Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer.

Tumor stroma plays a critical role in fostering tumor progression and metastasis. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma. Identifying the key molecular determinants for the pro-tumor properties of CAFs could enable the development of more effective treatment strategies. Herein, through analyses of single-cell sequencing data, we identified a population of CAFs expressing high levels of sulfatase 1 (SULF1), which was associated with poor prognosis in colorectal cancer (CRC) patients. CRC models using mice with conditional SULF1 knockout in fibroblasts revealed the tumor-supportive function of SULF1+ CAFs. Mechanistically, SULF1+ CAFs enhanced the release of vascular endothelial growth factor A (VEGFA) from heparan sulfate proteoglycan (HSPG). The increased bioavailability of VEGFA initiated the deposition of extracellular matrix (ECM) and enhanced angiogenesis. In addition, intestinal microbiota-produced butyrate suppressed SULF1 expression in CAFs through its HDAC inhibitory activity. The insufficient butyrate production in CRC patients increased the abundance of SULF1+ CAFs, thereby promoting tumor progression. Importantly, tumor growth inhibition by HDAC inhibition was dependent on SULF1 expression in CAFs, and CRC patients with more SULF1+ CAFs were more responsive to treatment with the HDAC inhibitor chidamide. Collectively, these findings unveil the critical role of SULF1+ CAFs in CRC and provide a strategy to stratify CRC patients for HDAC inhibitor treatment.

Mesonephric adenocarcinoma of the uterine cervix with a prominent spindle cell component.

Mesonephric adenocarcinomas (MAs) with spindle cell components are rare malignant cervical tumours. In the present study, a retrospective analysis of these tumours was performed. Clinicopathological data were gathered from electronic surgical pathology records, and both immunohistochemistry and targeted next-generation sequencing (NGS) were performed. The present study included three postmenopausal female patients diagnosed with primary uterine cervical MA with prominent spindle cell components, aged 51-60 years. All patients underwent hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph node dissection. There were no recurrences or deaths after surgery. NGS analysis identified KRAS mutations in 2 cases and a PIK3-catalytic subunit α (PIK3CA) mutation in another. Spindle cell components may indicate MAs at an advanced stage. Spindle cell components in MAs are diagnostic pitfalls, and the use of immunohistochemical panels and molecular detection cases with overlapping morphological features is recommended. While KRAS mutations are the most common types of mutations in MAs with spindle cell components, the present study demonstrates that PIK3CA mutations can also occur independently in cases without KRAS mutations.

Involvement of the Metallothionein gene OsMT2b in Drought and Cadmium Ions Stress in Rice.

Abiotic stress is one of the major factors restricting the production of rice (Oryza sativa L.). Developing rice varieties with dual abiotic stress tolerance is essential to ensure sustained rice production, which is necessary to illustrate the regulation mechanisms underlying dual stress tolerance. At present, only a few genes that regulate dual abiotic stress tolerance have been reported. In this study, we determined that the expression of OsMT2b was induced by both drought and Cd2+ stress. After stress treatment, OsMT2b-overexpression lines exhibited enhanced drought tolerance and better physiological performance in terms of relative water content and electrolyte leakage compared with wild-type (WT). Further analysis indicated that ROS levels were lower in OsMT2b-overexpression lines than in WT following stress treatment, suggesting that OsMT2b-overexpression lines had a stronger ability to scavenge ROS under stress. Reverse transcription-quantitative PCR (RT-qPCR) results demonstrated that under drought stress, OsMT2b influenced the expression of genes involved in ROS scavenging to enhance drought tolerance in rice. In addition, OsMT2b-overexpression plants displayed increased tolerance to Cd2+ stress, and physiological assessment results were consistent with the observed phenotypic improvements. Thus, enhancing ROS scavenging ability through OsMT2b overexpression is a novel strategy to boost rice tolerance to both drought and Cd2+ stress, offering a promising approach for developing rice germplasm with enhanced resistance to the abiotic stressors.

Mechanism of Fatigue-Life Extension Due to Dynamic Strain Aging in Low-Carbon Steel at High Temperature.

An enhancement in fatigue life for ferrite-pearlite low-carbon steel (LCS) at high temperature (HT) has been discovered, where it increased from 190,873 cycles at room temperature (RT) to 10,000,000 cycles at 400 °C under the same stress conditions. To understand the mechanism behind this phenomenon, the evolution of microstructure and dislocation density during fatigue tests was comprehensively investigated. High-power X-ray diffraction (XRD) was employed to analyze the evolution of total dislocation density, while Electron Backscatter Diffraction (EBSD) and High-Resolution EBSD (HR-EBSD) were conducted to reveal the evolutions of kernel average misorientation (KAM), geometrically necessary dislocations (GND) and elastic strains. Results indicate that the enhancement was attributed to the dynamic strain aging (DSA) effect above the upper temperature limit, where serration and jerky flow disappeared but hindrance of dislocations persisted. Due to the DSA effect, periods of increase and decrease in the total dislocations were observed during HT fatigue tests, and the fraction of screw dislocations increased continuously, caused by viscous movement of the screw dislocations. Furthermore, the increased fraction of screw dislocations resulted in a lower energy configuration, reducing slip traces on sample surfaces and preventing fatigue-crack initiation.

High-sensitivity trace gas detection based on differential Helmholtz photoacoustic cell with dense spot pattern.

A high-sensitivity photoacoustic spectroscopy (PAS) sensor based on differential Helmholtz photoacoustic cell (DHPAC) with dense spot pattern is reported in this paper for the first time. A multi-pass cell based on two concave mirrors was designed to achieve a dense spot pattern, which realized 212 times excitation of incident laser. A finite element analysis was utilized to simulate the sound field distribution and frequency response of the designed DHPAC. An erbium-doped fiber amplifier (EDFA) was employed to amplify the output optical power of the laser to achieve strong excitation. In order to assess the designed sensor's performance, an acetylene (C2H2) detection system was established using a near infrared diode laser with a central wavelength 1530.3 nm. According to experimental results, the differential characteristics of DHPAC was verified. Compared to the sensor without dense spot pattern, the photoacoustic signal with dense spot pattern had a 44.73 times improvement. The minimum detection limit (MDL) of the designed C2H2-PAS sensor can be improved to 5 ppb when the average time of the sensor system is 200 s.

Efficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review, meta-analysis, and network meta-analysis.

BACKGROUND: The clinical benefits of immune checkpoint inhibitor (ICI)-based treatments in treating individuals with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who have progressed on EGFR tyrosine-kinase inhibitors (TKIs) remain controversial. We aimed to review the literature to comprehensively investigate the individual and comparative clinical outcomes of various ICI-based treatment strategies in this population. METHODS: In this systematic review and meta-analysis, we used single-arm, pairwise, and network meta-analytical approaches. We searched PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and relevant international conference proceedings from database inception to Jan 31, 2024, without language restrictions, to identify eligible clinical trials that assessed ICI-based treatments for individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs. Studies considered eligible were published and unpublished phase 1, 2, or 3 clinical trials enrolling participants with histologically or cytologically confirmed advanced EGFR-mutated NSCLC who had progressed after at least one EGFR-TKI treatment, and that evaluated ICI-based treatment strategies on at least one of the clinical outcomes of interest. The primary outcome analysed was progression-free survival. The protocol is registered with PROSPERO, CRD42021292626. FINDINGS: 17 single-arm trials and 15 randomised controlled trials, involving 2886 participants and seven ICI-based treatment strategies (ICI monotherapy, ICI plus chemotherapy [ICI-chemo], ICI plus antiangiogenesis [ICI-antiangio], ICI plus antiangiogenesis plus chemotherapy [ICI-antiangio-chemo], dual ICIs [ICI-ICI], dual ICIs plus chemotherapy [ICI-ICI-chemo], and ICI plus EGFR-TKI [ICI-TKI]), were included. Three of these strategies-ICI monotherapy, ICI-antiangio-chemo, and ICI-chemo-had sufficient data across the included studies to perform a pairwise meta-analysis. The pairwise meta-analysis showed that, compared with chemotherapy, ICI monotherapy led to shorter progression-free survival (hazard ratio [HR] 1·73 [95% CI 1·30-2·29], I2=0%), whereas ICI-antiangio-chemo (HR 0·54 [0·44-0·67], I2=0%) and ICI-chemo (HR 0·77 [0·67-0·88], I2=0%) prolonged progression-free survival. The network meta-analysis showed that ICI-antiangio-chemo yielded the best progression-free survival results, with substantial benefits over ICI-chemo (HR 0·71 [95% credible interval 0·59-0·85]), ICI monotherapy (HR 0·30 [0·22-0·41]), and non-ICI treatment strategies including antiangio-chemo (HR 0·76 [0·58-1·00]) and chemotherapy alone (HR 0·54 [0·45-0·64]). ICI-antiangio-chemo was associated with higher risks of both any-grade and grade 3 or worse adverse events over ICI-chemo and chemotherapy in the network meta-analysis. INTERPRETATION: For individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs, ICI-antiangio-chemo was identified as the optimal treatment option. The toxicity of this treatment was acceptable but needs careful attention. ICI-chemo showed appreciably greater efficacy than the standard-of-care chemotherapy. These findings clarified the roles of ICI-based treatment strategies in this difficult-to-treat refractory population, potentially complementing recent guidelines. FUNDING: None.

N6-methyladenosine RNA modification regulates photoperiod sensitivity in cotton.

The methylation of N6-methyladenosine (m6A) involves writers, erasers, and readers, acting synergistically in posttranscriptional regulation. These processes influence various biological processes, including plant floral transition. However, the specific role of m6A modifications in photoperiod sensitivity in cotton (Gossypium hirsutum) remains obscure. To elucidate this, in this study, we conducted transcriptome-wide m6A sequencing during critical flowering transition stages in the photoperiod-sensitive wild G. hirsutum var. yucatanense (yucatanense) and the photoperiod-insensitive cultivated cotton G. hirsutum acc. TM-1 (TM-1). Our results revealed significant variations in m6A methylation of 2 cotton varieties, with yucatanense exhibiting elevated m6A modification levels compared with TM-1 under long-day conditions. Notably, distinct m6A peaks between TM-1 and yucatanense correlated significantly with photoperiod sensitivity. Moreover, our study highlighted the role of the demethylase G. hirsutum ALKB homolog 5 (GhALKBH5) in modulating m6A modification levels. Silencing GhALKBH5 led to a decreased mRNA level of key photoperiodic flowering genes (GhADO3, GhAGL24, and GhFT1), resulting in delayed bud emergence and flowering. Reverse transcription quantitative PCR analyses confirmed that silencing GhADO3 and GhAGL24 significantly downregulated the expression of the floral integrator GhFT1. Collectively, our findings unveiled a transcriptional regulatory mechanism in which GhALKBH5-mediated m6A demethylation of crucial photoperiodic flowering transcripts modulated photoperiod sensitivity in cotton.

Assessment of the efficacy and safety of anlotinib for the treatment of recurrent epithelial ovarian cancer.

OBJECTIVE: The current research aims to evaluate the efficacy and safety of anlotinib, an orally administered small-molecular tyrosine kinase inhibitor (TKI), in the treatment of recurrent epithelial ovarian cancer (EOC). METHODS: Patients with recurrent EOC subjected to treatment with anlotinib in Fourth Hospital of Hebei Medical University from 2020 to 2022 were included. The evaluation involved a thorough review of medical records, focusing on parameters such as the objective response rate (ORR), disease control rate (DCR), survival outcomes, and safety profile. RESULTS: This study recorded 51 patients, with 26 patients undergoing anlotinib monotherapy. The median progression-free survival (PFS) was 4.0 months, whereas the median overall survival (OS) was not reached. Seven cases underwent a combined treatment of anlotinib with chemotherapy. Among them, two patients achieved partial response (PR), two were categorized as stable disease (SD), and three were identified as having progressive disease (PD). The ORR and DCR were 28.5% (2/7) and 57.1% (4/7), respectively. Additionally, 18 cases received anlotinib maintenance therapy, and the median PFS and the median OS were 7.0 months and 25.5 months, respectively. The most prevalent adverse effects included fatigue (38.6%), hypertension (27.3%), nausea and vomiting (25.0%) and hand-foot syndrome (25.0%). CONCLUSION: Anlotinib demonstrated mild efficacy in the treatment of recurrent EOC, whether employed as monotherapy, chemotherapy-combined therapy, or maintenance therapy. The safety profile was proven manageable and well-tolerated, suggesting that anlotinib may emerge as a viable and novel treatment option for recurrent EOC.

AI-powered omics-based drug pair discovery for pyroptosis therapy targeting triple-negative breast cancer.

Due to low success rates and long cycles of traditional drug development, the clinical tendency is to apply omics techniques to reveal patient-level disease characteristics and individualized responses to treatment. However, the heterogeneous form of data and uneven distribution of targets make drug discovery and precision medicine a non-trivial task. This study takes pyroptosis therapy for triple-negative breast cancer (TNBC) as a paradigm and uses data mining of a large TNBC cohort and drug databases to establish a biofactor-regulated neural network for rapidly screening and optimizing compound pyroptosis drug pairs. Subsequently, biomimetic nanococrystals are prepared using the preferred combination of mitoxantrone and gambogic acid for rational drug delivery. The unique mechanism of obtained nanococrystals regulating pyroptosis genes through ribosomal stress and triggering pyroptosis cascade immune effects are revealed in TNBC models. In this work, a target omics-based intelligent compound drug discovery framework explores an innovative drug development paradigm, which repurposes existing drugs and enables precise treatment of refractory diseases.