Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications.

CDK9 is a cyclin-dependent kinase that plays pivotal roles in multiple cellular functions including gene transcription, cell cycle regulation, DNA damage repair, and cellular differentiation. Targeting CDK9 is considered an attractive strategy for antitumor therapy, especially for leukemia and lymphoma. Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials. However, many of them face challenges such as low clinical efficacy and multiple adverse reactions and may necessitate the exploration of novel strategies to lead to success in the clinic. In this perspective, we present a comprehensive overview of the structural characteristics, biological functions, and preclinical status of CDK9 inhibitors. Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.

A Highly Selective Implantable Electrochemical Fiber Sensor for Real-Time Monitoring of Blood Homovanillic Acid.

Homovanillic acid (HVA) is a major dopamine metabolite, and blood HVA is considered as central nervous system (CNS) dopamine biomarker, which reflects the progression of dopamine-associated CNS diseases and the behavioral response to therapeutic drugs. However, facing blood various active substances interference, particularly structurally similar catecholamines and their metabolites, real-time and accurate monitoring of blood HVA remains a challenge. Herein, a highly selective implantable electrochemical fiber sensor based on a molecularly imprinted polymer is reported to accurately monitor HVA in vivo. The sensor exhibits high selectivity, with a response intensity to HVA 12.6 times greater than that of catecholamines and their metabolites, achieving 97.8% accuracy in vivo. The sensor injected into the rat caudal vein tracked the real-time changes of blood HVA, which paralleled the brain dopamine fluctuations and indicated the behavioral response to dopamine increase. This study provides a universal design strategy for improving the selectivity of implantable electrochemical sensors.

Low-intensity pulsed ultrasound activated the anti-tumor immunity by irradiating the spleen of mice in 4 T-1 breast cancer.

Tumor immunotherapy is booming around the world. However, strategies to activate the immune system and alleviate the immunosuppression still need to be refined. Here, we demonstrate for the first time that low-intensity pulsed ultrasound (LIPUS, spatial average time average intensity (Isata) is 200 mW/cm2, frequency is 0.3 MHz, repetition frequency is 1 kHz, and duty cycle is 20%) triggers the immune system and further reverses the immunosuppressive state in the mouse models of breast cancer by irradiating the spleen of mice. LIPUS inhibited tumor growth and extended survival in mice with 4 T-1 tumors. Further studies had previously shown that LIPUS enhanced the activation of CD4+ and CD8+ T cells in the spleen and led to significant changes in cytokines, as well as induced upregulation of mRNA levels involved in multiple immune regulatory pathways in the spleen. In addition, LIPUS promoted tumor-infiltrating lymphocyte accumulation and CD8+ T cell activation and improved the dynamics of cytokines/chemokines in the tumor microenvironment, resulting in a reversal of the immunosuppressive state of the tumor microenvironment. These results suggest a novel approach to activate the immune response by irradiating the spleen with LIPUS.

Moiré effect enables versatile design of topological defects in nematic liquid crystals.

Recent advances in surface-patterning techniques of liquid crystals have enabled the precise creation of topological defects, which promise a variety of emergent applications. However, the manipulation and application of these defects remain limited. Here, we harness the moiré effect to engineer topological defects in patterned nematic liquid crystal cells. Specifically, we combine simulation and experiment to examine a nematic cell confined between two substrates of periodic surface anchoring patterns; by rotating one surface against the other, we observe a rich variety of highly tunable, novel topological defects. These defects are shown to guide the three-dimensional self-assembly of colloids, which can conversely impact defects by preventing the self-annihilation of loop-defects through jamming. Finally, we demonstrate that certain nematic moiré cells can engender arbitrary shapes represented by defect regions. As such, the proposed simple twist method enables the design and tuning of mesoscopic structures in liquid crystals, facilitating applications including defect-directed self-assembly, material transport, micro-reactors, photonic devices, and anti-counterfeiting materials.

Intratumor APOL3 delineates a distinctive immunogenic ferroptosis subset with prognosis prediction in colorectal cancer.

With the essential role of lipid transporting signaling in cancer-related immunity, apolipoprotein L3 (APOL3), a member of the apolipoprotein L gene family, demonstrated significant modulation ability in immunity. However, the expression profile and critical role of APOL3 in colorectal cancer (CRC) remain unclear. This study aimed to investigate the prognostic significance of APOL3 expression and its biological predictive value in CRC. The study enrolled multiple cohorts, consisting of 911 tumor microarray specimens of CRC patients from Zhongshan Hospital, 412 transcriptional data from The Cancer Genome Atlas, and 30 single-cell RNA sequencing (scRNA-seq) from internal and external CRC patients. APOL3 mRNA expression was directly acquired from public datasets, and APOL3 protein expression was detected using immunohistochemistry. Finally, the associations of APOL3 expression with clinical outcomes, immune context, and genomic and ferroptotic features were analyzed. Low APOL3 expression predicted poor prognosis and inferior responsiveness to 5-fluorouracil-based adjuvant chemotherapy (ACT) and targeted therapy. APOL3 fosters an immune-active microenvironment characterized by the promotion of ferroptosis, downregulation of macrophages, and upregulation of CD8+ T cell infiltration. Moreover, the expression of APOL3 in CD8+ T cells is intrinsically linked to ferroptosis and immune activation in CRC. In summary, APOL3 serves as an independent prognosticator and predictive biomarker for immunogenic ferroptosis, ACT, and targeted therapy in CRC. Furthermore, the APOL3 signaling activator could be a novel agent alone or in combination with current therapeutic strategies for CRC.

Sulfur bacteria-reinforced microbial electrochemical denitrification.

Two limiting factors of microbial electrochemical denitrification (MED) are the abundance and efficiency of the functional microorganisms. To supply these microorganisms, MED systems are inoculated with denitrifying sludge, but such method has much room for improvement. This study compared MED inoculated with autotrophic denitrifying inoculum (ADI) versus with heterotrophic denitrifying inoculum (HDI). ADI exhibited electroactivity for 50% less of timethan HDI. The denitrification efficiency of the ADI biocathode was42% higherthan that of the HDI biocathode. The HDI biocathode had high levels of polysaccharides while the ADI biocathode was rich in proteins, suggesting that two biocathodes may achieveMED but via differentpathways. Microbial communities of two biocathodes indicated MED of HDI biocathode may rely on interspecies electron transfer, whereas sulfur bacteria of ADI biocathode take electrons directly from the cathode to achieve MED. Utilizing autotrophic sulfur-oxidizing denitrifiers, this study offers a strategy for enhancing MED.

PANI-Coated VOx Nanobelts with Core-Shell Architecture for Flexible All-Solid-State Supercapacitor.

As a typical pseudocapacitor material, VOx possesses mixed valence states, making it an ideal electrode material for symmetric screen-printed supercapacitors. However, its high internal resistance and low energy density are the main hurdles to its widespread application. In this study, a two-dimensional PANI@VOx nanobelt with a core-shell architecture was constructed via a two-step route. This strategy involves the preparation of VOx using a solvothermal method, and a subsequent in situ polymerization process of the PANI. By virtue of the synergistic effect between the VOx core and the PANI shell, the optimal VOx@PANI has an enhanced conductivity of 0.7 ± 0.04 S/Ω, which can deliver a high specific capacitance of 347.5 F/g at 0.5 A/g, a decent cycling life of ~72.0%, and an outstanding Coulomb efficiency of ~100% after 5000 cycles at 5 A/g. Moreover, a flexible all-solid-state symmetric supercapacitor (VOx@PANI SSC) with an in-planar interdigitated structure was screen-printed and assembled on a nickel current collector; it yielded a remarkable areal energy density of 115.17 µWh/cm2 at an areal power density of 0.39 mW/cm2, and possessed outstanding flexibility and mechanical performance. Notably, a "Xiaomi" hygrothermograph (3.0 V) was powered easily by tandem SSCs with an operating voltage of 3.1 V. Therefore, this advanced pseudocapacitor material with core-shell architecture opens novel ideas for flexible symmetric supercapacitors in powering portable/wearable products.

A Rolling Bearing Fault Feature Extraction Algorithm Based on IPOA-VMD and MOMEDA.

Since the rolling bearing fault signal captured by a vibration sensor contains a large amount of background noise, fault features cannot be accurately extracted. To address this problem, a rolling bearing fault feature extraction algorithm based on improved pelican optimization algorithm (IPOA)-variable modal decomposition (VMD) and multipoint optimal minimum entropy deconvolution adjustment (MOMEDA) methods is proposed. Firstly, the pelican optimization algorithm (POA) was improved using a reverse learning strategy for dimensional-by-dimensional lens imaging and circle mapping, and the optimization performance of IPOA was verified. Secondly, the kurtosis-square envelope Gini coefficient criterion was used to select the optimal modal components from the decomposed components of the signal, and MOMEDA was used to process the optimal modal components in order to obtain the optimal deconvolution signal. Finally, the Teager energy operator (TEO) was employed to demodulate and analyze the optimally deconvoluted signal in order to enhance the transient shock component of the original fault signal. The effectiveness of the proposed method was verified using simulated and actual signals. The results showed that the proposed method can accurately extract failure characteristics in the presence of strong background noise interference.

From micro to macro: The role of seawater in maintaining structural integrity and bioactivity of granules in treating antibiotic-laden mariculture wastewater.

Granular sludge (GS) has superior antibiotic removal ability to flocs, due to GS's layered structure and rich extracellular polymeric substances. However, prolonged exposure to antibiotics degrades the performance and stability of GS. This study investigated how a seawater matrix might help maintain the structural integrity and bioactivity of granules. The results demonstrated that GS had better sulfadiazine (SDZ) removal efficiency in a seawater matrix (85.6 %) than in a freshwater matrix (57.6 %); the multiple ions in seawater enhanced boundary layer diffusion (kiR1 = 0.0805 mg·g-1·min-1/2 and kiR2 = 0.1112 mg·g-1·min-1/2) and improved adsorption performance by 15 % (0.123 mg/g-SS freshwater vs. 0.141 mg/g-SS seawater). Moreover, multiple hydrogen bonds (1-3) formed between each SDZ and lipid bilayer fortified the adsorption. Beyond S-N and S-C bond hydrolyses that took place in freshwater systems, there was an additional biodegradation pathway for GS to be cultivated in a saltwater system that involved sulfur dioxide extrusion. This additional pathway was attributable to the greater microbial diversity and larger presence of sulfadiazine-degrading bacteria containing SadAC genes, such as Leucobacter and Arthrobacter, in saltwater wastewater. The findings of this study elucidate how seawater influences GS properties and antibiotic removal ability.

Erratum: Zinc-α2-glycoprotein 1 promotes EMT in colorectal cancer by filamin A mediated focal adhesion pathway: Erratum.

[This corrects the article DOI: 10.7150/jca.35380.].

Flexible High-Performance and Screen-Printed Symmetric Supercapacitor Using Hierarchical Rodlike V3O7 Inks.

The emergence of the Internet of things stimulates the pursuit of flexible and miniaturized supercapacitors. As an advanced technology, screen printing displays vigor and tremendous potential in fabricating supercapacitors, but the adoption of high-performance ink is a great challenge. Here, hierarchical V3O7 with rodlike texture was prepared via a facile template-solvothermal route; and the morphology, component, and valence bond information are characterized meticulously. Then, the screen-printed inks composed of V3O7, acetylene black, and PVDF are formulated, and the rheological behaviors are studied detailedly. Benefitting from the orderly aligned ink, the optimal screen-printed electrode can exhibit an excellent specific capacitance of 274.5 F/g at 0.3 A/g and capacitance retention of 81.9% after 5000 cycles. In addition, a flexible V3O7 symmetrical supercapacitor (SSC) is screen-printed and assembled on the Ag current collector, exhibiting a decent areal specific capacitance of 322.5 mF/cm2 at 0.5 mA/cm2, outstanding cycling stability of 90.8% even after 5000 cycles, satisfactory maximum energy density of 129.45 µWh/cm2 at a power density of 0.42 mW/cm2, and remarkable flexibility and durability. Furthermore, a single SSC enables the showing of an actual voltage of 1.70 V after charging, and no obvious self-discharge phenomenon is found, revealing the great applied value in supply power. Therefore, this work provides a facile and low-cost reference of screen-printed ink for large-scale fabrication of flexible supercapacitors.

Anatomical resection improves relapse-free survival in colorectal liver metastases in patients with KRAS/NRAS/BRAF mutations or right-sided colon cancer: a retrospective cohort study.

BACKGROUND: The type of liver resection (anatomical resection, AR or non-anatomical resection, NAR) for colorectal liver metastases (CRLM) is subject to debate. The debate may persist because some prognostic factors, associated with aggressive tumor biological behavior, have been overlooked. OBJECTIVE: Our study aimed to investigate the characteristics of patients who would benefit more from anatomical resection for CRLM. METHODS: Seven hundred twenty-nine patients who underwent hepatic resection of CRLM were retrospectively collected from June 2012 to May 2019. Treatment effects between AR and NAR were compared in full subgroup analyses. Tumor relapse-free survival (RFS) was evaluated by a stratified log-rank test and summarized with the use of Kaplan-Meier and Cox proportional hazards methods. RESULTS: Among 729 patients, 235 (32.2%) underwent AR and 494 (67.8%) underwent NAR. We showed favorable trends in RFS for AR compared with NAR in the patients with KRAS/NRAS/BRAF mutation (interaction P <0.001) or right-sidedness (interaction P <0.05). Patients who underwent AR had a markedly improved RFS compared with NAR in the cohorts of RAS/NRAS/BRAF mutation (median RFS 23.2 vs. 11.1 months, P <0.001) or right-sidedness (median RFS 31.6 vs. 11.5 months, P <0.001); upon the multivariable analyses, AR [gene mutation: hazard ratio (HR)=0.506, 95% CI=0.371-0.690, P <0.001; right-sidedness: HR=0.426, 95% CI=0.261-0.695, P =0.001) remained prognostic independently. In contrast, patients who underwent AR had a similar RFS compared with those who underwent NAR, in the cohorts of patients with gene wild-type tumors (median RFS 20.5 vs. 21.6 months, P =0.333). or left-sidedness (median RFS 15.8 vs. 19.5 months, P =0.294). CONCLUSIONS: CRLM patients with gene mutation or right-sidedness can benefit more from AR rather than from NAR.

Treatment of metastatic colorectal cancer with BRAF V600E mutation: A multicenter real-world study in China.

BACKGROUND: BRAF V600E mutant-metastatic colorectal cancer (mCRC) is characterized by its short survival time. Treatment approaches vary depending on whether or not the metastases are initially resectable. The benefit of metastasectomy remains unclear, and the optimal first-line treatment is controversial. This study aimed to describe the prognosis of BRAF V600E mutant-mCRC, analyze the recurrence pattern in resectable patients, and explore the optimal first-line treatment for unresectable patients. METHODS: Patients diagnosed with BRAF V600E mutant-mCRC between February 2014 and January 2022 in five hospitals were enrolled. Date on clinical and pathological characteristics, treatment features, and survival outcomes were collected. RESULTS: Of the 220 included patients, 64 initially resectable patients had a significantly longer overall survival (OS) (37.07 vs. 20.20 months, P < 0.001) than initially unresectable patients. Of 156 unresectable patients, 54 received doublet (FOLFOX, XELOX or FOLFIRI) or triplet (FOLFOXIRI) chemotherapies (Chemo), 55 received Chemo plus Bevacizumab (Chemo+Bev), and 33 received vemurafenib plus cetuximab and irinotecan (VIC). The VIC regimen had a better progression-free survival (PFS) (12.70 months) than the Chemo (6.70 months, P < 0.001) and Chemo+Bev (8.8 months, P = 0.044) regimens. Patients treated with VIC had the best overall response rate (60.16%, P < 0.001), disease control rate (93.94%, P < 0.001) and conversional resection rate (24.24%, P = 0.003). CONCLUSIONS: Metastasectomy is beneficial to the survival of patients with BRAF V600E mutant-mCRC. For initially unresectable patients, VIC as first-line therapy is associated with a better prognosis and efficacy than doublet and triplet chemotherapy with or without bevacizumab.

Preoperative chemotherapy prior to primary tumour resection for asymptomatic synchronous unresectable colorectal liver-limited metastases: The RECUT multicenter randomised controlled trial.

PURPOSE: Primary tumour resection (PTR) is still a selection for patients with low tumour burden and good condition, especially with conversion therapy purpose for colorectal liver-limited metastases (CRLMs). The objective was to evaluate whether pre-PTR chemotherapy could improve progression-free survival (PFS) for patients with asymptomatic synchronous unresectable CRLMs. PATIENTS AND METHODS: Patients with asymptomatic synchronous unresectable CRLMs were randomly assigned to receive pre-PTR chemotherapy (arm A) or upfront PTR (arm B). Chemotherapy regimens of mFOLFOX6 plus cetuximab, mFOLFOX6 plus bevacizumab or mFOLFOX6 alone were chosen according to the RAS genotype. The primary end-point was PFS; secondary end-points included overall survival (OS), tumour response, disease control rate (DCR), liver metastases resection rate, surgical complications and chemotherapy toxicity. RESULTS: Three hundred and twenty patients were randomly assigned to arm A (160 patients) and arm B (160 patients). Patients in arm A had significantly improved the median PFS compared with arm B (10.5 versus 9.1 months; P = 0.013). Patients in arm A also had significantly better DCR (84.4% versus 75.0%; P = 0.037). The median OS (29.4 versus 27.2 months; P = 0.058), objective response rate (ORR) (53.1% versus 45.0%; P = 0.146) and liver metastases resection rate (21.9% versus 18.1%; P = 0.402) were not significantly different. The Clavien-Dindo 3-4 complications post PTR (4.5% versus 3.8%, P = 0.759) and the incidence of grade 3/4 chemotherapy events (42.2% versus 40.4%, P = 0.744) reached no statistical significance. CONCLUSIONS: For asymptomatic synchronous unresectable CRLMs, Pre-PTR chemotherapy improved the PFS compared with upfront PTR.

B cells in tumor metastasis: friend or foe?

Metastasis is an important cause of cancer-related death. Immunotherapy may be an effective way to prevent and treat tumor metastasis in the future. Currently, many studies have focused on T cells, whereas fewer have focused on B cells and their subsets. B cells play an important role in tumor metastasis. They not only secrete antibodies and various cytokines but also function in antigen presentation to directly or indirectly participate in tumor immunity. Furthermore, B cells are involved in both inhibiting and promoting tumor metastasis, which demonstrates the complexity of B cells in tumor immunity. Moreover, different subgroups of B cells have distinct functions. The functions of B cells are also affected by the tumor microenvironment, and the metabolic homeostasis of B cells is also closely related to their function. In this review, we summarize the role of B cells in tumor metastasis, analyze the mechanisms of B cells, and discuss the current status and prospects of B cells in immunotherapy.

Novel Medicinal Chemistry Strategies Targeting CDK5 for Drug Discovery.

Cyclin-dependent kinase 5 (CDK5) protein plays an important role not only in the central nervous system but also in the periphery, including immune response, regulation of insulin secretion, and cancer development and progression. Consequently, targeting the CDK5 protein is a potential strategy for the treatment of many diseases, especially cancer and neurodegenerative diseases. To date, numerous pan-CDK inhibitors have entered clinical trials. Nevertheless, limited clinical efficacy and severe adverse effects have prompted the application of new techniques to optimize clinical efficacy and minimize adverse events. In this Perspective, we highlight the protein properties, biofunctions, relevant signaling pathways, and associations with cancer development and proliferation of CDK5, and analyze the clinical status of pan-CDK inhibitors and the preclinical status of CDK5-specific inhibitors. In addition, CDK5-selective inhibitors, protein-protein interaction inhibitors, proteolytic-targeting chimera (PROTAC) degraders, and dual-target CDK5 inhibitors are discussed.

Collective transport and reconfigurable assembly of nematic colloids by light-driven cooperative molecular reorientations.

Nanomotors in nature have inspired scientists to design synthetic molecular motors to drive the motion of microscale objects by cooperative action. Light-driven molecular motors have been synthesized, but using their cooperative reorganization to control the collective transport of colloids and to realize the reconfiguration of colloidal assembly remains a challenge. In this work, topological vortices are imprinted in the monolayers of azobenzene molecules which further interface with nematic liquid crystals (LCs). The light-driven cooperative reorientations of the azobenzene molecules induce the collective motion of LC molecules and thus the spatiotemporal evolutions of the nematic disclination networks which are defined by the controlled patterns of vortices. Continuum simulations provide physical insight into the morphology change of the disclination networks. When microcolloids are dispersed in the LC medium, the colloidal assembly is not only transported and reconfigured by the collective change of the disclination lines but also controlled by the elastic energy landscape defined by the predesigned orientational patterns. The collective transport and reconfiguration of colloidal assemblies can also be programmed by manipulating the irradiated polarization. This work opens opportunities to design programmable colloidal machines and smart composite materials.

Anti-inflammatory Effect of Low-Intensity Ultrasound in Septic Rats.

OBJECTIVE: Sepsis is a severe systemic inflammatory response caused by infection. Here, the spleen region of Sprague-Dawley (SD) rats with sepsis was irradiated with low-intensity ultrasound (LIUS) to explore the regulation of inflammation and its mechanism by LIUS. METHODS: In this study, 30 rats used for survival analysis were randomly divided into the sham-operated group (Sham, n = 10), the group in which sepsis was induced by cecal ligation and puncture (CLP, n = 10) and the group treated with LIUS immediately after CLP (LIUS, n = 10). The other 120 rats were randomly divided into the aforementioned three groups for detection at each time point. The parameters used in the LIUS group were 200 mW/cm2, 0.37 MHz, 20% duty cycle and 20 min, and no ultrasonic energy was produced in the Sham and CLP groups. Seven-day survival rate, histopathology and expression of inflammatory factors and proteins were evaluated in the three groups. RESULTS: LIUS was able to improve the survival rate of septic SD rats (p < 0.05), significantly inhibit the expression of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), interleukin 6 (IL-6) and nuclear factor-κB p65 (NF-κB p65) (p < 0.05) and restore the ultrastructure of the spleen. CONCLUSION: Our study determined that LIUS can relieve spleen damage and alleviate severe cytokine storm to improve survival outcomes in septic SD rats, and its mechanism may be related to the inhibition of the NF-κB signaling pathway by downregulation of IL-1ß.

Budget impact analysis of comprehensive genomic profiling for untreated advanced or recurrent solid cancers in Japan.

AIMS: In Japan, the use of comprehensive genomic profiling (CGP) is only available for cancer patients who have no standard of care (SoC), or those who have completed SoC. This may lead to missed treatment opportunities for patients with druggable alterations. In this study, we evaluated the potential impact of CGP testing before SoC on medical costs and clinical outcome in untreated patients with advanced or recurrent biliary tract cancer (BTC), non-squamous non-small cell lung cancer (NSQ-NSCLC), or colorectal cancer (CRC) in Japan between 2022 and 2026. MATERIALS AND METHODS: We constructed a decision-tree model reflecting the healthcare environment of Japan, to estimate the clinical outcome and medical costs impact of CGP testing by comparing two groups (with vs without CGP testing before SoC). The epidemiological parameters, detection rates of druggable alterations, and overall survival were collected from literature and claims databases in Japan. Treatment options selected based on druggable alterations were set in the model based on clinical experts' opinions. RESULTS: In 2026, the number of untreated patients with advanced or recurrent BTC, NSQ-NSCLC, and CRC was estimated to be 8600, 32,103, and 24,896, respectively. Compared with the group without CGP testing before SoC, CGP testing before SoC increased druggable alteration detection and treatment rate with matched therapies in all three cancer types. The medical costs per patient per month were estimated to increase with CGP testing before SoC in the three cancer types by 19,600, 2900, and 2200 JPY (145, 21, and 16 USD), respectively. LIMITATIONS: Only those druggable alterations with matched therapies were considered in the analysis model, while the potential impact of other genomic alterations provided by CGP testing was not considered. CONCLUSIONS: The present study suggested that CGP testing before SoC may improve patient outcomes in various cancer types with a limited and controllable increase in medical costs.