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Rack1-mediated ferroptosis affects hindgut development in rats with anorectal malformations: Spatial transcriptome insights.

Anorectal malformation (ARM), a common congenital anomaly of the digestive tract, is a result of insufficient elongation of the urorectal septum. The cytoplasmic protein Receptor of Activated C-Kinase 1 (Rack1) is involved in embryonic neural development; however, its role in embryonic digestive tract development and ARM formation is unexplored. Our study explored the hindgut development and cell death mechanisms in ARM-affected rats using spatial transcriptome analysis. We induced ARM in rats by administering ethylenethiourea via gavage on gestational day (GD) 10. On GDs 14-16, embryos from b

EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction.

Myelomatous bone disease is a complication characterized by lytic bone lesions, reduced bone formation, bone pain, and increased fracture risk. Understanding these underlying mechanisms is crucial for developing effective therapeutic approaches. Here we show the role of enhancer of zeste homolog 2 (EZH2) in bone lesions induced by myeloma cells. Our research reveals that cytokines produced by myeloma-associated adipocytes activate the expression of EZH2 in myeloma cells. Furthermore, we find that EZH2 forms a transcriptional repression complex with transcription factor AP2α. This complex promo

p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells.

The Wnt inhibitor Dickkopf-1 (DKK-1) has been associated with the occurrence of bone metastases in osteotropic prostate cancer by inhibiting osteoblastogenesis. P38 mitogen-activated protein kinase (MAPK) activity is also dysregulated in advanced prostate cancer. However, the impact of p38 MAPK signaling on DKK-1 remains unknown. Inhibition of p38 MAPK signaling in osteolytic PC3 cells by small molecule inhibitors (doramapimod, LY2228820 and SB202190) suppressed DKK-1 expression, whereas activation of p38 MAPK by anisomycin increased DKK-1. Further dissection by targeting individual p38 MAPK i

m6A reader hnRNPA2B1 drives multiple myeloma osteolytic bone disease.

Rationale: Bone destruction is a hallmark of multiple myeloma (MM) and affects more than 80% of patients. Although previous works revealed the roles of N6-methyladenosine (m6A) reader hnRNPA2B1 in the development of tumors, whether hnRNPA2B1 regulates bone destruction in MM is still unknown. Methods: Alizarin red S staining, TRAP staining, ELISA and quantitative real-time PCR assays were used to evaluate osteogenesis and osteoclastogenesis in vitro. X ray and bone histomorphometric analysis were preformed to identify bone resorption and bone formation in vivo. Exosome isolation and characteriz

Targeting the E2F1/Rb/HDAC1 axis with the small molecule HR488B effectively inhibits colorectal cancer growth.

Colorectal cancer (CRC), the third most common cancer worldwide, remains highly lethal as the disease only becomes symptomatic at an advanced stage. Growing evidence suggests that histone deacetylases (HDACs), a group of epigenetic enzymes overexpressed in precancerous lesions of CRC, may represent promising molecular targets for CRC treatment. Histone deacetylase inhibitors (HDACis) have gradually become powerful anti-cancer agents targeting epigenetic modulation and have been widely used in the clinical treatment of hematologic malignancies, while only few studies on the benefit of HDACis in

Radiocopper in BCMA-targeted immunotheranostics of myeloma.

BACKGROUND: The theranostic potential of copper-64 (PET imaging) and copper-67 (SPECT imaging and therapy) is increasingly recognized. This work investigates the performance of this 'true' matched pair in a preclinical radioimmunotheranostic setting that utilizes experimental monoclonal antibodies (mAbs) directed against B cell maturation antigen (BCMA), a transmembrane glycoprotein that has emerged as a critical target for the treatment of multiple myeloma (MM). METHODS: The commercially available BCMA-directed mAbs MAB193 and Vicky-1 were modified with the bispidine N2py4 enabling chelation

Bavachin suppresses proliferation of laryngopharyngeal cancer by regulating the STAT3 and MAPK signaling pathways.

Purpose: The present study aimed to explore the underlying antitumor effects of bavachin on laryngopharyngeal cancer in-vitro and in-vivo. Methods: Tu212 and FaDu cells were cultured in the incubator. Cells were treated with 0.1% DMSO (control group) and different concentrations of bavachin (experimental groups) for exploring the results of proliferation and apoptosis. We revealed the underlying mechanism of bavachin on laryngopharyngeal cancer through western blotting, qRT-PCR assay and immunofluorescence staining. Results: Bavachin could suppress the proliferation and migration of laryngopha

Prices and Clinical Benefit of National Price-Negotiated Anticancer Medicines in China.

BackgroundHigh prices of anticancer medicines have increased the economic burden for both patients and health insurance systems. Since 2017, China has implemented national price negotiations for medicines, relying on evidence from health technology assessments. We aim to assess the relation between negotiated price and value of anticancer medicines listed in China's National Reimbursement Drug List (NRDL).MethodsFor all price-negotiated anticancer medicines and corresponding indications listed in the latest NRDL between 2017 and 2020, we collected their clinical outcomes data, including overal

Multiple myeloma hinders erythropoiesis and causes anaemia owing to high levels of CCL3 in the bone marrow microenvironment.

Anaemia is the most common complication of myeloma and is associated with worse clinical outcomes. Although marrow replacement with myeloma cells is widely considered a mechanistic rationale for anaemia, the exact process has not been fully understood. Our large cohort of 1363 myeloma patients had more than 50% of patients with moderate or severe anaemia at the time of diagnosis. Anaemia positively correlated with myeloma cell infiltration in the bone marrow (BM) and worse patient outcomes. The quantity and erythroid differentiation of HSPCs were affected by myeloma cell infiltration in the BM

The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone.

Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells (DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with

CAR NK92 Cells Targeting BCMA Can Effectively Kill Multiple Myeloma Cells Both In Vitro and In Vivo.

Multiple myeloma (MM) is a hematological malignancy caused by malignant proliferation of plasma cells in bone marrow. Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents. However, MM remains an incurable neoplastic plasma cell disorder. In addition, almost all MM patients inevitably relapse due to drug resistance. Chimeric antigen receptor (CAR)-modified NK cells represent a promising immunotherapeutic modality for cancer treatment. In this study, NK92 cells were engineered to express t

Novel Small Molecular Compound AE-848 Potently Induces Human Multiple Myeloma Cell Apoptosis by Modulating the NF-κB and PI3K/Akt/mTOR Signaling Pathways.

BackgroundWe aimed to investigate the anti-multiple myeloma (MM) activity of the new small molecular compound AE-848 (5-bromo-2-hydroxyisophthalaldehyde bis[(1-methyl-1H-benzimidazol-2-yl)hydrazone]) and its underlying anti-MM mechanism.MethodsCell viability and apoptosis were detected and quantified by using MTT and flow cytometry, respectively. JC-1 dye-related techniques were used to assess mitochondrial membrane potential (MMP). Western blotting was applied to detect the expression of NF-κB and PI3K/Akt/mTOR pathway-associated proteins. The in vivo activity of AE-848 against MM was evaluat

Effect of the national reimbursement drug list negotiation policy on utilization of negotiated anticancer drugs in Chinese public hospital: a quasi-natural experiment.

BackgroundHigh prices have limited access to targeted anticancer drugs in China. In 2017, 18 such drugs were added to the National Reimbursement Drug List (NRDL) through national price negotiation.MethodMonthly hospital procurement data (2015-2019) from 887 public hospitals across 30 provinces were analyzed. Drug utilization was measured by expenditures and defined daily doses (DDDs). A difference-in-differences (DID) model and interrupted time series (ITS) analysis were employed to estimate policy effects.ResultsFollowing policy implementation, total DDDs of negotiated drugs rose 4.03-fold an

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… Future reforms should prioritize the institutionalization of a national HTA framework to guide drug inclusion and pricing decisions, the integration of real-world evidence into post-listing evaluations, and the alignment of hospital payment mechanisms with value-based purchasing principles. …

Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML.

Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor κB (NF-κB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-κB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-κB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor α (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment wi

Снижение уровня эстрогена лимфатического узла вызывает неиспускающее заболевание аутоиммунной энцефаломиелита.

Эстроген, стероидный гормон, синтезированный как гонадальными, так и негональными тканями, играет ключевую роль в модуляции иммунной реакции, включая снижение частоты рецидивов при повторном излучающем многократном склерозе (МС). В этом исследовании изучалось выражение ароматазы, фермента, ответственного за синтез эстрогенов, в лимфатических узлах (ЛН) и его потенциальная роль в патогенезе MS с использованием модели мыши. Мы использовали мыши Cyp19-RFP, где клетки, которые выражают или ранее выражали ген Cyp19 (кодирование ароматазы), обозначаются красным флуоресцентным белком (RFP). RPF был о

CS-6-induced p62 accumulation exacerbates DNA damage in colorectal cancer.

BACKGROUND: Gamabufotalin (CS-6), a bufadienolide derived from Chansu, has been reported to exhibit anti-tumor effects in various cancers, including glioblastoma, nonsmall cell lung cancer, and breast cancer. However,its role in colorectal cancer (CRC) remains unexplored. OBJECTIVE: Our study aimed to evaluate the inhibition of CS-6 to CRC cells by cell viability assay, colony formation assay, comet assay, and cell cycle analysis firstly. And its molecular mechanism was studied by immunofluorescence (IF) assay, western blot (WB) assay, siRNA transfection, protein-protein interaction (PPI) net

Нейропзащитное воздействие грелина на крысиную модель множественных склерозов.

Множественный склероз (MS) является воспалительным заболеванием центральной нервной системы, характеризующимся обезвоживанием и аксонной потерей, и является основной причиной нетравматических неврологических расстройств у молодых людей. Несмотря на то, что существует несколько методов лечения этого заболевания, не существует окончательного средства для лечения множественных склерозов. Известно, что воспаление и окислительный стресс играют важную роль в патофизиологии MS. Грелин, пептид, скрытый желудком, обладает нейрозащитными свойствами по нескольким путям, включая ослабление окислительного

Мак-1 регулирует иммуноусилительное подавление конкретной стадии болезни через нитриковый путь в аутоиммунном заболевании.

Интегрин Мак-1 играет важнейшую роль в развитии множественного склероза (MS); однако лежащий в его основе механизм не в полной мере изучен. Здесь мы разработали мышь с миелоидной мышью Мак-1-дефицит. Используя экспериментальную аутоиммунную энцефаломиэлит (EAE) модель мыши MS, мы сообщаем, что Мак-1 на миелиоидных клетках является ключом к развитию болезней. Наши данные показывают, что миелиоидный Мак-1 значительно повышает интенсивность EAE и затрудняет регрессию заболеваний. Потеря Mac-1 увеличивает количество клеток Gr-1+ в периферийных тканях и CNS и предпочтительно ускоряет переход моноци

Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice.

Given the role of macrophage-derived high mobility group box 1 (HMGB1) in chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel, we analyzed the role of HMGB1 and macrophages in the CIPN caused by bortezomib, a proteasome-inhibiting chemotherapeutic agent used for the treatment of multiple myeloma. Repeated administration of bortezomib caused CIPN accompanied by early-stage macrophage accumulation in the dorsal root ganglion. This CIPN was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin alfa capable of accelerating thrombin-dependent degradation of HMGB1, anta

GPER1 Активация Антитуморной активности в Множестве миелом.

G белковый рецептор эстрогена. 1 Активация (GPER1) становится перспективной терапевтической стратегией борьбы с различными видами рака. Несмотря на то, что в контексте твердых опухолей широко изучался вопрос о адресации GPER, его воздействие на гематологию еще предстоит понять в полной мере. Здесь мы показываем, что GPER1 mRNA понижается в плазменных клетках от открытой множественной миэломы (MM) и лейкемии от плазмы по сравнению с нормальными спонсорами или преднасыщенными условиями (моноклональная гаммопатия неопределённого значения и удушающая MM); кроме того, более низкое выражение GPER1 а