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In 75 unselected and untreated patients with small cell carcinoma of the lung, plasma ACTH, serum calcitonin, and antidiuretic hormone (ADH) in plasma and urine were related to corresponding clinical symptoms and biochemical findings at the time of diagnosis. The significance of elevated concentrations of these substances in relation to treatment was also investigated. Plasma ACTH concentrations were increased in 22 patients (29%), and 25 patients (33%) were considered to have inappropriate ADH secretion. Only one patient had definite hypokalaemic alkalosis, and one patient pronounced hyponatraemia, with associated clinical syndromes of ectopic ACTH and ADH secretion. Serum calcitonin concentrations were increased in 48 patients (65%). No related clinical symptoms were disclosed, and all these patients had normal serum calcium concentrations. Thirty-three of 66 patients (50%) had raised levels of free cortisol in a 24-hour urine and these levels were significantly related to plasma ACTH concentrations. The median survival was slightly shorter in patients with increased values of the three substances, but this was not related to increased plasma ACTH concentrations and was not statistically significant. Survival rates and results of treatment were independent of the pretreatment levels of the three substances. [ABSTRACT FROM PUBLISHER]

FLT3 mutations occur in approximately 25% of all acute myeloid leukemia (AML) patients. While several FLT3 inhibitors have received FDA approval, their use is currently limited to combination therapies with chemotherapy, as resistance occurs, and efficacy decreases when the inhibitors are used alone. Given the highly heterogeneous nature of AML, there is an urgent need for novel targeted therapies that address the disease from multiple angles. Recent research has identified the NLRP3 inflammasome as a potential new driver in AML. Here, we investigated the efficacy of different NLRP3 inhibitors in targeting AML cells in vitro. Our findings reveal that NLRP3 inhibition induces cell cycle arrest as well as signs of senescence in multiple AML cell lines. In contrast, NLRP3 inhibition selectively induced apoptosis in FLT3 mutant AML cell lines, but not in FLT3 wild-type AML cells. Moreover, we show that NLRP3 inhibition impairs FLT3 signaling by reducing both FLT3 expression as well as downstream signaling in FLT3 mutant cells. A database analysis revealed a strong positive correlation between FLT3 and NLRP3 in cancer, which was particularly evident in AML patients. Strikingly, the simultaneous inhibition of NLRP3 and FLT3 markedly enhanced apoptosis in FLT3-ITD mutant AML cells, but not in FLT3 wild-type cells. In summary, this study reveals a promising combined therapeutic strategy specifically targeting NLRP3/FLT3-ITD positive AML blasts in vitro, highlighting a potential new avenue for AML treatment., Competing Interests: Declarations. Ethics approval and consent to participate: All studies involving human cells were conducted in accordance with the guidelines of the World Medical Association’s Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Acute myeloid leukemia (AML) is characterized by the abnormal proliferation of myeloid precursor cells and presents significant challenges in treatment due to its heterogeneity. Recently, the NLRP3 inflammasome has emerged as a potential contributor to AML pathogenesis, although its precise mechanisms remain poorly understood., Methods: Public genome datasets were utilized to evaluate the expression of NLRP3 inflammasome-related genes (IL-1β, IL-18, ASC, and NLRP3) in AML patients compared to healthy individuals. CRISPR/Cas9 technology was employed to generate NLRP3-deficient MOLM-13 AML cells, followed by comprehensive characterization using real-time PCR, western blotting, FACS analysis, and transmission electron and immunofluorescence microscopy. Proteomic analyses were conducted to identify NLRP3-dependent alterations in protein levels, with a focus on the eIF2 kinase PERK-mediated signaling pathways. Additionally, in vivo studies were performed using a leukemic mouse model to elucidate the pathogenic role of NLRP3 in AML., Results: Elevated expression of NLRP3 was significantly associated with diminished overall survival in AML patients. Genetic deletion, pharmacological inhibition and silencing by RNA interference of NLRP3 led to decreased AML cell survival through the induction of apoptosis. Proteomic analyses uncovered NLRP3-dependent alterations in protein translation, characterized by enhanced eIF2α phosphorylation in NLRP3-deficient AML cells. Moreover, inhibition of PERK-mediated eIF2α phosphorylation reduced apoptosis by downregulating pro-apoptotic Bcl-2 family members. In vivo studies demonstrated reduced leukemic burden in mice engrafted with NLRP3 knockout AML cells, as evidenced by alleviated leukemic symptoms., Conclusion: Our findings elucidate the involvement of the NLRP3/PERK/eIF2 axis as a novel driver of AML cell survival. Targeting NLRP3-induced signaling pathways, particularly through the PERK/eIF2 axis, presents a promising therapeutic strategy for AML intervention. These insights into the role of the NLRP3 inflammasome offer potential avenues for improving the prognosis and treatment outcomes of AML patients., (© 2024. The Author(s).)

An instrument to measure total integrated scattering (TIS) in space was built as part of the Optical Properties Monitor instrument package and flown on the Russian Mir Space Station in a low Earth orbit. TIS at two wavelengths was measured in space at approximately weekly intervals from 29 April to 26 December 1997 and telemetered to Earth during the mission. Of the 20 TIS samples, 13 are described here to illustrate the performance of the TIS instrument. These include ten optical samples and three thermal control samples. Two optical samples and one thermal control sample were severely degraded by atomic oxygen. All samples received a light dusting of particles during the mission and an additional heavier layer after the samples returned to Earth. The initial brassboard instrument and the validation tests of the flight instrument are also described.