In light of the burgeoning successes of cancer immunotherapy, glioblastoma (GBM) remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity. Thus, identifying promising therapeutic targets for treating GBM and discovering methodologies to effectively regulate them is still a tremendous challenge. Here we describe photodynamic protein tyrosine phosphatase 1B (PTP1B) proteolysis mediated by a proteolysis-targeting chimera (PROTAC) nanoassembly. The PTP1B-targeting PROTAC is conjugated with a photosensitizer via a cathepsin B (Cat B)-cleavable peptide, which spontaneously forms nanoassemblies due to intermolecular π-π stacking interactions. In GBM models, PROTAC nanoassemblies significantly accumulate in the tumor region across the disrupted blood-brain barrier (BBB), triggering a burst release of the photosensitizer and active PROTAC by Cat B-mediated enzymatic cleavage. Upon laser irradiation, photodynamic therapy (PDT) synergizes with PROTAC-mediated PTP1B proteolysis to induce potent immunogenic cell death (ICD) in tumor cells. Subsequently, persistent PTP1B degradation by nanoassemblies in Cat B-overexpressed intratumoral T cells downregulates exhaustion markers, reinvigorating their functionality. These sequential processes of photodynamic PTP1B proteolysis ultimately augment T cell-mediated antitumor immunity as well as protective immunity, completely eradicating the primary GBM and preventing its recurrence. Overall, our findings underscore the therapeutic potential of combining PDT with PROTAC activity for GBM immunotherapy.

Like other bodily materials, lipids such as plasma triacylglycerol, cholesterols, and free fatty acids are in a dynamic state of constant turnover (i.e., synthesis, breakdown, oxidation, and/or conversion to other compounds) as essential processes for achieving dynamic homeostasis in the body. However, dysregulation of lipid turnover can lead to clinical conditions such as obesity, fatty liver disease, and dyslipidemia. Assessment of “snap-shot” information on lipid metabolism (e.g., tissue contents of lipids, abundance of mRNA and protein and/or signaling molecules) are often used in clinical and research settings, and can help to understand one's health and disease status. However, such “snapshots” do not provide critical information on dynamic nature of lipid metabolism, and therefore may miss “true” origin of the dysregulation implicated in related diseases. In this regard, stable isotope tracer methodology can provide the in vivo kinetic information of lipid metabolism. Combining with “static” information, knowledge of lipid kinetics can enable the acquisition of in depth understanding of lipid metabolism in relation to various health and disease status. This in turn facilitates the development of effective therapeutic approaches (e.g., exercise, nutrition, and/or drugs). In this review we will discuss 1) the importance of obtaining kinetic information for a better understanding of lipid metabolism, 2) basic principles of stable isotope tracer methodologies that enable exploration of “lipid kinetics” in vivo, and 3) quantification of some aspects of lipid kinetics in vivo with numerical examples.

The precise mechanism involved in DIC and delayed traumatic subarachnoid hemorrhage (DT-SAH) remains unclear in multiple-trauma patients. Hereby, we describe a polytraumatized patient with DIC who died due to DT-SAH. A 75-year-old female patient was admitted to our Emergency Department complaining of abdominal pain and drowsiness after a pedestrian accident. Her initial brain computerized tomography (CT) finding was negative for intracranial injury. However, her abdominal CT scan revealed a collection of retroperitoneal hematomas from internal iliac artery bleeding after a compressive pelvic fracture. This event eventually resulted in shock and DIC. An immediate angiographic embolization of the bleeding artery was performed along with transfusion and anti-thrombin III. Her vital signs were stabilized without neurological change. Fourteen hours after admission, she suddenly became comatose, and her follow-up brain CT scan revealed a dense DT-SAH along the basal cisterns with acute hydrocephalus. This event rapidly prompted brain CT angiography and digital subtraction angiography, which both confirmed the absence of any cerebrovascular abnormality. Despite emergency extraventricular drainage to reverse the hydrocephalus, the patient died three days after the trauma. This paper presents an unusual case of DT-SAH in a polytraumatized patient with DIC.
Abdominal Pain ; Aged ; Angiography ; Angiography, Digital Subtraction ; Arteries ; Brain ; Coma ; Dacarbazine ; Disseminated Intravascular Coagulation* ; Drainage ; Emergencies ; Emergency Service, Hospital ; Female ; Follow-Up Studies ; Hematoma ; Hemorrhage ; Humans ; Hydrocephalus ; Iliac Artery ; Multiple Trauma ; Shock ; Sleep Stages ; Subarachnoid Hemorrhage, Traumatic* ; Tomography, X-Ray Computed ; Vital Signs

The precise mechanism involved in DIC and delayed traumatic subarachnoid hemorrhage (DT-SAH) remains unclear in multiple-trauma patients. Hereby, we describe a polytraumatized patient with DIC who died due to DT-SAH. A 75-year-old female patient was admitted to our Emergency Department complaining of abdominal pain and drowsiness after a pedestrian accident. Her initial brain computerized tomography (CT) finding was negative for intracranial injury. However, her abdominal CT scan revealed a collection of retroperitoneal hematomas from internal iliac artery bleeding after a compressive pelvic fracture. This event eventually resulted in shock and DIC. An immediate angiographic embolization of the bleeding artery was performed along with transfusion and anti-thrombin III. Her vital signs were stabilized without neurological change. Fourteen hours after admission, she suddenly became comatose, and her follow-up brain CT scan revealed a dense DT-SAH along the basal cisterns with acute hydrocephalus. This event rapidly prompted brain CT angiography and digital subtraction angiography, which both confirmed the absence of any cerebrovascular abnormality. Despite emergency extraventricular drainage to reverse the hydrocephalus, the patient died three days after the trauma. This paper presents an unusual case of DT-SAH in a polytraumatized patient with DIC.
Abdominal Pain ; Aged ; Angiography ; Angiography, Digital Subtraction ; Arteries ; Brain ; Coma ; Dacarbazine ; Disseminated Intravascular Coagulation ; Drainage ; Emergencies ; Emergency Service, Hospital ; Female ; Follow-Up Studies ; Hematoma ; Hemorrhage ; Humans ; Hydrocephalus ; Iliac Artery ; Multiple Trauma ; Shock ; Sleep Stages ; Subarachnoid Hemorrhage, Traumatic ; Tomography, X-Ray Computed ; Vital Signs