to the team's perfectionistic climate and further improve individual and team athletic performance.

LncRNA CBR3-AS1 is associated with the BCR::ABL1 kinase independent mechanism of tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia patients.

Background: It is difficult for chronic myeloid leukemia (CML) patients with BCR::ABL1 independent drug resistance to achieve optimal efficacy. The aim of this study is to investigate the BCR::ABL1 kinase independent mechanism of tyrosine kinase inhibitor (TKI) resistance in CML patients to develop targeted therapeutic strategy. Methods: Herein, we analyzed the long non-coding RNA (lncRNA) and messenger RNA (mRNA) expression profiles of patients who achieved sustained deep molecular response (DMR) after TKI treatment and patients with non-DMR using RNA-seqencing. Furthermore, the differentially expressed lncRNAs and mRNAs were identified. The expression of chosen lncRNA was validated in an expanded cohort, and bioinformatics analysis was performed to analyze the function of selected mRNA. Results: LncRNA data analysis indicated the diversity lncRNA profiles among healthy individuals, CML patients with non-DMR, and CML patients with DMR. Differential expression analysis and Veen plot of up-regulated lncRNAs in patients with non-DMR (compared with healthy individuals) and down-regulated lncRNAs in patients with DMR (compared to patients with non-DMR) revealed that lncRNA CBR3-AS1 overexpression might be related to BCR::ABL1 independent TKI resistance of CML patients. The expression of CBR3-AS1 was then verified in an expanded cohort, suggesting that, compared with control group, there was no statistical difference of CBR3-AS1 expression in DMR group, whereas, CBR3-AS1 was up-regulated in non-DMR group. Moreover, the mRNA data analysis of RNA-sequencing was performed. We considered genes that up-regulated in non-DMR group (compared with control group), down-regulated in DMR group (compared with non-DMR group), showed no statistical difference between control and DMR group as the potential genes that associated with TKI resistance of CML patients. A total of 55 corresponding mRNAs were obtained including KCNA6, a target gene of CBR3-AS1. Further bioinformatics analysis showed that the major interacted genes of KCNA6 were enriched in several resistance-associated pathways including interleukin -17 signaling pathway and cyclic adenosine monophosphate signaling pathway. Conclusions: In conclusion, this work indicates that CBR3-AS1 might be involved in BCR::ABL1 independent TKI resistance of CML patients through targeting KCNA6, providing a novel target for intervention treatment of CML patients with BCR::ABL1 independent TKI resistance.

Swollen Necrotic Lymphadenitis Infected with Mycobacterium Paracondontium in an AIDS Patient: a Case Report and Literature Review.

Background: Non-tuberculous mycobacteria (NTM) are a group of mycobacteria that are commonly found in the environment and can cause disease in humans. The symptoms of NTM infection can be similar to those of tuberculosis, making diagnosis challenging. The morbidity associated with NTM is increasing, and clinical management can be challenging. Case Description: This report details the case of a 32-year-old male who was found to have multiple enlarged and partially necrotic lymph nodes in the neck, axilla, mediastinum, and retroperitoneum. The causative agent was rapidly identified as Mycobacterium paracondontium through pathogen-targeted sequencing (tNGS). After two weeks of treatment with azithromycin, moxifloxacin, rifabutin, and amikacin, the patient's uncomfortable symptoms had resolved, and he is currently undergoing further review. Conclusion: It is imperative that clinicians remain vigilant for the presence of NTM, particularly those that are rare, given their pervasiveness in the environment. Prompt diagnosis is of paramount importance, and molecular identification techniques represent a crucial tool in this regard. In vitro drug sensitivity testing should be conducted whenever feasible to guarantee the administration of an efficacious treatment regimen.

Rhizosphere effects and microbial N limitations drive the root N limitations in the rhizosphere during secondary succession in a Pinus tabuliformis forest in North China.

Introduction: Rhizosphere effects (REs) have recently been identified as important regulators of root and microbial nutrient acquisition and are positively involved in nutrient cycling of belowground carbon (C), nitrogen (N), and phosphorus (P). Nutrient conditions of the fine roots and soil N are likely to influence REs. Still, it is unclear how REs of soil nutrients themselves variably impact the supply of nutrients to plants in terms of the responses to soil N due to succession. Methods: In this study, we applied both fine roots and extracellular enzymes for vector analysis and stoichiometry of N:P to explore the metabolic limitations of roots and rhizospheric soil microbes and their relationships with REs across five levels of soil N (0, 5, 10, 15, and 20 kg N m-2 year-1) along successional age classes of 42, 55, and 65 years in a Pinus tabuliformis forest. Results: Overall, the metabolism of root and rhizospheric soil microbes was mediated by soil N. N limitation of roots initially decreased before increasing, whereas that of microbes demonstrated opposite trends to the N levels owing to competition for inorganic N between them by REs of NO3 --N. However, N limitations of both roots and microbes were alleviated in young stands and increased with succession after the application of N. In addition, root N limitations were manipulated by REs of three different soil N-related indicators, i.e., total N, NH4 +-N, and NO3 --N. Rhizospheric soil microbial N limitation was almost unaffected by REs due to their strong homeostasis but was an important driver in the regulation of root N limitation. Discussion: Our results indicated that successional age was the most critical driver that directly and indirectly affected root N metabolism. However, the level of N application had a slight effect on root N limitation. Microbial N limitation and variations in the REs of N indicators regulated root N limitation in the rhizosphere. As a result, roots utilized REs to sequester N to alleviate N limitations. These findings contribute to novel mechanistic perspectives on the sustainability of N nutrition by regulating N cycling in a system of plant-soil-microbes in the rhizosphere to adapt to global N deposition or the heterogeneous distribution of bioavailable soil N with succession.

An Updated Comprehensive Review of Existing Transcatheter Aortic Valve Replacement Access.

For the past 20 years, transcatheter aortic valve replacement (TAVR) has been the treatment of choice for symptomatic aortic stenosis. The transfemoral (TF) access is considered the gold standard approach for TAVR. However, TF-TAVR cannot be performed in some patients; thus, alternative accesses are required. Our review paper generalises the TAVR accesses currently available, including the transapical, transaortic, trans-subclavian/axillary, transcarotid, transcaval, and suprasternal approaches. Their advantages and disadvantages have been analysed. Since there is no standard recommendation for an alternative approach, access selection depends on the expertise of the local cardiac team, patient characteristics, and access properties. Each TAVR centre is recommended to master a minimum of one non-TF access alternative. Of note, more evidence is required to delve into the clinical outcomes of each approach, at both early and long-term (Figure 1).

Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial.

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1-32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7-18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 .

Coinfection of Cytomegalovirus, Pneumocystis jirovecii pneumonia, COVID-19, and Mycobacterium colombiense in an AIDS patient: A case report.

We present an AIDS patient coinfected with Cytomegalovirus, Pneumocystis jirovecii pneumonia, nontuberculous mycobacteria, and COVID-19, who finally recovered from the coinfection. The 36-year-old man had two hospitalizations. In the first hospitalization, the patient was diagnosed with Cytomegalovirus, Pneumocystis jirovecii pneumonia, HIV, and COVID-19 quickly and accurately, and the corresponding treatment worked well. The second hospitalization can be divided into four stages: (1) Persistent fever period; (2) Persistent fever and Pulmonary Progression; (3) ICU period; and (4) Pneumothorax period. During the second hospitalization, the diagnosis of Mycobacterium colombiense was hard because the NGS, acid-fast bacilli, and culture of vomit, sputum, and bronchoalveolar lavage fluid were all negative. Still, we detected acid-fast bacilli in the blood mycobacterium culture. In conclusion, we report a severe pneumonia AIDS patient coinfected with Cytomegalovirus, Pneumocystis jirovecii pneumonia, COVID-19, and Mycobacterium colombiense who finally recovered from the disease. Nontuberculous mycobacteria infection is common in HIV patients, but bronchoalveolar lavage fluid NGS cannot identify nontuberculous mycobacteria in our report. Traditional blood culture was useful in detecting acid-fast bacilli in our study and then detecting the pathogens with NGS. Combining traditional microbial culture and emerging rapid NGS methods is more conducive to clinical diagnosis and treatment.

Chlorin e6 and BLZ945 Based Self-Assembly for Photodynamic Immunotherapy Through Immunogenic Tumor Induction and Tumor-Associated Macrophage Depletion.

Immunotherapeutic effect is restricted by the nonimmunogenic tumor phenotype and immunosuppression behaviors of tumor-associated macrophages (TAMs). In this work, a drug self-assembly (designated as CeBLZ) is fabricated based on chlorin e6 (Ce6) and BLZ945 to activate photodynamic immunotherapy through tumor immunogenic induction and tumor-associated macrophage depletion. It is found that Ce6 tends to assemble with BLZ945 without any drug excipients, which can enhance the cellular uptake, tumor penetration, and blood circulation behaviors. The robust photodynamic therapy effect of CeBLZ efficiently suppresses the primary tumor growth and also triggers immunogenic cell death to reverse the nonimmunogenic tumor phenotype. Moreover, CeBLZ can deplete TAMs in tumor tissues to reverse the immunosuppression microenvironment, activating abscopal effect for distant tumor inhibition. In vitro and in vivo results confirm the superior antitumor effect of CeBLZ with negligible side effect, which might promote the development of sophisticated drug combinations for systematic tumor management.

Comprehensive multi-omics analysis of resectable locally advanced gastric cancer: Assessing response to neoadjuvant camrelizumab and chemotherapy in a single-center, open-label, single-arm phase II trial.

BACKGROUND: The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain. METHODS: A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy. RESULTS: This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response. CONCLUSION: The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.

Preparation and Properties of Low-Dielectric Polyimide Films Containing Tert-Butyl.

The design of high-performance polyimide (PI) films and understanding the relationship of the structure-dielectric property are of great significance in the field of the microelectronics industry, but are challenging. Herein, we describe the first work to construct a series of novel tert-butyl PI films (denoted as PI-1, PI-2, PI-3, and PI-4) based on a low-temperature polymerization strategy, which employed tetracarboxylic dianhydride (pyromellitic anhydride, 3,3',4,4'-biphenyl tetracarboxylic anhydride, 4,4'-diphenyl ether dianhydride, and 3,3',4,4'-benzophenone tetracarboxylic anhydride) and 4,4'-diamino-3,5-ditert butyl biphenyl ether as monomers. The results indicate that introducing tert-butyl branches in the main chain of PIs can enhance the free volume of the molecular chain and reduce the interaction between molecular chains of PI, resulting in a low dielectric constant. Particularly, the optimized PI-4 exhibits an excellent comprehensive performance with a high (5) wt% loss temperature (454 °C), tensile strength (117.40 MPa), and maximum hydrophobic angle (80.16°), and a low dielectric constant (2.90), which outperforms most of the results reported to date.

First-line camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and chemotherapy for advanced gastric cancer (SPACE): a phase 1 study.

Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1-14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8-89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).

Chemotherapy-Enabled Colorectal Cancer Immunotherapy of Self-Delivery Nano-PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance.

The chemo-regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c-Myc, which also inhibits the expression of programmed death ligand 1 (PD-L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self-delivery nano-PROTACs (designated as DdLD NPs) are further fabricated by the self-assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE-PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo-regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD-L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo-regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self-delivery nano-PROTACs may provide a new insight for chemotherapy-enabled tumor immunotherapy.

Clinical significance and management of low-level HIV viremia in the era of integrase strand transfer inhibitors.

BACKGROUND: People living with HIV (PLWH) and receiving antiretroviral therapy (ART) have a goal of achieving and maintaining viral suppression; however, the existence of PLWH that show events of low-level viremia (LLV) between 50 and 1000 copies/mL and with different virological consequences have been observed. Moreover, some reports indicate that LLV status can lead to residual immune activation and inflammation, leading to a higher occurrence of non-AIDS-defining events (nADEs) and other adverse clinical outcomes. Until now, however, published data have shown controversial results that hinder understanding of this phenomenon's actual cause(s) and origin(s). Integrase strand transfer inhibitors (INSTIs)-based therapies could lead to lower LLV over time and, therefore, more effective virological control. OBJECTIVES: This review aims to assess recent findings to provide a view of the clinical significance and management of low-level HIV viremia in the era of INSTIs.

Epidemiological Insights into the Omicron Outbreak via MeltArray-Assisted Real-Time Tracking of SARS-CoV-2 Variants.

The prolonged course of the COVID-19 pandemic necessitates sustained surveillance of emerging variants. This study aimed to develop a multiplex real-time polymerase chain reaction (rt-PCR) suitable for the real-time tracking of Omicron subvariants in clinical and wastewater samples. Plasmids containing variant-specific mutations were used to develop a MeltArray assay. After a comprehensive evaluation of both analytical and clinical performance, the established assay was used to detect Omicron variants in clinical and wastewater samples, and the results were compared with those of next-generation sequencing (NGS) and droplet digital PCR (ddPCR). The MeltArray assay identified 14 variant-specific mutations, enabling the detection of five Omicron sublineages (BA.2*, BA.5.2*, BA.2.75*, BQ.1*, and XBB.1*) and eight subvariants (BF.7, BN.1, BR.2, BQ.1.1, XBB.1.5, XBB.1.16, XBB.1.9, and BA.4.6). The limit of detection (LOD) of the assay was 50 copies/reaction, and no cross-reactivity was observed with 15 other respiratory viruses. Using NGS as the reference method, the clinical evaluation of 232 swab samples exhibited a clinical sensitivity of > 95.12% (95% CI 89.77-97.75%) and a specificity of > 95.21% (95% CI, 91.15-97.46%). When used to evaluate the Omicron outbreak from late 2022 to early 2023, the MeltArray assay performed on 1408 samples revealed that the epidemic was driven by BA.5.2* (883, 62.71%) and BF.7 (525, 37.29%). Additionally, the MeltArray assay demonstrated potential for estimating variant abundance in wastewater samples. The MeltArray assay is a rapid and scalable method for identifying SARS-CoV-2 variants. Integrating this approach with NGS and ddPCR will improve variant surveillance capabilities and ensure preparedness for future variants.

Chimeric Peptide Engineered Nanomedicine for Synergistic Suppression of Tumor Growth and Therapy-Induced Hyperlipidemia by mTOR and PCSK9 Inhibition.

Chemotherapy-induced side effects restrain anti-tumor efficiency, with hyperlipidemia being the most common accompanying disease to cause treatment failure. In this work, a chimeric peptide-engineered nanomedicine (designated as PRS) was fabricated for the synergistic suppression of tumor growth and therapy-induced hyperlipidemia. Within this nanomedicine, the tumor matrix-targeting peptide palmitic-K(palmitic)CREKA can self-assemble into a nano-micelle to encapsulate Rapamycin (mTOR inhibitor) and SBC-115076 (PCSK9 inhibitor). This PRS nanomedicine exhibits a uniform nano-distribution with good stability which enhances intracellular drug delivery and tumor-targeting delivery. Also, PRS was found to synergistically inhibit tumor cell proliferation by interrupting the mTOR pathway and reducing Rapamycin-induced hyperlipidemia by increasing the production of LDLR. In vitro and in vivo results demonstrate the superiority of PRS for systematic suppression of tumor growth and the reduction of hyperlipidemia without initiating any other toxic side effects. This work proposes a sophisticated strategy to inhibit tumor growth and also provides new insights for cooperative management of chemotherapy-induced side effects.

Leaf nutrient resorption of two life-form tree species in urban gardens and their response to soil nutrient availability.

Background: Leaf nutrient resorption is a key strategy in plant conservation that minimizes nutrient loss and enhances productivity. However, the differences of the nutrient resorption among garden tree species in urban ecosystems were not clearly understood, especially the differences of nitrogen resorption efficiency (NRE) and phosphorous resorption efficiency (PRE) between evergreen and deciduous trees. Methods: We selected 40 most generally used garden tree specie belonged two life forms (evergreen and deciduous) and investigated the nitrogen (N) and phosphorus (P) concentrations in green and senesced leaves and soil nutrient concentrations of nine samples trees for each species. Then, the nutrient concentrations and resorption efficiency were compared, and the soil nutrients utilization strategies were further analyzed. Results: The results showed that the N concentration was significantly higher in the green and senesced leaves of deciduous trees than in the leaves of evergreen trees. The two life-form trees were both N limited and evergreen trees were more sensitive to N limitation. The NRE and PRE in the deciduous trees were significantly higher than those in the evergreen trees. The NRE was significantly positively correlated with the PRE in the deciduous trees. As the soil N and P concentrations increased, the nutrient resorption efficiency (NuRE) of the evergreen trees increased, but that of the deciduous trees decreased. Compared with the deciduous trees, the evergreen trees were more sensitive to the feedback of soil N and P concentrations. These findings reveal the N and P nutrient resorption mechanism of evergreen and deciduous trees and fill a gap in the understanding of nutrient resorption in urban ecosystems.

Carrier-Free Nano-PROTACs to Amplify Photodynamic Therapy Induced DNA Damage through BRD4 Degradation.

Therapy-induced DNA damage is the most common strategy to inhibit tumor cell proliferation, but the therapeutic efficacy is limited by DNA repair machinery. Carrier-free nanoproteolysis targeting chimeras (PROTACs), designed as SDNpros, have been developed to enhance photodynamic therapy (PDT) by blocking the DNA damage repair pathway through BRD4 degradation. Specifically, SDNpros are constructed through noncovalent interactions between the photosensitizer of chlorine e6 (Ce6) and PROTACs of BRD4 degrader (dBET57) via self-assembly. SDNpro has favorable dispersibility and a uniform nanosize distribution without drug excipients. Upon light irradiation, SDNpro produces abundant reactive oxygen species (ROS) to induce DNA oxidative damage. Meanwhile, the DNA repair pathway would be interrupted by the concurrent degradation of BRD4, which could intensify the oxidative DNA damage and elevate PDT efficiency. Beneficially, SDNpro suppresses tumor growth and avoids systemic side effects, providing a promising strategy to promote the clinical translation of PROTACs for tumor treatment.