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Abstract Objectives Recently, defects in the protein kinase mTOR (mammalian target of rapamycin) and its associated pathway have been correlated with hemimegalencephaly (HME). mTOR acts as a central regulator of important physiological cellular functions such as growth and proliferation, metabolism, autophagy, death, and survival. This study was aimed at identifying specific variants in mTOR signaling pathway genes in patients diagnosed with HME. Methods Using amplicon and whole exome sequencing (WES) of resected brain and paired blood samples from five HME patients, we were able to identify pathogenic mosaic variants in the mTOR pathway genes MTOR, PIK3CA, and DEPDC5. Results These results strengthen the hypothesis that somatic variants in PI3K‐Akt‐mTOR pathway genes contribute to HME. We also describe one patient presenting with a pathogenic variant on DEPDC5 gene, which reinforces the role of DEPDC5 on cortical structural changes due to mTORC1 hyperactivation. These findings also provide insights into when in brain development these variants occurred. An early developmental variant is expected to affect a larger number of cells and to result in a larger malformation, whereas the same variant occurring later in development would cause a minor malformation. Significance In the future, numerous somatic variants in known or new genes will undoubtedly be revealed in resected brain samples, making it possible to draw correlations between genotypes and phenotypes and allow for a genetic clinical diagnosis that may help to predict a given patient's outcome.

Abstract Insulin resistance is a metabolic disorder affecting multiple tissues and is a precursor event to type 2 diabetes (T2D). As T2D affects over 425 million people globally, there is an imperative need for research into insulin resistance to better understand the underlying mechanisms. The proposed mechanisms involved in insulin resistance include both whole body aspects, such as inflammation and metabolic inflexibility; as well as cellular phenomena, such as lipotoxicity, ER stress, and mitochondrial dysfunction. Despite numerous studies emphasizing the role of lipotoxicity in the pathogenesis of insulin resistance, an understanding of the interplay between tissues and these proposed mechanisms is still emerging. Furthermore, the tissue‐specific and unique responses each of the three major insulin target tissues and how each interconnect to regulate the whole body insulin response has become a new priority in metabolic research. With an emphasis on skeletal muscle, this mini‐review highlights key similarities and differences in insulin signaling and resistance between different target‐tissues, and presents the latest findings related to how these tissues communicate to control whole body metabolism.

The most frequent pathogen that causes bacterial meningitis is the Gram-positive bacterium Streptococcus pneumoniae. By entering the brain, host cells will be activated and proinflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are released. The goal of the current study was to examine the interaction between IL-6 and TNFR1 as receptor for TNF-α and the innate immune response in vivo in a model of Streptococcus pneumoniae-induced meningitis. For the experiments IL-6−/−, TNFR1−/−, and TNFR1-IL-6−/− KO mice were used. Our results revealed higher mortality rates and bacterial burden after infection in TNFR1−/−, IL-6−/−, and TNFR1-IL-6−/− mice and a decreased immune response including lower neutrophil infiltration in the meninges of TNFR1−/− and TNFR1-IL-6−/− mice in contrast to IL-6−/− and wild type mice. Furthermore, the increased mortality of TNFR1−/− and TNFR1-IL-6−/− mice correlated with decreased glial cell activation compared to IL-6−/− or wild type mice after pneumococcal meningitis. Altogether, the results show the importance of TNFR1 and IL-6 in the regulation of the innate immune response. The lack of TNFR1 and IL-6 results in higher mortality by weakened immune defence, whereas the lack of TNFR1 results in more severe impairment of the innate immune response than the lack of IL-6 alone.

Abstract The combination of de novo hepatic dysfunction and AML in a medically fit patient presents an unusual predicament. Cases present with obstructive jaundice and imaging typically shows diffuse hepatosplenomegaly, with some cases visualizing myeloid sarcomas causing biliary ductal dilatation. Guidelines for use of anthracyclines in hepatic dysfunction recommend dose reduction based on bilirubin blood levels, either to 50% or even omitting anthracycline. Randomized data however has shown that reduction of anthracycline in AML induction decreases overall survival and lowers remission rate. This case suggests, along withthe literature reviewed, that some medically fit patients with hepatic dysfunction benefit from and tolerate intensive induction therapy well without toxicity.

An immunosuppressive tumor microenvironment promotes tumor growth and is one of the main factors limiting the response to cancer immunotherapy. We have previously reported that inhibition of vacuolar protein sorting 34 (VPS34), a crucial lipid kinase in the autophagy/endosomal trafficking pathway, decreases tumor growth in several cancer models, increases infiltration of immune cells and sensitizes tumors to anti‐programmed cell death protein 1/programmed cell death 1 ligand 1 therapy by upregulation of C‐C motif chemokine 5 (CCL5) and C‐X‐C motif chemokine 10 (CXCL10) chemokines. The purpose of this study was to investigate the signaling mechanism leading to the VPS34‐dependent chemokine increase. NanoString gene expression analysis was applied to tumors from mice treated with the VPS34 inhibitor SB02024 to identify key pathways involved in the anti‐tumor response. We showed that VPS34 inhibitors increased the secretion of T‐cell‐recruitment chemokines in a cyclic GMP‐AMP synthase (cGAS)/stimulator of interferon genes protein (STING)‐dependent manner in cancer cells. Both pharmacological and small interfering RNA (siRNA)‐mediated VPS34 inhibition increased cGAS/STING‐mediated expression and secretion of CCL5 and CXCL10. The combination of VPS34 inhibitor and STING agonist further induced cytokine release in both human and murine cancer cells as well as monocytic or dendritic innate immune cells. Finally, the VPS34 inhibitor SB02024 sensitized B16‐F10 tumor‐bearing mice to STING agonist treatment and significantly improved mice survival. These results show that VPS34 inhibition augments the cGAS/STING pathway, leading to greater tumor control through immune‐mediated mechanisms. We propose that pharmacological VPS34 inhibition may synergize with emerging therapies targeting the cGAS/STING pathway.

Abstract Nearly four decades have passed since IBM scientists pioneered atomic force microscopy (AFM) by merging the principles of a scanning tunneling microscope with the features of a stylus profilometer. Today, electrical AFM modes are an indispensable asset within the semiconductor and nanotechnology industries, enabling the characterization and manipulation of electrical properties at the nanoscale. However, electrical AFM measurements suffer from reproducibility issues caused, for example, by surface contaminations, Joule heating, and hard‐to‐minimize tip drift and tilt. Using as experimental system nanoscale Schottky diodes assembled on oxide‐free silicon crystals of precisely defined surface chemistry, it is revealed that voltage‐dependent adhesion forces lead to significant rotation of the AFM platinum tip. The electrostatics‐driven tip rotation causes a strain gradient on the silicon surface, which induces a flexoelectric reverse bias term. This directional flexoelectric internal‐bias term adds to the external (instrumental) bias, causing both an increased diode leakage as well as a shift of the diode knee voltage to larger forward biases. These findings will aid the design and characterization of silicon‐based devices, especially those that are deliberately operated under large strain or shear, such as in emerging energy harvesting technologies including Schottky‐based triboelectric nanogenerators (TENGs).

Abstract We performed a cohort study that included all patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) who received ibrutinib in the Italian National Health Service. With a median follow‐up of 42.2 months (IQR 30.8–54.6 months), the study involved 3306 patients with a median age of 72.1 years, of whom 42.6% had received ≥2 previous lines of treatment. The estimated 24‐month probabilities of being on treatment and alive were 57.9% (95% confidence interval [CI]: 59.6–56.2) and 76.6% (95% CI: 75.2–78.1), respectively. The median time to treatment discontinuation (TTD) was 31.3 months (95% CI: 29.5–33.5). Out of 3306 patients, 2015 (60.9%) discontinued treatment, with 993 cases attributed to death or disease progression (30.0% of all cases). Among the 1022 patients who discontinued treatment for reasons other than progression or death, 564 (17.1%) patients did so due to toxicity or medical decision, while 458 patients (13.8%) were lost to follow‐up. Multivariable analysis revealed that age, Eastern Cooperative Oncology Group Performance Status, the number of previous lines of therapy, refractoriness to the last treatment, and reduced renal function were associated with shorter TTD and overall survival (OS). The coexistence of 17p− and TP53 mutations had an independent unfavorable impact on TTD and OS. Nonstandard doses were associated with shorter TTD and advanced stage with shorter OS. The median OS postprogression and postdiscontinuation for other reasons were estimated at 12.9 (95% CI: 11.3–16.2) and 22.7 months (95% CI: 20.2–28.3), respectively. This large real‐world study shows that ibrutinib is an effective treatment for R/R CLL. Baseline patient characteristics and double‐hit TP53 aberrations were associated with inferior prognosis, and discontinuation due to CLL progression portended a poor outcome.

Abstract Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder caused by autoantibodies against FVIII. Severe AHA is life‐threatening. Currently, licensed hemostatic agents for the treatment of severe AHA have short half‐lives and require intravenous administration, leading to a need for hospitalization, higher costs, and negative effects on quality of life. We present two cases of severe AHA with high inhibitor titers where emicizumab was safely and effectively used with intensive immunosuppression. These reports suggest in vivo efficacy even in high inhibitor environments. The optimal dosing regimen (accelerated vs. standard loading, maintenance frequency) is unknown and we discuss the current approaches.

Abstract Introduction We sought to determine potential patient reported advantages of the da Vinci single‐port (SP) robotic system for urological procedures compared with the previous model, the da Vinci multiport (MP) system. The SP model utilizes a single 30 to 40 mm incision rather than multiple 5 to 22 mm incisions. This project aims to prospectively investigate the impact of the novel SP system on patient reported cosmetic and psychometric surgical outcomes. Methods We conducted a prospective study of patients who underwent uro‐oncologic surgery by three urologists at the University of Illinois Chicago from April to November 2021. Study participants completed a Patient Scar Assessment Questionnaire 20 and 90 days post‐procedure. The Patient Scar Assessment Questionnaire is a reliable measure of surgical scars that includes five subscales: Appearance, Symptoms, Consciousness, Satisfaction with Appearance, and Satisfaction with Symptoms. Higher scores represented worse reported outcomes. Results On Postoperative Day 20, there were 77 responses (53 SP and 24 MP). Patients receiving SP procedures reported more favourable outcomes in terms of appearance, symptoms, consciousness, and pain medication. On Day 90, there were 37 responses (24 SP and 13 MP). Patients receiving SP procedures reported more favourable outcomes in terms of appearance. No significant differences were seen on Day 90 in terms of pain, medication, symptoms, consciousness, or satisfaction. Conclusions This study demonstrates the superiority of the SP in patient reported cosmetic and pain outcomes on short‐ and long‐term follow‐up after uro‐oncological surgical procedures. Symptomatic and cosmetic advantages are present at the 20 day follow‐up, with better scar appearance being significant 90 days after surgery.