Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.

Spin-Phonon Coupling and Magnetic Transition in an Organic Molecule Intercalated Cr2Ge2Te6.

The manipulation of spin-phonon coupling in both formations and explorations of magnetism in two-dimensional van der Waals ferromagnetic semiconductors facilitates unprecedented prospects for spintronic devices. The interlayer engineering with spin-phonon coupling promises controllable magnetism via organic cation intercalation. Here, spectroscopic evidence reveals the intercalation effect on the intrinsic magnetic and electronic transitions in quasi-two-dimensional Cr2Ge2Te6 using tetrabutyl ammonium (TBA+) as the intercalant. The temperature evolution of Raman modes, Eg3 and Ag1, along with the magnetization measurements, unambiguously captures the enhancement of the ferromagnetic Curie temperature in the intercalated heterostructure. Moreover, the Eg4 mode highlights the increased effect of spin-phonon interaction in magnetic-order-induced lattice distortion. Combined with the first-principle calculations, we observed a substantial number of electrons transferred from TBA+ to Cr through the interface. The interplay between spin-phonon coupling and magnetic ordering in van der Waals magnets appeals for further understanding of the manipulation of magnetism in layered heterostructures.

First-in-man study of the PSMA Minibody IR800-IAB2M for molecularly targeted intraoperative fluorescence guidance during radical prostatectomy.

PURPOSE: Prostate-specific membrane antigen (PSMA) is increasingly used to image prostate cancer in clinical practice. We sought to develop and test a humanised PSMA minibody IAB2M conjugated to the fluorophore IRDye 800CW-NHS ester in men undergoing robot-assisted laparoscopic radical prostatectomy (RARP) to image prostate cancer cells during surgery. METHODS: The minibody was evaluated pre-clinically using PSMA positive/negative xenograft models, following which 23 men undergoing RARP between 2018 and 2020 received between 2.5 mg and 20 mg of IR800-IAB2M intravenously, at intervals between 24 h and 17 days prior to surgery. At every step of the procedure, the prostate, pelvic lymph node chains and extra-prostatic surrounding tissue were imaged with a dual Near-infrared (NIR) and white light optical platform for fluorescence in vivo and ex vivo. Histopathological evaluation of intraoperative and postoperative microscopic fluorescence imaging was undertaken for verification. RESULTS: Twenty-three patients were evaluated to optimise both the dose of the reagent and the interval between injection and surgery and secure the best possible specificity of fluorescence images. Six cases are presented in detail as exemplars. Overall sensitivity and specificity in detecting non-lymph-node extra-prostatic cancer tissue were 100% and 65%, and 64% and 64% respectively for lymph node positivity. There were no side-effects associated with administration of the reagent. CONCLUSION: Intraoperative imaging of prostate cancer tissue is feasible and safe using IR800-IAB2M. Further evaluation is underway to assess the benefit of using the technique in improving completion of surgical excision during RARP. REGISTRATION: ISCRCTN10046036: https://www.isrctn.com/ISRCTN10046036 .

Complexity in a Simple Self-Assembling System: Lecithin-Water-Ethanol Mixtures Exhibit a Re-Entrant Phase Transition and a Vesicle-Micelle Transition (VMT) on Heating.

We report surprising results for the self-assembly of lecithin (a common phospholipid) in water-ethanol mixtures. Lecithin forms vesicles (∼100 nm diameter) in water. These vesicles are transformed into small micelles (∼5 nm diameter) by a variety of destabilizing agents such as single-tailed surfactants and alcohols. In a surfactant-induced vesicle-micelle transition (VMT), vesicles steadily convert to micelles upon adding the surfactant─thereby, the turbidity of the solution drops monotonically. Instead, when an alcohol like ethanol is added to lecithin vesicles, we find a new, distinctive pattern in phase behavior as the ethanol fraction feth in water is increased. The turbidity first decreases (from feth = 0 to 37%), then rises sharply (feth = 37 to 50%), and then eventually decreases again (feth > 55%). Concomitant with the turbidity rise, the vesicles separate into two phases around feth = 50% before a single phase reappears at higher feth─in other words, there is a "re-entrant" phase transition from 1-phase to 2-phase and back to 1-phase with increasing feth. Vesicles near the phase boundary (∼feth = 45%) also show a VMT upon heating. Similar patterns are seen with other alcohols such as methanol and propanol. We ascribe these complex trends to the dual role played by alcohols: (a) first, alcohols reduce the propensity for flat lipid bilayers to bend and form closed spherical vesicles; and (b) second, alcohols diminish the tendency of lipids to self-assemble in the solvent mixture. At low alcohol fractions, (a) dominates, causing the initially unilamellar vesicles to grow into multilamellar vesicles (MLVs), which eventually phase-separate. Thereafter, (b) dominates, and the vesicles convert into micelles. Support for our hypothesis comes from scattering (SANS) and microscopy (cryo-TEM). Thus, we have uncovered a general paradigm for lipid self-assembly in solvent mixtures, and this may even have physiological relevance.

Editor's Choice - Comparison of Open Surgery and Endovascular Techniques for Juxtarenal and Complex Neck Aortic Aneurysms: The UK COMPlex AneurySm Study (UK-COMPASS) - Peri-operative and Midterm Outcomes.

OBJECTIVE: Treatment of juxtarenal and complex neck abdominal aortic aneurysms (AAAs) is now commonly by endovascular rather than open surgical repair (OSR). Published comparisons show poor validity and scientific precision. UK-COMPASS is a comparative cohort study of endovascular treatments vs. OSR for patients with an AAA unsuitable for standard on label endovascular aneurysm repair (EVAR). METHODS: All procedures for AAA in England (November 2017 to October 2019) were identified, AAA anatomy assessed in a Corelab, peri-operative risk scores determined, and propensity scoring used to identify patients suitable for either endovascular treatment or OSR. Patients were stratified by aneurysm neck length (0 - 4 mm, 5 - 9 mm, or ≥ 10 mm) and operative risk; the highest quartile was considered high risk and the remainder standard risk. Death was the primary outcome measure. Endovascular treatments included fenestrated EVAR (FEVAR) and off label standard EVAR (± adjuncts). RESULTS: Among 8 994 patients, 2 757 had AAAs that were juxtarenal, short neck, or complex neck in morphology. Propensity score stratification and adjustment method comparisons included 1 916 patients. Widespread off label use of standard EVAR devices was noted (35.6% of patients). The adjusted peri-operative mortality rate was 2.9%, lower for EVAR (1.2%; p = .001) and FEVAR (2.2%; p = .001) than OSR (4.5%). In standard risk patients with a 0 - 4 mm neck, the mortality rate was 7.4% following OSR and 2.3% following FEVAR. Differences were smaller for patients with a neck length ≥ 5 mm: 2.1% OSR vs. 1.0% FEVAR. At 3.5 years of follow up, the overall mortality rate was 20.7% in the whole study population, higher following FEVAR (27.6%) and EVAR (25.2%) than after OSR (14.2%). However, in the 0 - 4 mm neck subgroup, overall survival remained equivalent. The aneurysm related mortality rate was equivalent between treatments, but re-intervention was more common after EVAR and FEVAR than OSR. CONCLUSION: FEVAR proves notably safer than OSR in the peri-operative period for juxtarenal aneurysms (0 - 4 mm neck length), with comparable midterm survival. For patients with short neck (5 - 9 mm) and complex neck (≥ 10 mm) AAAs, overall survival was worse in endovascularly treated patients compared with OSR despite relative peri-operative safety. This warrants further research and a re-appraisal of the current clinical application of endovascular strategies, particularly in patients with poor general survival outlook owing to comorbidity and age.

Update on Pathologic Conditions, Imaging Findings, Prevention, and Management of Human Papillomavirus-related Neoplasms.

Human papillomavirus (HPV) is the most common sexually transmitted infection that proliferates in the squamous epithelium and is the most common source of viral-related neoplasms. Low-risk subtypes (HPV-6 and -11) cause respiratory papillomas (laryngeal, tracheal, and bronchial) and condyloma acuminata of the penis, anus, and perineal region (anogenital warts). High-risk subtypes (HPV-16, -18, -31, and -33) are responsible for oropharyngeal squamous cell carcinoma (SCC) that involves the tongue base, tonsils, posterior pharyngeal wall, and larynx and malignancies of the anogenital region (cancers of the cervix, vagina, vulva, penis, and anal canal). Recent studies have increasingly shown a favorable treatment response and substantial differences in the overall prognosis associated with HPV-associated oropharyngeal cancers. Given this fact, oropharyngeal, cervical, and penile SCCs are classified as HPV-associated and HPV-independent cancers in the current World Health Organization classification. Imaging is essential in the early detection, diagnosis, and staging of HPV-associated cancers. Imaging also helps assess treatment response and postoperative complications and is used for long-term surveillance. HPV-associated oropharyngeal SCCs have well-defined borders and solid and cystic nodal metastases at imaging. Updated screening and vaccination guidelines are currently available that have great potential to decrease the overall disease burden and help control this worldwide public health concern. Novel therapeutic strategies, such as immunotherapies, are being explored, and imaging biomarkers that can predict treatment response and prognosis are being investigated; radiologists play a pivotal role in these efforts. ©RSNA, 2024 Supplemental material is available for this article.

Cell-Like Capsules with "Smart" Compartments.

Eukaryotic cells have inner compartments (organelles), each with distinct properties and functions. One mimic of this architecture, based on biopolymers, is the multicompartment capsule (MCC). Here, MCCs in which the inner compartments are chemically unique and "smart," i.e., responsive to distinct stimuli in an orthogonal manner are created. Specifically, one compartment alone is induced to degrade when the MCC is contacted with an enzyme while other compartments remain unaffected. Similarly, just one compartment gets degraded upon contact with reactive oxygen species generated from hydrogen peroxide (H2 O2 ). And thirdly, one compartment alone is degraded by an external, physical stimulus, namely, by irradiating the MCC with ultraviolet (UV) light. All these specific responses are achieved without resorting to complicated chemistry to create the compartments: the multivalent cation used to crosslink the biopolymer alginate (Alg) is simply altered. Compartments of Alg crosslinked by Ca2+ are shown to be sensitive to enzymes (alginate lyases) but not to H2 O2 or UV, whereas the reverse is the case with Alg/Fe3+ compartments. These results imply the ability to selectively burst open a compartment in an MCC "on-demand" (i.e., as and when needed) and using biologically relevant stimuli. The results are then extended to a sequential degradation, where compartments in an MCC are degraded one after another, leaving behind an empty MCC lumen. Collectively, this work advances the MCC as a platform that not only emulates key features of cellular architecture, but can also begin to capture rudimentary cell-like behaviors.

Aligning germline and somatic mutations in prostate cancer. Are genetics changing practice?

OBJECTIVE: To review the current status of germline and somatic (tumour) genetic testing for prostate cancer (PCa), and its relevance for clinical practice. METHODS: A narrative synthesis of various molecular profiles related to their clinical context was carried out. Current guidelines for genetic testing and its feasibility in clinical practice were analysed. We report the main identified genetic sequencing results or functional genomic scores for PCa published in the literature or obtained from the French PROGENE study. RESULTS: The molecular alterations observed in PCa are mostly linked to disruption of the androgen receptor (AR) pathway or DNA repair deficiency. The main known germline mutations affect the BReast CAncer gene 2 (BRCA2) and homeobox B13 (HOXB13) genes, whereas AR and tumour protein p53 (TP53) are the genes with most frequent somatic alterations in tumours from men with metastatic PCa. Molecular tests are now available for detecting some of these germline or somatic alterations and sometimes recommended by guidelines, but their utilisation must combine rationality and feasibility. They can guide specific therapies, notably for the management of metastatic disease. Indeed, following androgen deprivation, targeted therapies for PCa currently include poly-(ADP-ribose)-polymerase (PARP) inhibitors, immune checkpoint inhibitors, and prostate-specific membrane antigen (PSMA)-guided radiotherapy. The genetic tests currently approved for targeted therapies remain limited to the detection of BRCA1 and BRCA2 mutation and DNA mismatch repair deficiency, while large panels are recommended for germline analyses, not only for inherited cancer predisposing syndrome, but also for metastatic PCa. CONCLUSIONS: Further consensus aligning germline with somatic molecular analysis in metastatic PCa is required, including genomics scars, emergent immunohistochemistry, or functional pre-screen imaging. With rapid advances in knowledge and technology in the field, continuous updating of guidelines to help the clinical management of these individuals, and well-conducted studies to evaluate the benefits of genetic testing are needed.

Chemically Fueled Dissipative Cross-Linking of Protein Hydrogels Mediated by Protein Unfolding.

Cells assemble dynamic protein-based nanostructures far from equilibrium, such as microtubules, in a process referred to as dissipative assembly. Synthetic analogues have utilized chemical fuels and reaction networks to form transient hydrogels and molecular assemblies from small molecule or synthetic polymer building blocks. Here, we demonstrate dissipative cross-linking of transient protein hydrogels using a redox cycle, which exhibit protein unfolding-dependent lifetimes and mechanical properties. Fast oxidation of cysteine groups on bovine serum albumin by hydrogen peroxide, the chemical fuel, formed transient hydrogels with disulfide bond cross-links that degraded over hours by a slow reductive back reaction. Interestingly, despite increased cross-linking, the hydrogel lifetime decreased as a function of increasing denaturant concentration. Experiments showed that the solvent-accessible cysteine concentration increased with increasing denaturant concentration due to unfolding of secondary structures. The increased cysteine concentration consumed more fuel, which led to less direction oxidation of the reducing agent and affected a shorter hydrogel lifetime. Increased hydrogel stiffness, disulfide cross-linking density, and decreased oxidation of redox-sensitive fluorescent probes at a high denaturant concentration provided evidence supporting the unveiling of additional cysteine cross-linking sites and more rapid consumption of hydrogen peroxide at higher denaturant concentrations. Taken together, the results indicate that the protein secondary structure mediated the transient hydrogel lifetime and mechanical properties by mediating the redox reactions, a feature unique to biomacromolecules that exhibit a higher order structure. While prior works have focused on the effects of the fuel concentration on dissipative assembly of non-biological molecules, this work demonstrates that the protein structure, even in nearly fully denatured proteins, can exert similar control over reaction kinetics, lifetime, and resulting mechanical properties of transient hydrogels.

Tumefactive Nonneoplastic Proliferative Pseudotumors of the Kidneys and Urinary Tract: CT and MRI Findings with Histopathologic Correlation.

A diverse spectrum of pathologically distinct, nonneoplastic, proliferative conditions of the kidneys and urinary tract demonstrate a expansile growth pattern similar to that of neoplasms. The renal pseudotumors include myriad causes of infections as well as rare noninfectious causes such as sarcoidosis, amyloidosis, and immunoglobulin G4-related disease (IgG4-RD). Rare entities such as cystitis cystica, endometriosis, nephrogenic adenoma, and pseudosarcomatous myofibroblastic proliferation and distinct types of prostatitis comprise tumefactive nontumorous disorders that affect specific segments of the urinary tract. The pseudotumors of the kidneys and urinary tract demonstrate characteristic histopathologic and epidemiologic features, as well as protean clinical manifestations, natural history, and imaging findings. Many patients present with genitourinary tract-specific symptoms or systemic disease. Some cases may be incidentally discovered at imaging. Some entities such as perinephric myxoid pseudotumors, IgG4-RD, fibroepithelial polyp, and nephrogenic adenoma display specific anatomic localization and disease distribution. Imaging features of multisystem disorders such as tuberculosis, sarcoidosis, and IgG4-RD provide supportive evidence that may allow precise diagnosis. Fungal pyelonephritis, xanthogranulomatous pyelonephritis, IgG4-RD, actinomycosis, and endometriosis show markedly low signal intensity on T2-weighted MR images. Although some pseudotumors exhibit characteristic imaging findings that permit correct diagnosis, laboratory correlation and histopathologic confirmation are required for definitive characterization in most cases. A high index of suspicion is a prerequisite for diagnosis. Accurate diagnosis is critical for instituting optimal management while preventing use of inappropriate therapies or interventions. Surveillance CT and MRI are frequently used for monitoring the response of pseudotumors to therapy. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Mesotheliomas and Benign Mesothelial Tumors: Update on Pathologic and Imaging Findings.

A diverse spectrum of benign entities and malignant neoplasms originate from the monotonous mesothelium that lines the serosal membranes of the pleural, pericardial, and peritoneal cavities. The mesothelium of myriad sites shows a common origin from the lateral plate mesoderm; primary mesothelial tumors thus demonstrate similar pathogenesis, imaging findings, and treatment options. Significant changes have been made in the 2021 World Health Organization (WHO) classification schemata of the pleural and pericardial tumors on the basis of recent advances in pathology and genetics. While malignant mesotheliomas are biologically aggressive malignancies that occur primarily in patients exposed to asbestos with attendant poor survival rates, well-differentiated papillary mesothelial tumors and adenomatoid tumors charter a benign clinical course with an excellent prognosis. Mesothelioma in situ is a newly characterized entity represented by recurrent unexplained pleural effusions without any identifiable mass at imaging or thoracoscopy. Immunohistochemical markers based on BAP1, MTAP, CDKN2A, and TRAF7 gene mutations help differentiate diffuse mesotheliomas from benign mesothelial proliferations and localized mesotheliomas. Cross-sectional imaging modalities, including US, CT, MRI, and fluorine 18-fluorodeoxyglucose (FDG) PET/CT, permit diagnosis and play a major role in staging and assessing surgical resectability. Imaging studies are invaluable in providing noninvasive and quantitative assessment of tumor response in patients with unresectable disease. Owing to significant overlap in patient characteristics and pathomorphology, accurate diagnosis based on advanced histopathology techniques and genetic abnormalities is imperative for optimal management and prognostication. While patients with nonepithelioid pleural mesotheliomas benefit from immunotherapy, novel targeted therapies for CDKN2A-, NF2-, and BAP1-altered mesotheliomas are under consideration. © RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Wunderlich Syndrome: Comprehensive Review of Diagnosis and Management.

Wunderlich syndrome (WS), which was named after Carl Wunderlich, is a rare clinical syndrome characterized by an acute onset of spontaneous renal hemorrhage into the subcapsular, perirenal, and/or pararenal spaces, without a history of antecedent trauma. Patients may present with a multitude of symptoms ranging from nonspecific flank or abdominal pain to serious manifestations such as hypovolemic shock. The classic symptom complex of flank pain, a flank mass, and hypovolemic shock referred to as the Lenk triad is seen in a small subset of patients. Renal neoplasms such as angiomyolipomas and clear cell renal cell carcinomas that display an increased proclivity for hemorrhage and rupture contribute to approximately 60%-65% of all cases of WS. A plethora of renal vascular diseases (aneurysms or pseudoaneurysms, arteriovenous malformations or fistulae, renal vein thrombosis, and vasculitis syndromes) account for 20%-30% of cases of WS. Rare causes of WS include renal infections, cystic diseases, calculi, kidney failure, and coagulation disorders. Cross-sectional imaging modalities, particularly multiphasic CT or MRI, are integral to the detection, localization, and characterization of the underlying causes and facilitate optimal management. However, large-volume hemorrhage at patient presentation may obscure underlying causes, particularly neoplasms. If the initial CT or MRI examination shows no contributary causes, a dedicated CT or MRI follow-up study may be warranted to establish the cause of WS. Renal arterial embolization is a useful, minimally invasive, therapeutic option in patients who present with acute or life-threatening hemorrhage and can help avoid emergency radical surgery. Accurate diagnosis of the underlying cause of WS is critical for optimal patient treatment in emergency and nonemergency clinical settings. ©RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Differential pericyte marker expression in craniofacial benign and malignant vascular tumors.

BACKGROUND: Vascular anomalies and tumors are common in the head, neck, and craniofacial areas and are associated with abnormalities in the angiomatous architecture. However, the etiology and molecular basis for the pathogenesis of most vascular lesions are still unknown. Pericytes are mural cells that surround endothelial cells. Besides angiogenesis and other physiological functions, pericytes play an important role in vascularized tissue repair and as resident mesenchymal stem/progenitor cells. Perivascular cells demonstrate a distinct immunohistochemical profile, including expression of alpha-smooth muscle actin (α-SMA), CD146, CD105, and PDGFRß, without endothelial differentiation (absence of CD31 and CD34 immunoreactivity). These pericyte markers have been shown to be expressed in soft tissue hemangiomas. However, they have not been fully examined in intraosseous hemangiomas. METHODS: In this study, we compared mesenchymal stem cell (MSC) expression of CD146 and α-SMA markers in pericytes from hemangiomas from different tissues and malignant vascular tumors. RESULTS: The results demonstrated an increased expression of pericyte markers in perivascular cells of benign hemangiomas, especially intraosseous hemangiomas and a significantly reduced expression of pericyte markers in malignant angiosarcomas. CONCLUSION: The evidence provides insight into the function of pericytes in vascular tumors and suggests their role in vascular tumor disease types.

Cost drivers in endovascular pulmonary embolism interventions.

AIM: To determine the costs associated with endovascular pulmonary embolism (PE) interventions. MATERIALS AND METHODS: Procedural costs were determined utilising time-driven activity-based costing (TDABC). A multidisciplinary team created process maps describing personnel, space, equipment, materials, and time required for each procedural step. Costs and capacity cost rates were determined using institutional and publicly available financial data. RESULTS: Process maps were developed for catheter-directed thrombolysis (CDT), ultrasound-assisted thrombolysis (USAT), pharmaco-mechanical thrombectomy (PMT), mechanical-aspiration thrombectomy (MAT), and aspiration thrombectomy (AT). Total costs were CDT $3,889, USAT $9,017.10, PMT $9,565.98, AT $12,126.42, and MAT $13,748.01. Tissue plasminogen activator costs represented 46.4% of the total materials cost for CDT, 13.1% for PMT, and 10.8% for USAT. Intensive care unit costs constitute 33.4% in CDT, 13.5% in USAT, and 13.1% in PMT of the total procedure costs. Highest total procedural costs were AT and MAT with materials cost comprising 82.6% and 80.3% of total costs, respectively. CONCLUSION: Costs were greatest with large-bore mechanical aspiration and least with catheter-directed thrombolysis using a multi-side hole infusion catheter. In the absence of a reference standard technique, physician-driven device selection can substantially impact the price of a procedure. Device choice and costs must be weighed against long-term technical and clinical success to maximise the healthcare value equation.

Proteome Landscape of Epithelial-to-Mesenchymal Transition (EMT) of Retinal Pigment Epithelium Shares Commonalities With Malignancy-Associated EMT.

Stress and injury to the retinal pigment epithelium (RPE) often lead to dedifferentiation and epithelial-to-mesenchymal transition (EMT). These processes have been implicated in several retinal diseases, including proliferative vitreoretinopathy, diabetic retinopathy, and age-related macular degeneration. Despite the importance of RPE-EMT and the large body of data characterizing malignancy-related EMT, comprehensive proteomic studies to define the protein changes and pathways underlying RPE-EMT have not been reported. This study sought to investigate the temporal protein expression changes that occur in a human-induced pluripotent stem cell-based RPE-EMT model. We utilized multiplexed isobaric tandem mass tag labeling followed by high-resolution tandem MS for precise and in-depth quantification of the RPE-EMT proteome. We have identified and quantified 7937 protein groups in our tandem mass tag-based MS analysis. We observed a total of 532 proteins that are differentially regulated during RPE-EMT. Furthermore, we integrated our proteomic data with prior transcriptomic (RNA-Seq) data to provide additional insights into RPE-EMT mechanisms. To validate these results, we have performed a label-free single-shot data-independent acquisition MS study. Our integrated analysis indicates both the commonality and uniqueness of RPE-EMT compared with malignancy-associated EMT. Our comparative analysis also revealed that multiple age-related macular degeneration-associated risk factors are differentially regulated during RPE-EMT. Together, our integrated dataset provides a comprehensive RPE-EMT atlas and resource for understanding the molecular signaling events and associated biological pathways that underlie RPE-EMT onset. This resource has already facilitated the identification of chemical modulators that could inhibit RPE-EMT, and it will hopefully aid in ongoing efforts to develop EMT inhibition as an approach for the treatment of retinal disease.

Genomic Evolution and Transcriptional Changes in the Evolution of Prostate Cancer into Neuroendocrine and Ductal Carcinoma Types.

Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuroendocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease, and the former often arises on a background of androgen deprivation therapy, although it can also arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tissue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with three longitudinal samples over 5 years. Case 2 was a single time point after the development of treatment-related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all samples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, and 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small-cell neuroendocrine and ductal prostatic carcinoma can have a common ancestry. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.

Facilitating Safe Discharge Through Predicting Disease Progression in Moderate Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study to Develop and Validate a Clinical Prediction Model in Resource-Limited Settings.

BACKGROUND: In locations where few people have received coronavirus disease 2019 (COVID-19) vaccines, health systems remain vulnerable to surges in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Tools to identify patients suitable for community-based management are urgently needed. METHODS: We prospectively recruited adults presenting to 2 hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 to develop and validate a clinical prediction model to rule out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 < 94%; respiratory rate > 30 BPM; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex, and SpO2) and 1 of 7 shortlisted biochemical biomarkers measurable using commercially available rapid tests (C-reactive protein [CRP], D-dimer, interleukin 6 [IL-6], neutrophil-to-lymphocyte ratio [NLR], procalcitonin [PCT], soluble triggering receptor expressed on myeloid cell-1 [sTREM-1], or soluble urokinase plasminogen activator receptor [suPAR]), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration, and clinical utility of the models in a held-out temporal external validation cohort. RESULTS: In total, 426 participants were recruited, of whom 89 (21.0%) met the primary outcome; 257 participants comprised the development cohort, and 166 comprised the validation cohort. The 3 models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72-0.74) and calibration (calibration slopes: 1.01-1.05) in the validation cohort and provided greater utility than a model containing the clinical parameters alone. CONCLUSIONS: We present 3 clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources.

Murine cytomegalovirus promotes renal allograft inflammation via Th1/17 cells and IL-17A.

Human cytomegalovirus (HCMV) infection is associated with renal allograft failure. Allograft damage in animal models is accelerated by CMV-induced T helper 17 (Th17) cell infiltrates. However, the mechanisms whereby CMV promotes Th17 cell-mediated pathological organ inflammation are uncharacterized. Here we demonstrate that murine CMV (MCMV)-induced intragraft Th17 cells have a Th1/17 phenotype co-expressing IFN-γ and/or TNF-α, but only a minority of these cells are MCMV specific. Instead, MCMV promotes intragraft expression of CCL20 and CXCL10, which are associated with recruitment of CCR6+ CXCR3+ Th17 cells. MCMV also enhances Th17 cell infiltrates after ischemia-reperfusion injury, independent of allogeneic responses. Pharmacologic inhibition of the Th17 cell signature cytokine, IL-17A, ameliorates MCMV-associated allograft damage without increasing intragraft viral loads or reducing MCMV-specific Th1 cell infiltrates. Clinically, HCMV DNAemia is associated with higher serum IL-17A among renal transplant patients with acute rejection, linking HCMV reactivation with Th17 cell cytokine expression. In summary, CMV promotes allograft damage via cytokine-mediated Th1/17 cell recruitment, which may be pharmacologically targeted to mitigate graft injury while preserving antiviral T cell immunity.

On-chip integration of 2D Van der Waals germanium phosphide (GeP) for active silicon photonics devices.

The outstanding performance and facile processability turn two-dimensional materials (2DMs) into the most sought-after class of semiconductors for optoelectronics applications. Yet, significant progress has been made toward the hybrid integration of these materials on silicon photonics (SiPh) platforms for a wide range of mid-infrared (MIR) applications. However, realizing 2D materials with a strong optical response in the NIR-MIR and excellent air stability is still a long-term goal. Here, we report a waveguide integrated photodetector based on a novel 2D GeP. This material uniquely combines narrow and wide tunable bandgap energies (0.51-1.68 eV), offering a broadband operation from visible to MIR spectral range. In a significant advantage over graphene devices, hybrid Si/GeP waveguide photodetectors work under bias with a low dark current of few nano-amps and demonstrate excellent stability and reproducibility. Additionally, 65 nm thick GeP devices integrated on silicon waveguides exhibit a remarkable photoresponsivity of 0.54 A/W and attain high external quantum efficiency of ∼ 51.3% under 1310 nm light and at room temperature. Furthermore, a measured absorption coefficient of 1.54 ± 0.3 dB/µm at 1310 nm suggests the potential of 2D GeP as an alternative infrared material with broad optical tunability and dynamic stability suitable for advanced optoelectronic integration.

Editor's Choice - Comparison of Open, Standard, and Complex Endovascular Aortic Repair Treatments for Juxtarenal/Short Neck Aneurysms: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Abdominal aortic aneurysms (AAAs) with adverse morphology of the aneurysm neck are "complex". Techniques employed to repair complex aneurysms include open surgical repair (OSR) and a number of on label endovascular techniques such as fenestrated endovascular aneurysm repair (FEVAR) and endovascular aneurysm repair (EVAR) with adjuncts (including chimneys and endo-anchors), as well as off label use of standard EVAR. The aim was to conduct a network meta-analysis (NMA) of published comparative outcomes. DATA SOURCES: An electronic search was performed in Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL). These databases were interrogated using the PubMed interface and the Healthcare Databases Advanced Search (HDAS) interface developed by the National Institute of Health and Care Excellence. REVIEW METHODS: Online databases were interrogated up to April 2020. Studies were included if they compared outcomes between at least two methods of repair for complex aneurysms (those with at least one adverse neck feature: absent/short neck, conicality, angulation, calcification, large diameter, and thrombus). The primary outcome measure was peri-operative death. Pre-registration was done in PROSPERO (CRD42020177482). RESULTS: The search identified 24 observational studies and 7854 patients who underwent OSR, FEVAR, off label EVAR, or chimney EVAR. No comparative studies included EVAR with endo-anchors. NMA was performed on 23 studies that reported outcomes of aneurysms with short/absent infrarenal neck. Compared with OSR, off label EVAR (relative risk [RR] 0.10, 95% confidence interval [CI] 0.01 - 0.41) and FEVAR (RR 0.62, 95% CI 0.32-0.94) were associated with lower peri-operative mortality. This difference was not seen at the midterm follow up (30 months). Compared with OSR, FEVAR was associated with a lower peri-operative myocardial infarction (MI) rate (RR 0.37, 95% CI 0.16 - 0.62) but a higher midterm re-intervention rate (hazard ratio 1.65, 95% CI 1.04 - 2.66). All studies had a "moderate" or "high" risk of bias. Confidence in the network findings (GRADE) was generally "low". CONCLUSION: This NMA demonstrated a peri-operative survival benefit for off label EVAR and FEVAR compared with OSR, potentially due to reduced risk of MI. FEVAR carries a greater midterm re-intervention risk than OSR, with potential implications for cost effectiveness. There is paucity of comparative data for cases with adverse neck features other than short length.