Assessing the Clinical Efficacy of Stereotactic Puncture in Combination with Postoperative Rehabilitation Training for Hypertensive Cerebral Hemorrhage.

Objective: This study aims to investigate the clinical efficacy of stereotactic puncture for intracerebral hematoma removal, combined with postoperative individualized health education and rehabilitation training concerning hypertensive cerebral hemorrhage. We also assessed its impact on rebleeding prevention and neurological function recovery. Methods: A retrospective study was conducted, including 90 patients diagnosed with hypertensive cerebral hemorrhage in our hospital between March 2020 and June 2022. The inclusion criteria were patients with an episcleral hematoma volume exceeding 30 ml. The control group underwent minimally invasive removal using neuroendoscopy (45 patients), while the observation group received stereotactic puncture for intracerebral hematoma removal (45 patients). After surgery, both groups received individualized health education and rehabilitation training. The assessment included: (1) determination of clinical efficacy, (2) monitoring for rebleeding within 72 hours after surgery, (3) evaluation of daily living ability using the Barthel index, (4) assessment of motor function using the Fugl-Meyer Assessment (FMA) scale, and (5) monitoring for adverse reactions. Results: The observation group, which underwent stereotactic puncture for intracerebral hematoma removal combined with postoperative individualized health education and rehabilitation training, exhibited significantly better clinical efficacy, Barthel index scores, and FMA scores compared to the control group that underwent neuroendoscopic minimally invasive removal (P < .05). Notably, no complications were observed in either group, and there was no significant difference in the postoperative bleeding rate within 72 hours. Conclusions: The combined treatment approach of stereotactic puncture for intracerebral hematoma removal and postoperative individualized health education and rehabilitation training demonstrates promising therapeutic effects in managing hypertensive cerebral hemorrhage. This approach also contributes significantly to the rehabilitation of patients with hypertensive cerebral hemorrhage, warranting widespread clinical adoption.

Immunohistochemistry and immunofluorescence utilization audit by subspecialty in an academic setting: A step toward stewardship.

There are immunohistochemistry (IHC) and immunofluorescence (IF) panels described in the literature and established by personal and institutional experiences that are in common use by pathologists in their daily practice. Stewardship is a difficult discussion because IHC utilization is influenced by many factors including the pathologist's experience, background, practice setting, personal bias, and medicolegal culture. We developed the methodology to audit the IHC/IF utilization in our academic subspecialty practice. We aim to share this methodology and to provide our data that can be used for consideration by other subspecialized academic practices. This analysis included a total of 63,157 specimens that were accessioned during 2022, representing 38,612 cases. The likelihood of ordering IHC/IF ranged from 1 % (in genitourinary pathology) to 59 % (in renal pathology). The average percentage of specimens with IHC/IF was 21 % for the entire practice. In cases where IHC/IF was ordered, the number of stained slides averaged 4.9 per specimen for the entire practice. The number of IHC/IF slides per specimen ranged from 1.9 (in gastrointestinal pathology) to 12.2 (in renal pathology). The highest number of antibodies ordered for a single specimen by subspecialty ranged from 11 (in cardiac pathology) to 63 (in dermatopathology). Renal pathology was the only subspecialty that had an average number of IHC/IF slides that was statistically significantly different from all other subspecialties. We described the various patterns of utilization by subspecialty and rationalized their subtle differences. We also analyzed the types of cases that exceeded the reimbursement limits set by the Centers for Medicare and Medicaid Services (CMS).

Efficient carbon removal and excellent anti-clogging performance have been achieved in multilayer quartz sand horizontal subsurface flow constructed wetland for domestic sewage treatment.

The present study aimed to investigate the application of a multilayer quartz sand substrate horizontal subsurface flow constructed wetland (HSFCW) for campus sewage treatment. It aimed to assess the pollutant removal efficiency and anti-clogging performance under the suggested maximum organic loading rate (250 g/m2/d). The results of the multilayer HSFCW (CW6) were compared to the mololayer HSFCW (CW1) for the removal of the chemical oxygen demand (COD), solid accumulation, and microbial communities. During operation, the combination conditions of high hydraulic loading rate (HLR) with low COD concentration were better for COD removal under a high organic loading rate (OLR) of 200-300 g/m2/d. The maximum removal rate reached 80.4% in CW6 under high HLR, which was 13.8% higher than that in CW1, showing better adsorption and biodegradation ability of organic matter. Impressive clogging resistance capacity was found in CW6 due to the lower contents of the insoluble organic matter (IOM) that are prone to clogging, indicating full degradation of organic matters, particularly IOM, in CW6 under high HLR. Less abundance of unclassified Chitinophagaceae (under low HLR), Pedobacter and Saccharibacteria_genera_incertae_sedis (under high HLR) in CW6, which contributed to aerobic membrane fouling, helped to prevent clogging. Moreover, Brevundimonas, Cloacibacterium, Citrobacter, Luteimonas contributed to IOM degradation, thus further enhancing the anti-clogging performance. In view of the better clogging resistance performance, the application of CW6 operated under high HLR and low COD concentrations was recommended to achieve economical, efficient, and steady COD removal for domestic sewage treatment in long-term operation.

Enhanced Spatial Mapping of Histone Proteoforms in Human Kidney Through MALDI-MSI by High-Field UHMR-Orbitrap Detection.

Core histones including H2A, H2B, H3, and H4 are key modulators of cellular repair, transcription, and replication within eukaryotic cells, playing vital roles in the pathogenesis of disease and cellular responses to environmental stimuli. Traditional mass spectrometry (MS)-based bottom-up and top-down proteomics allows for the comprehensive identification of proteins and of post-translational modification (PTM) harboring proteoforms. However, these methodologies have difficulties preserving near-cellular spatial distributions because they typically require laser capture microdissection (LCM) and advanced sample preparation techniques. Herein, we coupled a matrix-assisted laser desorption/ionization (MALDI) source with a Thermo Scientific Q Exactive HF Orbitrap MS upgraded with ultrahigh mass range (UHMR) boards for the first demonstration of complementary high-resolution accurate mass (HR/AM) measurements of proteoforms up to 16.5 kDa directly from tissues using this benchtop mass spectrometer. The platform achieved isotopic resolution throughout the detected mass range, providing confident assignments of proteoforms with low ppm mass error and a considerable increase in duty cycle over other Fourier transform mass analyzers. Proteoform mapping of core histones was demonstrated on sections of human kidney at near-cellular spatial resolution, with several key distributions of histone and other proteoforms noted within both healthy biopsy and a section from a renal cell carcinoma (RCC) containing nephrectomy. The use of MALDI-MS imaging (MSI) for proteoform mapping demonstrates several steps toward high-throughput accurate identification of proteoforms and provides a new tool for mapping biomolecule distributions throughout tissue sections in extended mass ranges.

Nanocomposites of immobilized nano-zirconia on low-cost activated carbon derived from hazelnut shell for enhanced removal of 3-Nitro-4-Hydroxy-Phenylarsonic acid from water.

3-Nitro-4-hydroxy-phenylarsonic acid (NHPA) as a veterinary drug can degraded into highly toxic inorganic arsenic and will be harmful to environment and food safety. Nanocomposites for the uptake of NHPA were obtained by efficiently immobilizing the nano-sized zirconium oxide onto hazelnut shell-based activated carbon using pyrolysis method. We found that the pyrolysis temperature played a crucial role in the adsorptive performances of the nanocomposites. The prepared nanocomposite at pyrolysis temperature of 600 °C with a mass ratio of ZrOCl2/activated carbon of 1:3 exhibited a fast adsorption equilibrium for NHPA within 5 min, excellent adsorption capacity of 825.7 mg g-1 and the higher adsorption capacity with the increase in temperature from 20 to 45 °C across a pH range of 4-6. 90% of the NHPA uptake was sustained in the NaNO3 solution of 0.7 mol L-1. The adsorption data were well simulated by the Langmuir and pseudo-second order equations. Thermodynamic parameters suggested that the uptake of the NHPA occurred spontaneously (ΔG0<0) with an endothermic characteristic (ΔH0>0). A synergetic effect of electrostatic attraction, As-O-Zr surface coordination and π-π interaction is the main adsorption mechanism of the nanocomposites for the removal of the NHPA.

Effect of substrate types on contaminant removals, electrochemical characteristics and microbial community in vertical flow constructed wetlands for treatment of urban sewage.

The purpose of this study was to investigate the influence of substrates (quartz sand and coke) on the removal of pollutants (COD, NH4+-N and TP), electrochemical characteristics and microbial communities of vertical flow constructed wetlands (VFCW) under high pollutant loads. During operation, the removal rates of COD, NH4+-N and TP by VFCW-C (coke as substrate) were higher than that of VFCW-Q (quartz sand as substrate) by 9.73-19.41%, 5.03%-13.15% and 8.83%-14.58%, respectively. And the resistances of the VFCW-Q and VFCW-C were increased by 1228.9 Ω and 38.3 Ω, while their potentials were dropped from 182.4 mV to 377.9 mV-85.6 mV and 222.0 mV, respectively. The dominant bacteria at the bottoms of VFCW-Q and VFCW-C were individually aerobic denitrifying bacteria (ADNB; 14.98%)/ammonia oxidizing bacteria (AOB; 5.73%) and organics aerobic degrading bacteria (OADB; 12.48%)/ammonia oxidizing bacteria (AOB; 7.24%), while the predominant bacteria at their tops were separately ADNB (11.36%)/OADB (10.52%)/AOB (4.69%) and ADNB (15.09%)/AOB (8.86%) and OADB (3.20%) The removal of pollutants by VFCW-Q and VFCW-C may be mainly attributed to substrate adsorption and microbial degradation.

Effect of Maize Straw Biochar on Bacterial Communities in Agricultural Soil.

Biochar has become a popular soil amendment. However, its effect on soil microbial community is still unclear. In the present study, maize straw biochar was pyrolysed at 300°C, 450°C and 600°C, respectively, and then was added to agricultural soil at the ratio of 0.5%, 1% and 2%. Bacterial dynamics was analyzed in the pot experiments using denaturing gradient gel electrophoresis. The results indicated that the pyrolysis temperature has great impact on the elemental composition, pH and porous structures of biochar. Moreover, pyrolysis temperature was primary factor to drive the variation of bacterial community structure in biochar amended soil. In addition, the results suggested that biochar amendments on agricultural soil would decrease the bacterial diversity, and selectively promote growth of functional bacteria to become the dominant community, which could increase the bacterial community organization and improve the stability of bacteria to counteract effects of perturbation.

Impact of active antibody-mediated rejection treatment on donor-specific antibodies in pediatric kidney transplant recipients.

AMR is a major cause of graft loss after kidney transplantation. We evaluated a retrospective cohort of 13 pediatric kidney transplant patients diagnosed with active AMR. All 13 patients were treated with plasmapheresis (PP), IVIg, and rituximab. Anti-HLA DSAs were measured at the time of transplantation, AMR diagnosis, 30 days post-rejection treatment, 90 days post-rejection treatment, and 24 ± 12 months post-AMR. A total of 68 DSAs were identified from 13 patients at the time of active AMR diagnosis. The primary objective of this study was to differentiate treatment response rates between class I and class II anti-HLA DSA post-AMR treatment. Overall, DSAs were significantly reduced at 30 days, and the reduction was sustained at 90 days post-treatment, even for class II anti-HLA and strongly positive DSAs. A significant difference between class I and class II anti-HLA DSA was observed at 30 days; however, between class significance was lost at 90-day follow-up due to continued class II anti-HLA DSA treatment response. Low DSA strength was predictive of treatment response. eGFR demonstrated significant improvement 90 days after AMR diagnosis compared to the initial value at the time of AMR, and the effect was sustained for 12 months. These results suggest that the AMR treatment is effective in pediatric kidney transplant recipients with an early diagnosis of active AMR across both class I and class II anti-HLA DSAs.

Recurrent membranous nephropathy and acute cellular rejection in a patient treated with direct anti-HCV therapy (ledipasvir/sofosbuvir).

Direct-acting antiviral agents (DAAs) are very effective therapy for chronic hepatitis C infection, and have revolutionized the treatment of hepatitis C in kidney allograft recipients. Although well tolerated in general, rare renal complications have been reported. We describe a case of recurrent membranous nephropathy and acute cellular rejection in a kidney allograft recipient after DAA (ledipasvir/sofosbuvir) therapy, whose allograft function had been stable for more than 30 years. The patient was presented with nephrotic range proteinuria with stable creatinine. The kidney allograft biopsy revealed recurrent membranous nephropathy with fine granular deposits of IgG1/IgG4 codominance and positive phospholipase A2 receptor (PLA2R) staining. The patient was treated with pulse steroid and rituximab, leading to a decrease in proteinuria. As DAAs are more frequently used, physicians should be aware of immune-related renal complications.

Durable renal response after combination of bortezomib, corticosteroids, rituximab, and plasmapheresis for late antibody-mediated renal transplant rejection
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Late occurrence of antibody-mediated rejection (AMR), defined as occurring 6 months after transplantation, is associated with poor renal allograft survival, compared to early acute AMR and acute cellular rejection. The proteasome inhibitor bortezomib has multiple immunomodulatory effects on plasma cells, the source of donor-specific HLA antibodies which mediate AMR. MATERIALS AND METHODS: Consecutive patients who presented with biopsy-proven AMR and donor-specific anti-HLA antibodies (DSA) at a single institution between July 2011 and February 2015 were included. They received rituximab 375 mg/m2 on day 1, bortezomib 1.3 mg/m2 and methylprednisolone on days 1, 4, 8, 11, and plasmapheresis on days -1, 4, 8, 11, 14, 15, 17, with herpes zoster prophylaxis. The primary outcome was graft survival independent of dialysis. Patients were prospectively assessed with serial monitoring of renal function and proteinuria, and neuropathy symptoms. Toxicity determination was made by medical record review for hospitalizations within 3 months of therapy, or documentation of opportunistic infection. RESULTS: Eleven patients were treated for late AMR (diagnosed at a median of 38 months post renal transplant) with this bortezomib-based protocol; 2 patients underwent the regimen twice. Of the 11 patients, 9 have functioning allografts (82% graft survival) with a median creatinine of 2.1 mg/dL (range 1.1 - 3.4 mg/dL), at a median follow-up of 50 months after AMR therapy (range 24 - 63 months). One patient was re-transplanted at 4 years post AMR treatment with no AMR recurrence to date at 2-years' follow-up, and a second patient re-initiated dialysis at 2 years post AMR treatment. Patient survival is 91% (10/11): 1 patient relocated out of state and was reported to have died from complications of hypertensive encephalopathy. The majority of patients (7/11) had several class I and class II DSA specificities; of these, 4 patients had negative class I DSA but persistent class II DSAs at 2 - 3 months post therapy. Only 1 patient who was positive for class II DSAs alone (DR53 and DQ2) converted to negative DSA, although DSA testing was delayed to 2 years' follow-up. Two patients were hospitalized within 1 month of the protocol, 1 for ileus and 1 for urinary tract infection and ruptured ovarian cyst. One other patient had herpes zoster. CONCLUSION: Renal allograft survival was 82% at 4 years after bortezomib-based therapy for late onset AMR; toxicity profile of this regimen was acceptable. Eradication of DSAs may not be necessary for meaningful and durable renal response.
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Hyperpolarizing GABAergic transmission requires the KCC2 C-terminal ISO domain.

KCC2 is the neuron-specific member of the of K(+)-Cl(-) cotransporter gene family. It is also the only member of its family that is active under physiologically normal conditions, in the absence of osmotic stress. By extruding Cl(-) from the neuron under isotonic conditions, this transporter maintains a low concentration of neuronal Cl(-), which is essential for fast inhibitory synaptic transmission by GABA and glycine in the mature nervous system. The other members of this K(+)-Cl(-) cotransporter gene family are exclusively swelling-activated. Here we demonstrate that a 15 aa region near the end of the C terminus, unique to KCC2 (termed the ISO domain), is required for KCC2 to cotransport K(+) and Cl(-) out of the neuron under isotonic conditions. We made this discovery by overexpressing chimeric KCC2-KCC4 cDNA constructs in cultured hippocampal neurons prepared from Sprague Dawley rat embryos and assaying neuronal Cl(-) through gramicidin perforated patch-clamp recordings. We found that when neurons had been transfected with a chimeric KCC2 that lacked the unique ISO domain, hyperpolarizing responses to GABA were abolished. This finding indicates that the ISO domain is required for neuronal Cl(-) regulation. Furthermore, we discovered that when KCC2 lacks the ISO domain, it still retains swelling-activated transport, which demonstrates that there are exclusive molecular determinants of isotonic and swelling-induced K(+)-Cl(-) cotransport in neurons.

Construction of a telomere-related gene signature to predict prognosis and immune landscape for glioma.

Background: Glioma is one of the commonest malignant tumors of the brain. However, glioma present with a poor clinical prognosis. Therefore, specific detection markers and therapeutic targets need to be explored as a way to promote the survival rate of BC patients. Therefore, we need to search for quality immune checkpoints to support the efficacy of immunotherapy for glioma. Methods: We first recognized differentially expressed telomere-related genes (TRGs) and accordingly developed a risk model by univariate and multivariate Cox analysis. The accuracy of the model is then verified. We evaluated the variations in immune function and looked at the expression levels of immune checkpoint genes. Finally, to assess the anti-tumor medications often used in the clinical treatment of glioma, we computed the half inhibitory concentration of pharmaceuticals. Results: We finally identified nine TRGs and built a risk model. Through the validation of the model, we found good agreement between the predicted and observed values. Then, we found 633 differentially expressed genes between various risk groups to identify the various molecular pathways between different groups. The enrichment of CD4+ T cells, CD8+ T cells, fibroblasts, endothelial cells, macrophages M0, M1, and M2, mast cells, myeloid dendritic cells, and neutrophils was favorably correlated with the risk score, but the enrichment of B cells and NK cells was negatively correlated with the risk score. The expression of several immune checkpoint-related genes differed significantly across the risk groups. Finally, in order to create individualized treatment plans for diverse individuals, we searched for numerous chemotherapeutic medications for patients in various groups. Conclusion: The findings of this research provide evidence that TRGs may predict a patient's prognosis for glioma, assist in identifying efficient targets for glioma immunotherapy, and provide a foundation for an efficient, customized approach to treating glioma patients.

Coronaviral Main Protease Induces LPCAT3 Cleavage and Endoplasmic Reticulum (ER) Stress.

Zoonotic coronaviruses infect mammals and birds, causing pulmonary and gastrointestinal infections. Some animal coronaviruses, such as the porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV), lead to severe diarrhea and animal deaths. Gastrointestinal symptoms were also found in COVID-19 and SARS patients. However, the pathogenesis of gastrointestinal symptoms in coronavirus diseases remains elusive. In this study, the main protease-induced LPCAT3 cleavage was monitored by exogenous gene expression and protease inhibitors, and the related regulation of gene expression was confirmed by qRT-PCR and gene knockdown. Interestingly, LPCAT3 plays an important role in lipid absorption in the intestines. The Mpro of coronaviruses causing diarrhea, such as PEDV and MERS-CoV, but not the Mpro of HCoV-OC43 and HCoV-HKU1, which could induce LPCAT3 cleavage. Mutagenesis analysis and inhibitor experiments indicated that LPCAT3 cleavage was independent of the catalytic activity of Mpro. Moreover, LPCAT3 cleavage in cells boosted CHOP and GRP78 expression, which were biomarkers of ER stress. Since LPCAT3 is critical for lipid absorption in the intestines and malabsorption may lead to diarrhea in coronavirus diseases, Mpro-induced LPCAT3 cleavage might trigger gastrointestinal symptoms during coronavirus infection.

Inhibition of LSD1 induces ferroptosis through the ATF4-xCT pathway and shows enhanced anti-tumor effects with ferroptosis inducers in NSCLC.

Lysine-specific demethylase 1 (LSD1) has been identified as an important epigenetic target, and recent advances in lung cancer therapy have highlighted the importance of targeting ferroptosis. However, the precise mechanisms by which LSD1 regulates ferroptosis remain elusive. In this study, we report that the inhibition of LSD1 induces ferroptosis by enhancing lipid peroxidation and reactive oxygen species (ROS) accumulation. Mechanistically, LSD1 inhibition downregulates the expression of activating transcription factor 4 (ATF4) through epigenetic modification of histone H3 lysine 9 dimethyl (H3K9me2), which sequentially inhibits the expression of the cystine-glutamate antiporter (xCT) and decreases glutathione (GSH) production. Furthermore, LSD1 inhibition transcriptionally upregulates the expression of transferrin receptor (TFRC) and acyl-CoA synthetase long chain family member 4 (ACSL4) by enhancing the binding of histone H3 lysine 4 dimethyl (H3K4me2) to their promoter sequences. Importantly, the combination of an LSD1 inhibitor and a ferroptosis inducer demonstrates an enhanced anti-tumor effect in a xenograft model of non-small cell lung cancer (NSCLC), surpassing the efficacy of either agent alone. These findings reveal new insights into the mechanisms by which LSD1 inhibition induces ferroptosis, offering potential guidance for the development of new strategies in the treatment of NSCLC.

TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation.

The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.

ATRA promotes PD-L1 expression to control gastric cancer immune surveillance.

The vitamin A metabolite all-trans retinoic acid (ATRA) plays a key role in immune response, but effects of ATRA on cancer-associated immunity remains unclear. Previously, we have shown that ATRA regulates the expression of PD-L1 in gastric cancer (GC) cells. We herein reported the mechanism underlying ATRA-induced PD-L1 expression in GC cells and the effects of ATRA on cancer-associated immunosuppression in vitro and in vivo. ATRA enhanced PD-L1 expression through increasing its protein stability and protein synthesis, which was suppressed by JAK pan-inhibitor ruxolitinib (RUX) but enhanced in the combination with IFN-γ. In T-cell-mediated killing assay, the upregulation of PD-L1-induced by ATRA rendered GC cells strongly resistant to activated T-cell killing, which was reversed by RUX. In vivo, PD-L1 antibody restricted tumor growth, but ATRA antagonized PD-L1 antibody efficacy. Importantly, RUX not only inhibited the expression of PD-L1 induced by ATRA, but also resensitized GC cells to PD-L1 antibody. In conclusion, our study illustrated that ATRA attenuated the effect of PD-L1 blockade through upregulating PD-L1 and blocking PD-L1 expression is an important role for the generation of effective anti-tumor immune response in the combination of immunotherapy and chemotherapy or targeted therapy.

Case report: Two sisters with a germline CHEK2 variant and distinct endocrine neoplasias.

Genetic testing has become the standard of care for many disease states. As a result, physicians treating patients who have tumors often rely on germline genetic testing results for making clinical decisions. Cases of two sisters carrying a germline CHEK2 variant are highlighted whereby possible other genetic drivers were discovered on tumor analysis. CHEK2 (also referred to as CHK2) loss of function has been firmly associated with breast cancer development. In this case report, two siblings with a germline CHEK2 mutation also had distinct endocrine tumors. Pituitary adenoma and pancreatic neuroendocrine tumor (PNET) was found in the first sibling and pheochromocytoma (PCC) discovered in the second sibling. Although pituitary adenomas, PNETs, and PCC have been associated with NF1 gene mutations, the second sister with a PCC did have proven germline CHEK2 with a pathogenic somatic NF1 mutation. We highlight the clinical point that unless the tumor is sequenced, the real driver mutation that is causing the patient's tumor may remain unknown.

A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions.

The RET kinase receptor is a target of mutations in neural crest tumors, including pheochromocytomas, and of oncogenic fusions in epithelial cancers. We report a RET::GRB2 fusion in a pheochromocytoma in which RET, functioning as the upstream partner, retains its kinase domain but loses critical C-terminal motifs and is fused to GRB2, a physiological RET interacting protein. RET::GRB2 is an oncogenic driver that leads to constitutive, ligand-independent RET signaling; has transforming capability dependent on RET catalytic function; and is sensitive to RET inhibitors. These observations highlight a new driver event in pheochromocytomas potentially amenable for RET-driven therapy.