Selective regulation of chemosensitivity in glioblastoma by phosphatidylinositol 3-kinase beta.

Resistance to chemotherapies such as temozolomide is a major hurdle to effectively treat therapy-resistant glioblastoma. This challenge arises from the activation of phosphatidylinositol 3-kinase (PI3K), which makes it an appealing therapeutic target. However, non-selectively blocking PI3K kinases PI3Kα/ß/δ/γ has yielded undesired clinical outcomes. It is, therefore, imperative to investigate individual kinases in glioblastoma's chemosensitivity. Here, we report that PI3K kinases were unequally expressed in glioblastoma, with levels of PI3Kß being the highest. Patients deficient of O6-methylguanine-DNA-methyltransferase (MGMT) and expressing elevated levels of PI3Kß, defined as MGMT-deficient/PI3Kß-high, were less responsive to temozolomide and experienced poor prognosis. Consistently, MGMT-deficient/PI3Kß-high glioblastoma cells were resistant to temozolomide. Perturbation of PI3Kß, but not other kinases, sensitized MGMT-deficient/PI3Kß-high glioblastoma cells or tumors to temozolomide. Moreover, PI3Kß-selective inhibitors and temozolomide synergistically mitigated the growth of glioblastoma stem cells. Our results have demonstrated an essential role of PI3Kß in chemoresistance, making PI3Kß-selective blockade an effective chemosensitizer for glioblastoma.

In-hospital triggers of takotsubo syndrome: a case report on witnessing sudden death in a hospital roommate.

Background: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, mimicking an acute myocardial infarction, in the absence of obstructed coronary arteries. It is often triggered by physical or emotional stress, with catecholamines playing a central role in its pathophysiology. Recent advances have been made in categorizing TTS patients based on trigger events and comorbidities, as well as proposed classifications differentiating primary and secondary TTS. In-hospital triggers for (secondary) TTS appear to be quite common, and our aim is to bring attention of this prevalent phenomenon. Case summary: We present the clinical course of an 80-year-old man who developed TTS after witnessing the sudden death of his roommate during his hospital stay. Initially hospitalized for bradycardia and complete atrioventricular block, the patient was discharged after a pacemaker implantation. However, he returned to the hospital 3 days later with chest pain and other symptoms indicative of TTS. Diagnostic tests confirmed apical ballooning consistent with TTS, and subsequent echocardiograms showed a substantial improvement in left ventricular function. Discussion: The case is classified as in-hospital TTS, occurring unexpectedly during medical care, and suggests that secondary TTS could represent a certain 'basic risk' for hospitalized patients. We want to emphasize the importance of reducing pain and fear in the hospital setting and encourage further research to understand the association between TTS and medical procedures and therapies. Overall, this case underscores the need for strategies to reduce the frequency of TTS in hospitalized patients.

Cannabis Pen-Induced Psychosisin a First-Time Adolescent User.

Cannabis is a widely used illicit substance that is historically consumed via smoking, but alternative methods of cannabis consumption have been growing in popularity over the past several decades. One such modality is vaporization, which can appeal specifically to adolescent consumers given these pen devices' ease of concealment, lack of characteristic odor, and marketability. Cannabis products designed for vaping often have higher concentrations of the psychoactive component of cannabis, tetrahydrocannabinol (THC), when compared with traditional cannabis leaf smoking. This can increase the intensity of cannabis-related effects such as analgesia, relaxation, appetite stimulation, and reduced nausea and emesis, but also potentially increases the risk for adverse effects such as dysphoria, and more severely, cannabis-induced psychosis (CIP). Here, we present the case of an adolescent female who was brought after school to our emergency department presenting with symptoms of acute psychosis. Her subsequent workup was effectively normal apart from a urine drug screen positive for THC, which the patient confirmed was due to use of a cannabis pen prior to leaving school that day. This prompted the diagnosis of CIP, which was self-limited and resolved without significant intervention. We use this case to provide the symptomatology and treatment of CIP secondary to cannabis pen use, as well as more broadly discuss the potential implications of cannabis vaping on adolescent neurodevelopment, substance use, and psychiatric comorbidities.

Friend or Foe: Factor XII Deficiency Discovered Incidentally during Management of NSTEMI.

Factor XII (FXII) deficiency is a rare coagulopathy that typically goes undiagnosed due to the lack of abnormal bleeding or thrombosis. However, the accompanying prolonged activated partial thromboplastin time (aPTT) can create difficulties with maintaining therapeutic anticoagulation in the setting of acute coronary syndrome (ACS). Here, we present the case of a 52-year-old man presenting with chest pain and diagnosed with an NSTEMI but also found with a prolonged baseline aPTT ultimately secondary to FXII deficiency. Here, we discuss the diagnostic work-up of an isolated prolonged aPTT to identify possible etiologies, such as FXII deficiency, and ultimately inform ACS management.

Inhibition of Lysosomal Function Mitigates Protective Mitophagy and Augments Ceramide Nanoliposome-Induced Cell Death in Head and Neck Squamous Cell Carcinoma.

Therapies for head and neck squamous cell carcinoma (HNSCC) are, at best, moderately effective, underscoring the need for new therapeutic strategies. Ceramide treatment leads to cell death as a consequence of mitochondrial damage by generating oxidative stress and causing mitochondrial permeability. However, HNSCC cells are able to resist cell death through mitochondria repair via mitophagy. Through the use of the C6-ceramide nanoliposome (CNL) to deliver therapeutic levels of bioactive ceramide, we demonstrate that the effects of CNL are mitigated in drug-resistant HNSCC via an autophagic/mitophagic response. We also demonstrate that inhibitors of lysosomal function, including chloroquine (CQ), significantly augment CNL-induced death in HNSCC cell lines. Mechanistically, the combination of CQ and CNL results in dysfunctional lysosomal processing of damaged mitochondria. We further demonstrate that exogenous addition of methyl pyruvate rescues cells from CNL + CQ-dependent cell death by restoring mitochondrial functionality via the reduction of CNL- and CQ-induced generation of reactive oxygen species and mitochondria permeability. Taken together, inhibition of late-stage protective autophagy/mitophagy augments the efficacy of CNL through preventing mitochondrial repair. Moreover, the combination of inhibitors of lysosomal function with CNL may provide an efficacious treatment modality for HNSCC.

The Role of Fibroblast Growth Factor-Binding Protein 1 in Skin Carcinogenesis and Inflammation.

Fibroblast growth factor-binding protein 1 (FGFBP1) is a secreted chaperone that mobilizes paracrine-acting FGFs, stored in the extracellular matrix, and presents them to their cognate receptors. FGFBP1 enhances FGF signaling including angiogenesis during cancer progression and is upregulated in various cancers. Here we evaluated the contribution of endogenous FGFBP1 to a wide range of organ functions as well as to skin pathologies using Fgfbp1-knockout mice. Relative to wild-type littermates, knockout mice showed no gross pathologies. Still, in knockout mice a significant thickening of the epidermis associated with a decreased transepidermal water loss and increased proinflammatory gene expression in the skin was detected. Also, skin carcinogen challenge by 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoyl-phorbol-13-acetate resulted in delayed and reduced papillomatosis in knockout mice. This was paralleled by delayed healing of skin wounds and reduced angiogenic sprouting in subcutaneous matrigel plugs. Heterozygous green fluorescent protein (GFP)-knock-in mice revealed rapid induction of gene expression during papilloma induction and during wound healing. Examination of wild-type skin grafted onto Fgfbp1 GFP-knock-in reporter hosts and bone marrow transplants from the GFP-reporter model into wild-type hosts revealed that circulating Fgfbp1-expressing cells migrate into healing wounds. We conclude that tissue-resident and circulating Fgfbp1-expressing cells modulate skin carcinogenesis and inflammation.