Access to essential and innovative anti-cancer medicines: a longitudinal study in Nanjing, China.

PURPOSE: To evaluate the availability, cost, affordability of anti-cancer medicines in Nanjing, Jiangsu. METHODS: A longitudinal tracking investigation study was performed to collect information about 24 essential anti-cancer medicines (EAMs) and 17 innovative anti-cancer medicines (IAMs) in 26 healthcare institutions in Nanjing from 2016 to 2020. The availability, cost, drug utilization and affordability of EAMs and IAMs were investigated. RESULTS: The availability of EAMs showed no significant changes in Nanjing, but the availability of IAMs showed a significant increase in 2018 and 2019 and tended to stabilize in 2020. For EAMs, the DDDc(Defined Daily Dose cost) of LPGs (Lowest-Priced Generics) showed no significant changes, and the DDDc of OBs (Originator Brands) and IAMs significantly decreased. The DDDs(Defined Daily Doses) of EAMs (LPGs) showed a decreasing trend since 2016 and rose again in 2019. Overall, the DDDs of EAMs (LPGs) decreased by 25.18% between 2016 and 2020, but the proportion selected for clinical treatment remained at 67.35% in 2020. The DDDs of EAMs (OBs) and IAMs both showed an increasing trend year by year, with a proportional increase of 207.72% and 652.68%, respectively; but the proportion selected for clinical treatment was only 16.09% and 16.56% respectively in 2020. EAMs (LPGs) had good affordability for urban residents but poor affordability for rural residents; the affordability of EAMs (OBs) and IAMs was poor for both urban and rural residents. CONCLUSIONS: There were no significant changes in the availability and cost of EAMs (LPGs), whose lower prices showed better affordability. Although their relative change in drug utilization showed a decreasing trend, they still dominated clinical treatment. Driven by the national drug price negotiation (NDPN) policy, the availability of IAMs was on the rise. It is necessary to further develop and strengthen policies for essential medicines procurement assessment to improve the accessibility of EAMs.

Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.

Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.

An exploration of the effect of Chinese herbal compound on the occurrence and development of large intestine cancer and intestinal flora.

This study was conducted to observe the effect of Chinese herbal compound on the treatment of colon cancer using AOM/DSS-induced C57BL/6J colon cancer mice and to validate potential influence on intestinal flora of mice. A colorectal cancer (CRC) mouse model was built with a total of 50 C57BL/6J mice that were induced by administrating AOM/DSS. These experimental animals were split up into 5 groups, a control group, a model group, and low-, medium- and high-dose Chinese herbal compound groups. All mice were given Chinese herbal compound treatment, and the colon tissues of each group were harvested with the length measured and the number of colon polyps accounted. The Ki-67 expression in the colon tissues was detected via immuno-histochemistry. Relative quantification of the expression of genes and proteins was determined through qPCR and WB assays. Contents of IL-6, TNF-α, IFN-γ, and IL-10 in serum and colon tissues of mice were determined by ELISA. An additional 16S rRNA sequencing analysis was implemented for the identification of mouse intestinal flora. The results suggested that all low-, medium- or high-dose Chinese herbal compound could markedly inhibit the shortening of colon length and significant number reduction of colon polyps in the model group. The relative expression of genes and proteins (PCNA, Muc16, and MMP-9) associated with proliferation in mouse colon tissues were inhibited. In addition, compared with the model group, the contents of IL-6, TNF-α, and IFN-γ in serum and colon tissues were substantially decreased in the high-dose Chinese herbal compound group, thereby reducing the structure damage in colon tissues and the infiltration degree of inflammatory cells. Besides, the expression of TLR4/MyD88/NF-κB protein was markedly decreased. The 16S rRNA sequencing analysis demonstrated that mice in the model group had decreased intestinal flora diversity, and there were significant changes in flora abundance and amino acid metabolism between the control group and the model group. Taken together, the treatment of Chinese herbal compound against CRC in this study might be regulated by the TLR4/MyD88/NF-κB signaling pathway, and the imbalance in intestinal flora was also closely related to CRC occurrence.

Female perspective: the burden of Alzheimer's disease and other dementias in China from 1990 to 2019 and prediction of their prevalence up to 2044.

Background: Dementia is more prevalent in women than in men across the world, and sex differences are reflected in the burden of dementia borne by women and men. However, a few studies have specifically analyzed the disease burden of dementia in Chinese women. Objective: This article aims to raise awareness of Chinese females with dementia (CFWD), outline an effective response to future trends in China from a female perspective, and provide a reference for the scientific formulation of dementia prevention and treatment policies in China. Methods: In this article, epidemiological data on dementia in Chinese women were obtained from the Global Burden of Disease Study 2019, and three risk factors, namely, smoking, a high body mass index, and a high fasting plasma glucose, were selected for the analysis. This article also predicted the burden of dementia in Chinese women in the next 25 years. Results: The prevalence of dementia, mortality, and disability-adjusted life year rates increased with age in CFWD in 2019. All three risk factors provided by the Global Burden of Disease Study 2019 showed positive correlations for the effect of disability-adjusted life years (DALYs) rates on CFWD. Among them, a high body mass index had the greatest effect (8%) and smoking had the smallest effect (6.4%). Over the next 25 years, the number of CFWD and its prevalence are expected to be on the rise, while mortality is expected to remain relatively stable and decline slightly, but deaths from dementia will continue to increase. Conclusions: The situation arising due to the spread of dementia among Chinese women in the future is going to become a serious issue. To reduce the burden of dementia, the Chinese government should prioritize its prevention and treatment. A multi-dimensional, long-term care system involving families, community, and hospitals should also be established and supported.

Contamination and Health Risk Assessment of Polycyclic Aromatic Hydrocarbons in Seasoning Flour Products in Hunan, China.

Polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants with carcinogenic, teratogenic, and mutagenic effects. Dietary intake is one of the significant exposure pathways of PAHs. In this study, gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS) was used to detect 16 priority PAHs listed by the United States Environmental Protection Agency (USEPA) in seasoning flour products distributed in Hunan Province. The consumption of seasoning flour products by the Hunan population was investigated by questionnaire. The results showed that the detection rate of PAHs in seasoning flour products in Hunan Province was 92.41%. Among them, benzo[a]anthracene (BaA), phenanthrene (PHE), fluoranthene (FLA), and chrysene (CHR) were dominant. The total PAHs and benzo[a]pyrene (BaP) contents of soggy seasoning flour product samples were higher than those of crisp samples and chewy samples. The total amount of PAHs in rod-shaped and flaky samples were higher than that in filamentous and granular samples. The margin of exposure (MOE) values of various seasoning flour products and all age groups (children, adolescents, and adults) was much more significant than 10,000. Moreover, the incremental lifetime of cancer risk (ILCR) values of all age groups were below 1 × 10-5. The above results indicate that PAHs in seasoning flour products have a relatively low health risk for the Hunan population. Still, it is recommended that susceptible populations (children, adolescents, etc.) should control their intake of flour products.

The Jarvik 2000 Left Ventricular Assist Device: Results of the United States Bridge to Transplant Trial.

The Jarvik 2000 bridge to transplant investigational device exemption study was a multicentered, prospective study of 150 UNOS status I patients implanted with the Jarvik 2000 between 2005 and 2012. During the study period, there were numerous modifications of the system that included converting from pin to cone bearings. Results were analyzed for three cohorts: total (n = 150), pin (n = 128), and cone (n = 22). Baseline demographics included age (52 ± 13), gender (79% male), size (BSA 1.98), and etiology (37% idiopathic dilated cardiomyopathy; 43% Ischemic). Seventy percent of patients were either INTERMACS 1 or 2. The primary endpoint-defined as successful transplantation or listing at 180 days (prespecified at 65%; 95% lower CI: 57%)-was successfully achieved for the total cohort (67.3%; 95% CI: 59.5%-74.3%; p = 0.006). In subgroup analysis of the more contemporary, cone-bearing group, the primary endpoint was met in 91% (95% CI: 72%-97.5%; p = 0.001). Compared with pin patients, cone-bearing patients had less hemolysis as well as decreased end-organ dysfunction. Functional and quality of life scores improved after implantation independent type of bearing. In conclusion, despite a particularly sick patient population, the Jarvik 2000 was shown to be effective in supporting the advanced HF patient.

Case Report: Severe rash/desquamation induced by sorafenib in an uHCC patient and its clinical management.

Background: Sorafenib-related dermatological toxicity is a well-known adverse reaction that can severely affect therapeutic outcomes. Rash/desquamation with its variable manifestations is one of the common clinical presentations. Currently, no standard continuum of care for sorafenib-related rash/desquamation has been established. Case summary: A 75-year-old woman with colorectal cancer who developed unresectable hepatocellular carcinoma (uHCC) received, six years later, sorafenib 400 mg twice daily. She developed a Grade-3 Common Terminology Criteria for Adverse Events (CTCEA) rash and bullae bilaterally on her lower extremities after 2 weeks of sorafenib use. Rash and blisters began to appear on the left calf and then merged as large bullae full of liquid and spread to both lower extremities. The bullae then erupted and skin began to slough off, which affected the patient's normal daily functioning. To lessen the condition, sorafenib was stopped permanently and dexamethasone intravenous (IV) infusion at 5 mg daily for 3 days and piperacillin/tazobactam were used. The skin dried without exudate or ulcerations after a month. Conclusion: For severe (CTCAE Grade 3 or above) sorafenib-related rash/desquamation, short-term corticosteroid pulse therapy at large doses is usually effective with routine skin care, and antibiotics can be considered if infection is present. Permanent cessation of sorafenib should be considered if severe manifestations such as erythema multiforme (EM) and Steven-Johnson syndrome (SJS) are suspected.

ADAR1 downregulation by autophagy drives senescence independently of RNA editing by enhancing p16INK4a levels.

Cellular senescence plays a causal role in ageing and, in mice, depletion of p16INK4a-expressing senescent cells delays ageing-associated disorders1,2. Adenosine deaminases acting on RNA (ADARs) are RNA-editing enzymes that are also implicated as important regulators of human ageing, and ADAR inactivation causes age-associated pathologies such as neurodegeneration in model organisms3,4. However, the role, if any, of ADARs in cellular senescence is unknown. Here we show that ADAR1 is post-transcriptionally downregulated by autophagic degradation to promote senescence through p16INK4a upregulation. The ADAR1 downregulation is sufficient to drive senescence in both in vitro and in vivo models. Senescence induced by ADAR1 downregulation is p16INK4a-dependent and independent of its RNA-editing function. Mechanistically, ADAR1 promotes SIRT1 expression by affecting its RNA stability through HuR, an RNA-binding protein that increases the half-life and steady-state levels of its target mRNAs. SIRT1 in turn antagonizes translation of mRNA encoding p16INK4a. Hence, downregulation of ADAR1 and SIRT1 mediates p16INK4a upregulation by enhancing its mRNA translation. Finally, Adar1 is downregulated during ageing of mouse tissues such as brain, ovary and intestine, and Adar1 expression correlates with Sirt1 expression in these tissues in mice. Together, our study reveals an RNA-editing-independent role for ADAR1 in the regulation of senescence by post-transcriptionally controlling p16INK4a expression.

Identification of environmental microorganism using optimally fine-tuned convolutional neural network.

To not only optimize the hyper-parameters of the classification layer of dense convolutional network with 201 convolutional layers (DenseNet-201) but also use data augmentation processes could enhance the performance of DenseNet-201, and DenseNet-201 is rarely applied to the identifications of the environmental microorganism (EM) images. Hence, this study was to propose the optimally fine-tuned DenseNet-201 (OFTD) with data augmentation to better classify the EM images on Environmental Microorganism Dataset (EMDS). The training dataset was composed of 70% Environmental Microorganism Dataset (EMDS) images and so was mainly used to fit the parameters of convolutional layers of optimally fine-tuned DenseNet-201 (OFTD). Meanwhile, the other EMDS images were considered as the testing dataset and used to qualify the performance of the OFTD. Also, gradient-weighted class activation mapping method (Grad-CAM) was adopted to visually illustrate the dominant features of the EM images. Based on the results, the OFTD model with data augmentation achieved the highest classification accuracy of 98.4%. In this case, so its stability and accuracy were guaranteed. Besides, the optimally fine-tuned classification layer is considered a more efficient method than the data augmentation technique adopted in this study when it comes to the improvement of the performance in DenseNet-201 implemented on EMDS. Grad-CAM highlighted the coarse EM features identified effectively by the OFTD; for example, foot and stalk were considered as the dominated features of Rotifera and Vorticella, respectively. In summary, the proposed OFTD with data augmentation could provide an efficient solution for the EM detection in digital microscope.

Somatic Mutation Analysis in Salix suchowensis Reveals Early-Segregated Cell Lineages.

Long-lived plants face the challenge of ever-increasing mutational burden across their long lifespan. Early sequestration of meristematic stem cells is supposed to efficiently slow down this process, but direct measurement of somatic mutations that accompanies segregated cell lineages in plants is still rare. Here, we tracked somatic mutations in 33 leaves and 22 adventitious roots from 22 stem-cuttings across eight major branches of a shrub willow (Salix suchowensis). We found that most mutations propagated separately in leaves and roots, providing clear evidence for early segregation of underlying cell lineages. By combining lineage tracking with allele frequency analysis, our results revealed a set of mutations shared by distinct branches, but were exclusively present in leaves and not in roots. These mutations were likely propagated by rapidly dividing somatic cell lineages which survive several iterations of branching, distinct from the slowly dividing axillary stem cell lineages. Leaf is thus contributed by both slowly and rapidly dividing cell lineages, leading to varied fixation chances of propagated mutations. By contrast, each root likely arises from a single founder cell within the adventitious stem cell lineages. Our findings give straightforward evidence that early segregation of meristems slows down mutation accumulation in axillary meristems, implying a plant "germline" paralog to the germline of animals through convergent evolution.

m6A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.

Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N6-methyladenosine (m6A) modification. Despite the expanding list of m6A-dependent functions of the methyltransferase complex, the m6A-independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives the senescence-associated secretory phenotype (SASP) in an m6A-independent manner. METTL14 is redistributed to the enhancers, whereas METTL3 is localized to the pre-existing NF-κB sites within the promoters of SASP genes during senescence. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m6A mRNA modification. METTL3 and METTL14 are required for both the tumour-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. In summary, our results report an m6A-independent function of the METTL3 and METTL14 complex in transcriptionally promoting SASP during senescence.

Comparison of the Safety and Efficacy of Valveless and Standard Insufflation During Robotic Partial Nephrectomy: A Prospective, Randomized, Multi-institutional Trial.

OBJECTIVE: To use a randomized, prospective, multi-institutional study to compare the safety and efficacy of conventional insufflation (CIS) and valveless insufflation (AirSeal Insufflation - AIS) at the conventional pressure of 15 mm Hg in robot-assisted partial nephrectomy - a surgery where AIS has gained popularity for maintaining visualization despite suction. This study was also powered to evaluate the effect of decreasing pneumoperitoneum by 20% in the valveless system. MATERIALS AND METHODS: Three high-volume institutions randomized subjects into CIS 15, AIS 15, and AIS 12 mm Hg cohorts. Endpoints included rates of subcutaneous emphysema (SCE), pneumothorax (PTX), pneumomediastinum (PMS), intraoperative end-tidal carbon dioxide (ET CO2), and peak airway pressure (PAP), as well as hospital stay, post-operative pain, and complications. Given the substantial proportion of retroperitoneal surgery, a secondary analysis evaluated the effect of surgical approach. RESULTS: Two hundred and two patients were accrued. SCE was decreased in the AIS 12 mm Hg group (p=0.003). PTX and PMS rates were not statistically significantly different across the 3 insufflation groups. Higher rates of SCE and PMS, although not PTX, were noted in all retroperitoneal surgery groups - with lower SCE rates for AIS 12 mm Hg regardless of surgical approach. CONCLUSION: AIS is often preferred for complex procedures including retroperitoneal and transperitoneal robotic-assisted partial nephrectomy, for its maintenance of pneumoperitoneum despite continuous suction necessary for visualization. This study shows that AIS is safe when compared to CIS at 15 mm Hg, and shows improvement in outcomes when pneumoperitoneum pressure is reduced by 20% to 12 mmHg.

ARID2 Deficiency Correlates with the Response to Immune Checkpoint Blockade in Melanoma.

The SWI/SNF chromatin remodeler family includes the BAF and PBAF complexes. ARID2, encoding a PBAF complex subunit, is frequently mutated in melanoma independently of BRAF/RAS mutations. Emerging evidence shows that SWI/SNF complexes regulate tumor immunity; for instance, the loss of PBRM1, another PBAF complex subunit, enhances susceptibility to immune checkpoint inhibitors in melanoma. Notably, ARID2 mutations are more frequent in melanoma than PBRM1 mutations. However, the role of ARID2 as a modulator of tumor immunity remains unclear. In this study, we show that ARID2 knockout sensitizes melanoma to immune checkpoint inhibitors. Anti‒PD-L1 treatment restricts tumor growth in mice bearing ARID2-knockout melanoma cells, correlating with an increase in the infiltration of cytotoxic CD8+ T cells. Furthermore, ARID2 deficiency leads to signal transducer and activator of transcription 1 upregulation, which subsequently causes increased expression of T-cell‒attracting chemokines such as CXCL9, CXCL10, and CCL5. These results demonstrate that ARID2 is an immunomodulator and a potential biomarker that indicates immune checkpoint inhibitor effectiveness in patients with melanoma.

One-Year Echocardiographic, Functional, and Quality of Life Outcomes After Ultrasound-Facilitated Catheter-Based Fibrinolysis for Pulmonary Embolism.

BACKGROUND: Accelerated tPA (tissue-type plasminogen activator) dosing regimens for ultrasound-facilitated, catheter-directed fibrinolysis improve short-term computed tomographic-measured right ventricular (RV)-to-left ventricular diameter ratio in massive and submassive pulmonary embolism. The impact on RV remodeling, functional status, and quality of life over the long-term remains unclear. METHODS: To study 1-year changes in RV remodeling, functional status, and quality of life, we assessed patients with acute submassive pulmonary embolism randomly assigned to 1 of 4 tPA dosing regimens for ultrasound-facilitated, catheter-directed fibrinolysis in the OPTALYSE-PE trial (Optimum Duration and Dose of r-tPA With the Acoustic Pulse Thrombolysis Procedure for Intermediate-Risk Pulmonary Embolism; 8 mg/2 hours, 8 mg/4 hours, 12 mg/6 hours, and 24 mg/6 hours). Echocardiographic assessment included RV-to-left ventricular diameter ratio within 4 hours of treatment end, and at 48 hours, 30 days, 90 days, and 1 year. Functional status was assessed by 6-minute walk test at 30 days, 90 days, and 1 year and PROMIS-PF-6b scores at 30 days, 90 days, 180 days, 270 days, and 1 year. Quality of life was evaluated by PEmb-QOL scores at 30 days, 90 days, 180 days, 270 days, and 1 year. RESULTS: Mean RV-to-left ventricular diameter ratio decreased from baseline to 4 hours and further at 48 hours and 30 days, with reductions maintained at 90 days and 1 year in all groups. Mean 6-minute walk distance, PROMIS-PF-6b, and PEmb-QOL scores improved over the course of 1 year in all groups. CONCLUSIONS: Accelerated lower-dose tPA regimens for ultrasound-facilitated, catheter-directed fibrinolysis resulted in sustained recovery of RV-to-left ventricular diameter ratio and tricuspid annular plane systolic excursion and improvements in functional status and quality of life over 1 year. Registration: URL: https://www.ClinicalTrials.gov. Unique Identifier: NCT02396758.

Predictors of Treatment Response Following Ultrasound-Facilitated Catheter-Directed Thrombolysis for Submassive and Massive Pulmonary Embolism: A SEATTLE II Substudy.

BACKGROUND: Little is known about which factors predict improvement in clinical and imaging parameters among patients undergoing catheter-directed thrombolysis for submassive or massive pulmonary embolism. The identification of such predictors may allow for more appropriate patient selection for ultrasound-facilitated catheter-directed thrombolysis. METHODS: We conducted a retrospective cohort analysis of patients from the SEATTLE II trial (Prospective, Single-Arm, Multi-Center Trial of EkoSonic Endovascular System and Activase for Treatment of Acute Pulmonary Embolism) to identify clinical characteristics that independently predict pulmonary artery pressures, right ventricular-to-left ventricular (RV/LV) diameter ratio, and modified Miller angiographic index following ultrasound-assisted catheter-directed thrombolysis. Eligible patients had submassive or massive pulmonary embolism and an RV/LV diameter ratio ≥0.9 on chest computed tomography. Multivariable linear regression was used to identify independent clinical predictors of each outcome. RESULTS: One hundred fifty patients with massive (n=31) or submassive (n=119) pulmonary embolism were enrolled. Mean (±SD) baseline and postprocedure RV/LV diameter ratio, pulmonary artery systolic pressure, and modified Miller Score were 1.59 (±0.39) and 1.14 (±0.2), 51.45 (±16.0), and 37.47 (±11.9), and 23.0 (±5.7) and 15.7 (±5.9), respectively. The multivariable model adjusted R2 for absolute change in RV/LV ratio, pulmonary artery systolic pressure, modified Miller Score was 0.71, 0.57, and 0.43, respectively. After adjusting for age, gender, and baseline RV/LV ratio, pulmonary artery systolic pressure, and modified Miller Score, patients with higher body mass index, renal or hepatic dysfunction, active smoking, or a higher baseline heart rate showed less improvement. CONCLUSIONS: Patients with more life-threatening pulmonary embolism may derive the greatest benefit from ultrasound-assisted, catheter-directed thrombolysis.

Efficacy and safety of topical sofpironium bromide gel for the treatment of axillary hyperhidrosis: A phase II, randomized, controlled, double-blinded trial.

BACKGROUND: Primary axillary hyperhidrosis has limited noninvasive, effective, and well-tolerated treatment options. OBJECTIVE: To evaluate the topical treatment of axillary hyperhidrosis with the novel anticholinergic sofpironium bromide. METHODS: A phase II, multicenter, randomized, controlled, double-blinded study. Participants were randomized to 1 of 3 dosages or vehicle, with daily treatment for 42 days. Coprimary end points were the percentage of participants exhibiting ≥1-point improvement in the Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax) score by logistic regression, and change in HDSM-Ax as a continuous measure by analysis of covariance. Pair-wise comparisons were 1-sided with α = 0.10. RESULTS: At the end of therapy, 70%, 79%, 76%, and 54% of participants in the 5%, 10%, 15%, and vehicle groups exhibited ≥1-point improvement in HDSM-Ax (P < .05). Least-square mean (SE) changes in HDSM-Ax were -2.02 (0.14), -2.09 (0.14), 2.10 (0.14), and -1.30 (0.14) (all P ≤ .0001). Most treatment-related adverse events were mild or moderate. LIMITATIONS: Not powered to detect changes in gravimetric sweat production. CONCLUSION: Sofpironium bromide gel produced meaningful reductions in hyperhidrosis severity and had an acceptable safety profile.

Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence.

Cyclic cGMP-AMP synthase (cGAS) is a pattern recognition cytosolic DNA sensor that is essential for cellular senescence. cGAS promotes inflammatory senescence-associated secretory phenotype (SASP) through recognizing cytoplasmic chromatin during senescence. cGAS-mediated inflammation is essential for the antitumor effects of immune checkpoint blockade. However, the mechanism by which cGAS recognizes cytoplasmic chromatin is unknown. Here we show that topoisomerase 1-DNA covalent cleavage complex (TOP1cc) is both necessary and sufficient for cGAS-mediated cytoplasmic chromatin recognition and SASP during senescence. TOP1cc localizes to cytoplasmic chromatin and TOP1 interacts with cGAS to enhance the binding of cGAS to DNA. Retention of TOP1cc to cytoplasmic chromatin depends on its stabilization by the chromatin architecture protein HMGB2. Functionally, the HMGB2-TOP1cc-cGAS axis determines the response of orthotopically transplanted ex vivo therapy-induced senescent cells to immune checkpoint blockade in vivo. Together, these findings establish a HMGB2-TOP1cc-cGAS axis that enables cytoplasmic chromatin recognition and response to immune checkpoint blockade.

Targeting the untargetable KRAS in cancer therapy.

RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years. Despite its well-recognized importance in cancer malignancy, continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.

N6-Methylation of Adenosine of FZD10 mRNA Contributes to PARP Inhibitor Resistance.

Despite the high initial response rates to PARP inhibitors (PARPi) in BRCA-mutated epithelial ovarian cancers (EOC), PARPi resistance remains a major challenge. Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of mRNA, yet the role of m6A modification in PARPi resistance has not previously been explored. Here, we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/ß-catenin pathway in BRCA-mutated EOC cells. Global m6A profile revealed a significant increase in m6A modification in FZD10 mRNA, which correlated with increased FZD10 mRNA stability and an upregulation of the Wnt/ß-catenin pathway. Depletion of FZD10 or inhibition of the Wnt/ß-catenin sensitizes resistant cells to PARPi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 was sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity, which correlated with an increase in homologous recombination activity. Moreover, combined inhibition of PARP and Wnt/ß-catenin showed synergistic suppression of PARPi-resistant cells in vitro and in vivo in a xenograft EOC mouse model. Overall, our results show that m6A contributes to PARPi resistance in BRCA-deficient EOC cells by upregulating the Wnt/ß-catenin pathway via stabilization of FZD10. They also suggest that inhibition of the Wnt/ß-catenin pathway represents a potential strategy to overcome PARPi resistance. SIGNIFICANCE: These findings elucidate a novel regulatory mechanism of PARPi resistance in EOC by showing that m6A modification of FZD10 mRNA contributes to PARPi resistance in BRCA-deficient EOC cells via upregulation of Wnt/ß-catenin pathway.

Catheter-directed, ultrasound-facilitated fibrinolysis in obese patients with massive and submassive pulmonary embolism.

Obesity is a well-established risk factor for pulmonary embolism (PE). However, treatment of PE in obese patients is challenging because of limited outcomes data, especially with advanced therapies such as catheter-based fibrinolysis. We assessed the efficacy and safety of ultrasound-facilitated, catheter-directed fibrinolysis in obese patients with submassive and massive PE enrolled in the SEATTLE II Trial. Eligible patients had a right ventricular-to-left ventricular (RV/LV) diameter ratio ≥ 0.9 on chest computed tomography (CT). The primary efficacy outcome was the change in chest CT-measured RV/LV diameter ratio at 48 h after procedure initiation. The primary safety outcome was GUSTO major bleeding within 72 h. One-hundred and four patients were obese, as defined by a BMI ≥ 30 kg/m2, and 44 were non-obese. Mean RV/LV ratio was greater in obese patients at baseline compared with non-obese patients (1.60 vs. 1.43, p = 0.02). Reduction in RV/LV diameter ratio at 48 h was greater in obese patients compared with non-obese patients (absolute reduction: - 0.47 vs. - 0.30, p = 0.01; relative reduction: - 26 vs. - 18%, p = 0.03). Major bleeding occurred in 12 (12%) of obese patients and in 3 (7%) in non-obese patients (p = 0.55). In conclusion, ultrasound-facilitated, catheter-directed fibrinolysis shows promise in obese patients for whom advanced therapy for acute PE is warranted.