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Protein sequencing using nanopores represents the next frontier in bio-analytics. However, linearizing unfolded proteins and controlling their translocation speed through solid-state nanopores pose significant challenges in protein sequencing. In order to address these issues, this work proposes a biomimetic graphite-based nanopore construction. These nanopores feature a nanometer-sized pore with a constriction zone, mimicking the structure of the α-hemolysin protein pore. Our all-atom Molecular Dynamics simulations demonstrate the high practical potential of these nanopores by revealing how their charge state renders them complete ion-selective and generates an electro-osmotic flow. This study shows that this nanopore construction can detect peptides at the single amino acid level by analyzing the ionic current traces generated as peptides traverse the nanopore. The novelty of the proposed nanopore lies in its ability to modulate the hydrodynamic drag induced by electro-osmotic flow, relative to the electro-phoretic force. This investigation reveals that tuning these forces helps to linearize translocating peptides and extend the residence time of individual amino acids at the constriction zone of the pore. This significantly enhances the detection and sequencing efficiency of the pore. Furthermore, the high relevance of the proposed nanopores is underscored for seawater desalination through electrodialysis and extends to ion separation under salinity gradients., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Purpose: Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer, with approximately 225,419 new cases with over 125,000 deaths annually in India. This trial compared the efficacy and safety of biosimilar cetuximab versus innovator cetuximab (IC) in combination with platinum-based chemotherapy in patients with recurrent locoregional or metastatic SCCHN., Methods: This phase III trial is a multicenter, randomized, double-blind and parallel group study performed in Indian patients with recurrent locoregional or metastatic SCCHN. Patients were randomly assigned in 2:1 ratio to receive biosimilar cetuximab and IC in combination with cisplatin and fluorouracil via intravenous infusions. The primary end points were disease control rate (DCR) and overall response rate (ORR) as per response evaluation criteria in solid tumors version 1.1. The secondary end points included pharmacokinetics (PK), immunogenicity, safety, and tolerability., Results: Of 180 patients enrolled, 120 patients received biosimilar cetuximab and 60 patients received IC treatment. No significant statistical difference was observed in the primary outcomes between two groups. Treatment difference in DCR and ORR response was found to be -5.21 (90% CI, -8.94 to -1.48) and -4.79 (90% CI, -19.42 to 9.84), respectively, indicating noninferiority to reference product. The incidence of treatment-emergent adverse events (AEs; biosimilar cetuximab: 89.2% v IC: 91.7%; P = .8364) and serious AEs (biosimilar cetuximab: 23.3% v IC: 13.3%; P = .0603) and PK parameters were comparable between treatment groups. The immunogenicity findings showed higher incidence of anticetuximab antibodies in the biosimilar cetuximab group compared with the IC group at the end of Study., Conclusion: The findings of this study demonstrated noninferiority along with comparable PK, safety, and immunogenicity of biosimilar cetuximab and IC in patients with recurrent or metastatic SCCHN.

Neuroendocrine neoplasms (NENs) of the liver represent a rare entity. Amongst this group of uncommon diseases primary hepatic neuroendocrine neoplasm (PH-NEN) represent only 0.3% of all NENs. Moreover, PH-NEN has very rarely been reported in pregnancy. We report a 28-year-old young patient with metastatic small cell neuroendocrine carcinoma of the liver complicated with pregnancy. She was evaluated and managed through a multidisciplinary team approach and received two cycles of chemotherapy with a cisplatin/etoposide regimen during the antenatal period and delivered at 37 weeks period of gestation (POG). This case highlights the importance of major challenges faced during the diagnosis and management of this very rare disease in pregnancy and the successful fetomaternal outcome., (© 2024 International Federation of Gynecology and Obstetrics.)

Clinically localized prostate cancer is often treated with radical prostatectomy combined with pelvic lymph node dissection. Data suggest that lymph node dissection does improve disease staging, but its therapeutic value has often been debated, with few studies showing that lymph node removal directly improves oncological outcomes; however, lymph nodes are an important first site of antigen recognition and immune system activation and the success of many currently used immunological therapies hinges on this dogma. Evidence, particularly in the preclinical setting, has demonstrated that the success of immune checkpoint inhibitors is dampened by the removal of tumour-draining lymph nodes. Thus, whether lymph nodes are truly 'foes' or whether they are actually 'friends' in oncological care is an important idea to discuss., (© 2024. Springer Nature Limited.)

Androgen receptor (AR) is a ligand-responsive transcription factor that drives terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to activate malignant phenotypes, the molecular mechanisms of which remain unknown. Here, we show that tumor-specific AR enhancers are critically reliant on H3K36 dimethyltransferase activity of NSD2. NSD2 expression is abnormally induced in prostate cancer, where its inactivation impairs AR transactivation potential by disrupting over 65% of its cistrome. NSD2-dependent AR sites distinctively harbor the chimeric FOXA1:AR half-motif, which exclusively comprise tumor-specific AR enhancer circuitries defined from patient specimens. NSD2 inactivation also engenders increased dependency on the NSD1 paralog, and a dual NSD1/2 PROTAC degrader is preferentially cytotoxic in AR-dependent prostate cancer models. Altogether, we characterize NSD2 as an essential AR neo-enhanceosome subunit that enables its oncogenic activity, and position NSD1/2 as viable co-targets in advanced prostate cancer., (© 2024. The Author(s).)

Gall bladder cancer (GBC) is common among the socioeconomically deprived populations of certain geographical regions. Aflatoxin is a genotoxic hepatocarcinogen, which is recognized to have a role in the pathogenesis of hepatocellular carcinoma. However, the role of aflatoxin in the pathogenesis of GBC is largely unknown. We determined serum AFB1-Lys albumin adduct (AAA) levels as a marker of aflatoxin exposure in the patients with GBC and compared to those without GBC. The relationship of AAA levels to cytogenetic (TP53mutation&HER2/neu amplification) and radiological characteristics of the tumor was assessed. We included GBC cases (n = 51) and non-GBC controls (n = 100). Mean serum AAA levels were higher in the GBC group (n = 51) than those without GBC (n = 100) (26.1 ± 12.2 vs. 13.1 ± 11.9 ng/mL; p < .001). HER2/neu expression was associated with higher AAA levels compared to those with equivocal or negative expression (43.9 ± 3 vs. 28.6 ± 10 vs. 19.3 ± 7 ng/mL; p < .001). Older age (age >50 years) (odds ratio [OR] = 3.2 [CI: 1.3-8.2]; p = .013), positive Helicobacter pylori serology (OR = 5.1 [CI: 1.4-17.8]; p = .012), presence of GS (OR = 5 [CI: 1.5-16.9]; p = .009) and detectable AAA levels (OR = 6.8 [CI: 1.3-35.7]; p = .024) were independent risk factors for the presence of the GBC among all study subjects. Among patients harboring GS, older age (age >50 years) (OR = 4.5 [CI: 1.3-14.9]; p = .015), female gender (OR = 3.8 [CI: 1.2-12.5]; p = .027), presence of multiple GS (OR = 21.9 [CI: 4.8-100.4]; p < .001) and high serum AAA levels (OR = 5.3 [CI: 1.6-17.3]; p = .006) were independent risk factors for the presence of the GBC. Elderly age >50 years (OR = 2.6 [CI: 1.3-5.2]; p = .010) and frequent peanut consumption (OR = 2.3 [CI: 1.1-4.9]; p = .030) were independent risk factors for high serum AAA levels. The current study has implications for the prevention of GBC through the reduction of dietary aflatoxin exposure., (© 2024 UICC.)

Context: We explore the influence of strongly hydrophilic confinement on various properties of water, such as density, enthalpy, potential energy, radial distribution function, entropy, specific heat capacity, structural dynamics, and transition temperatures (freezing and melting temperatures), using monatomic water (mW) model. The properties of water are found to be dependent on confinement and the wall-fluid surface interaction. Hysteresis loops are observed for density, enthalpy, potential energy, and entropy around the transition temperatures, while the size of hysteresis loops varies with confinement and surface interaction. In smaller pore sizes (H ≤ 20), the solid phase displays a higher density compared to the liquid phase, which is unconventional behavior compared to bulk water systems due to the pronounced hydrophilic properties of the confinement surface. Specific heat capacity exhibits more oscillations in the confined system compared to bulk water, stemming from uneven enthalpy differences across equal temperature intervals. During phase transformation in both heating and quenching processes, there is an abrupt change observed in specific heat capacity. Confinement exerts a notable impact on entropy in the solid phase, but its influence is negligible in the liquid phase. At lower pore sizes (H < 25 Å), there is more fluctuation in freezing temperature for all wall-fluid interactions, which diminishes beyond pore sizes of H > 25 Å. Similarly, more oscillatory behavior is observed in melting temperatures at lower pore sizes (H < 40 Å), which diminishes at higher pore sizes (H > 40 Å). During the quenching process, a sudden jump in the in-plane orientational and tetrahedral order parameters indicates the formation of an ordered phase, specifically a diamond crystalline structure. The percentages of different crystalline structures (cubic diamond, hexagonal diamond, and 2D hexagonal) vary with both the confinement size and the wall-fluid interaction strength., Methods: Cooling and heating simulations are conducted with the mW water model using LAMMPS for different nanoscale confinement separation sizes ranging from 8.5 to 70 Å within the temperature range of 100-350 K. The water is modeled using two-body and three-body interaction potential (Stillinger-Weber potential) and the confinement is introduced using LJ 9-3 water-wall interaction potential. Entropy is calculated using RDF data obtained from the simulation experiments for each temperature point with increments or decrements of 2.5 K. The transition temperatures are estimated using the specific heat capacity analysis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Diagnosis of wall-thickening type gallbladder cancer (GBC) is challenging. Computed tomography (CT) and magnetic resonance imaging (MRI) are commonly utilized to evaluate gallbladder wall thickening. However, there is a lack of data comparing the performance of CT and MRI for the detection of wall-thickening type GBC., Aim: We aim to compare the diagnostic accuracy of CT and MRI in diagnosis of wall-thickening type GBC., Materials and Methods: This prospective study comprised consecutive patients suspected of wall-thickening type GBC who underwent preoperative contrast-enhanced CT and MRI. The final diagnosis was based on the histopathology of the resected gallbladder lesion. Two radiologists independently reviewed the characteristics of gallbladder wall thickening at CT and MRI. The association of CT and MRI findings with histological diagnosis and the interobserver agreement of CT and MRI findings were assessed., Results: Thirty-three patients (malignancy, 13 and benign, 20) were included. None of the CT findings were significantly associated with GBC. However, at MRI, heterogeneous enhancement, indistinct interface with the liver, and diffusion restriction were significantly associated with malignancy ( P  = 0.006, <0.001, and 0.005, respectively), and intramural cysts were significantly associated with benign lesions ( P  = 0.012). For all MRI findings, the interobserver agreement was substantial to perfect (kappa = 0.697-1.000). At CT, the interobserver agreement was substantial to perfect (k = 0.631-1.000)., Conclusion: These findings suggest that MRI may be preferred over CT in patients with suspected wall thickening type GBC. However, larger multicenter studies must confirm our findings., (© 2024 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Preserving a functional mitochondrial network is crucial for cellular well-being, considering the pivotal role of mitochondria in ensuring cellular survival, especially under stressful conditions. Mitophagy, the selective removal of damaged mitochondria through autophagy, plays a pivotal role in preserving cellular homeostasis by preventing the production of harmful reactive oxygen species from dysfunctional mitochondria. While the involvement of mitophagy in neurodegenerative diseases has been thoroughly investigated, it is becoming increasingly evident that mitophagy plays a significant role in cancer biology. Perturbations in mitophagy pathways lead to suboptimal mitochondrial quality control, catalyzing various aspects of carcinogenesis, including establishing metabolic plasticity, stemness, metabolic reconfiguration of cancer-associated fibroblasts, and immunomodulation. While mitophagy performs a delicate balancing act at the intersection of cell survival and cell death, mounting evidence indicates that, particularly in the context of stress responses induced by cancer therapy, it predominantly promotes cell survival. Here, we showcase an overview of the current understanding of the role of mitophagy in cancer biology and its potential as a target for cancer therapy. Gaining a more comprehensive insight into the interaction between cancer therapy and mitophagy has the potential to reveal novel targets and pathways, paving the way for enhanced treatment strategies for therapy-resistant tumors in the near future., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: This single-center retrospective study explores the safety and efficacy of 177 Lu-DOTATATE in children and young adult population with metastatic/inoperable neuroendocrine tumors (NETs)., Patients and Methods: This study is a retrospective analysis of all children and young adult patients (≤29 years) with advanced inoperable/metastatic epithelial or nonepithelial NETs who were administered a median of 4 cycles of 177 Lu-DOTATATE therapy and low-dose oral capecitabine as a radiosensitizer every 8-12 weeks, except 2 patients who received CAPTEM chemotherapy. The radiological response was assessed using RECIST 1.1 on interim and end-of-treatment 68 Ga-DOTANOC PET/CT. The primary endpoint was objective response rate, whereas disease control rate, toxicity profile, progression-free survival, and overall survival were secondary endpoints., Results: Nineteen biopsy-proven NET patients (median age, 22 ± 10 years) with 8 of them adolescents (10-18 years) and the remaining young adults (19-29 years) were included. Fourteen patients had gastroenteropancreatic neuroendocrine tumor (pancreas being most common primary site), whereas the rest had non-gastroenteropancreatic neuroendocrine tumor. A total of 65 cycles of 177 Lu-DOTATATE (range, 1-6 cycles) were administered with a median cumulative activity of 600 mCi (range, 100-1000 mCi). The objective response rate and disease control rate were 41% and 94%, respectively. Grade 1 and 2 adverse events were observed in 14 (74%) and 5 (26%) of 19 patients, respectively. In a total of 8 events (42%), 4 events each of disease progression and death occurred during a median follow-up of 80.1 months with an estimated 5-year progression-free survival and overall survival of 54% (95% confidence interval, 30-78) and 63% (95% confidence interval, 39-87), respectively., Conclusions: 177 Lu-DOTATATE appears safe and effective in children and young adults with metastatic/inoperable NETs. Large prospective trials are required to validate these results., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Context: Gallium, renowned for its notably low melting point and unique property of becoming liquid at room temperature, is a valuable constituent in phase change materials. In this study, we investigate the solid-liquid phase transition of gallium using the modified embedded atom method (MEAM) potential. It addresses the technique to compute the free energy difference between the solid and liquid without using a reference state. We examine various thermodynamic and dynamic properties, including density, specific heat capacity, diffusivity, and radial distribution functions. We compute the coexistence temperature of the solid-liquid phase transitions of gallium from free energy analysis. This information is crucial for understanding the behavior of the material under different pressure conditions and can be valuable for various applications, such as materials processing and high-pressure studies. The analysis, findings, and insights of the present work will be of great significance to the broad scientific and engineering communities in the field of phase transformation of materials., Methods: A series of molecular dynamics(MD) simulations were conducted using the LAMMPS software packages. The gallium atoms are modeled using the modified embedded atom method (MEAM) potential. To accurately predict the solid-liquid phase transitions of gallium, we calculated free energy by employing the "constrained λ integration" method, coupled with multiple histogram reweighting (MHR). The solid-liquid coexistence line is determined through the Gibbs-Duhem integration technique., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Urologic research often requires data abstraction from unstructured text contained within the electronic health record. A number of natural language processing (NLP) tools have been developed to aid with this time-consuming task; however, the generalizability of these tools is typically limited by the need for task-specific training., Objective: To describe the development and validation of a zero-shot learning NLP tool to facilitate data abstraction from unstructured text for use in downstream urologic research., Design, Setting, and Participants: An NLP tool based on the GPT-3.5 model from OpenAI was developed and compared with three physicians for time to task completion and accuracy for abstracting 14 unique variables from a set of 199 deidentified radical prostatectomy pathology reports. The reports were processed in vectorized and scanned formats to establish the impact of optical character recognition on data abstraction., Intervention: A zero-shot learning NLP tool for data abstraction., Outcome Measurements and Statistical Analysis: The tool was compared with the human abstractors in terms of superiority for data abstraction speed and noninferiority for accuracy., Results and Limitations: The human abstractors required a median (interquartile range) of 93 s (72-122 s) per report for data abstraction, whereas the software required a median of 12 s (10-15 s) for the vectorized reports and 15 s (13-17 s) for the scanned reports (p < 0.001 for all paired comparisons). The accuracies of the three human abstractors were 94.7% (95% confidence interval [CI], 93.8-95.5%), 97.8% (95% CI, 97.2-98.3%), and 96.4% (95% CI, 95.6-97%) for the combined set of 2786 data points. The tool had accuracy of 94.2% (95% CI, 93.3-94.9%) for the vectorized reports and was noninferior to the human abstractors at a margin of -10% (α = 0.025). The tool had slightly lower accuracy of 88.7% (95% CI 87.5-89.9%) for the scanned reports, making it noninferior to two of three human abstractors., Conclusions: The developed zero-shot learning NLP tool offers urologic researchers a highly generalizable and accurate method for data abstraction from unstructured text. An open access version of the tool is available for immediate use by the urologic community., Patient Summary: In this report, we describe the design and validation of an artificial intelligence tool for abstracting discrete data from unstructured notes contained within the electronic medical record. This freely available tool, which is based on the GPT-3.5 technology from OpenAI, is intended to facilitate research and scientific discovery by the urologic community., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

[FeFe]-hydrogenases are capable of reducing protons at a high rate. However, molecular oxygen (O 2 ) induces the degradation of their catalytic cofactor, the H-cluster, which consists of a cubane [4Fe4S] subcluster (4Fe H ) and a unique diiron moiety (2Fe H ). Previous attempts to prevent O 2 -induced damage have focused on enhancing the protein's sieving effect for O 2 by blocking the hydrophobic gas channels that connect the protein surface and the 2Fe H . In this study, we aimed to block an O 2 diffusion pathway and shield 4Fe H instead. Molecular dynamics (MD) simulations identified a novel water channel (W H ) surrounding the H-cluster. As this hydrophilic path may be accessible for O 2 molecules we applied site-directed mutagenesis targeting amino acids along W H in proximity to 4Fe H to block O 2 diffusion. Protein film electrochemistry experiments demonstrate increased O 2 stabilities for variants G302S and S357T, and MD simulations based on high-resolution crystal structures confirmed an enhanced local sieving effect for O 2 in the environment of the 4Fe H in both cases. The results strongly suggest that, in wild type proteins, O 2 diffuses from the 4Fe H to the 2Fe H . These results reveal new strategies for improving the O 2 stability of [FeFe]-hydrogenases by focusing on the O 2 diffusion network near the active site., (© 2023 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

Molybdenum disulfide (MoS 2 ) is a two-dimensional (2D) material that offers molecular transport and sieving properties and might be a potential candidate for membrane technologies for energy and environmental applications. To facilitate the separation application, understanding the structural and dynamic properties of water near the substrate-aqueous solution is essential. Employing the molecular dynamics simulation, we investigate the density, local water network at the solid-liquid interface, and water dynamics in aqueous electrolyte solutions with various chloride salts confined in MoS 2 nanochannels with different pore sizes and electrolyte concentrations. Our simulation results confirm that the layering of interfacial water at the hydrophilic MoS 2 surface and the water density variation depends on the nature of the ions. The simulation results imply a strong attraction of cations to the surface-liquid interfaces, whereas anions are expelled from the surface due to electrostatic interaction. An examination of the dynamical property of water reveals that the confinement effect is more pronounced on water mobility when the pore width is less than 3 nm, and the salt concentration is below 1 M, whereas the electrolyte concentration greater than 1 M, ions predominantly drive the water mobility as compared to confinement one. These simulation results enhance experimental observations and provide molecular insights into the local ordering mechanism that can be crucial in controlling water dynamics in nanofiltration applications.

Abstract: Various systemic treatment options are available for advanced pancreatic neuroendocrine tumors (NETs); however, individual treatment may be suboptimally effective. Sunitinib inhibits multiple kinases and signaling pathways with delay in tumor growth, whereas peptide radioreceptor therapy (PRRT) delivers targeted radiation to the tumors in pancreatic NETs. There is a dearth of literature on the combined or tandem use of these systemic treatment modalities. We present a case of 40-year-old man with advanced pancreatic NET where PRRT or sunitinib as monotherapy had a suboptimal treatment response, but the use of sunitinib in tandem with 177 Lu-PRRT reinforced the response to the treatment., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Prostate-specific membrane antigen (PSMA), in addition to its utility in prostate cancer, is also an angiogenic imaging marker for hypervascular tumors like renal cell carcinoma (RCC). Our study aims to assess the potential role of 68 Ga-PSMA-11 positron emission tomography (PET)/CT in metastatic RCC and compare it with contrast-enhanced computed tomography (CECT)., Methods: Biopsy-proven RCC patients with known or suspected distant metastases who underwent 68 Ga-PSMA-11 PET/CT for staging/restaging were prospectively recruited. Those patients who had undergone 18 F-FDG PET/CT within six weeks of 68 Ga-PSMA PET/CT were also included retrospectively for comparative analysis. A patient-based and lesion-based analysis was done to compare the lesion detection rates of CECT, 68 Ga-PSMA-11 PET and 18 F-FDG PET. PET-based quantitative parameters were also compared between both the PET modalities. Impact of baseline parameters on survival was assessed using Cox regression analysis. A p-value of < 0.05 was considered significant., Results: Thirty-seven patients with median age 60 years ± 13 years (range = 26-76 years) were included in the study. Twenty-seven patients had clear cell (cc) RCC, six had papillary RCC (pRCC), and one each had an eosinophilic variant of ccRCC, collecting duct RCC, translocation RCC and poorly differentiated RCC. 68 Ga-PSMA-11 PET performed better in detecting marrow and equivocal bone lesions and worse in detecting liver lesions compared to CECT. 68 Ga-PSMA-11 PET-based angiogenic tumor burden estimation using Total Lesion-PSMA (TL-PSMA) and PSMA-Total volume (PSMA-TV) had a prognostic impact on the survival of patients. 68 Ga-PSMA-11 PET also detected more lesions and showed significantly higher SUVmax than 18 F-FDG PET., Conclusion: 68 Ga-PSMA-11 PET/CT performs better than CECT and 18 F-FDG PET/CT in metastatic evaluation and has prognostic value in the management of clear cell RCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Context: This article presents a theoretical study of three insensitive high explosives based on the FOX-7 moiety. A few heterocyclic five- and six-member nitrogen-rich compounds have been created in an effort to better serve as a potential insensitive high explosive. It has been addressed how these molecules should be optimised in terms of stability, sensitivity, detonation properties, IR frequency computations, formal charge calculations, and more. Comprehensive research has been done on these compounds' molecular density and energy of activation associated with the conversion from nitro (C-NO 2 ) to nitrito (C-ONO) during the initial phase of their decomposition. The bond dissociation energy along with BSSE correction for the most reactive C-NO 2 bond is examined. The two designed molecules have intra-molecular hydrogen-bonding while other does not have any intra-molecular hydrogen-bonding. The newly designed compounds exhibit higher detonation values compared to TNT, which suggests that they ought to be prepared in a laboratory by skilled experimenters., Methods: The stability of the C-NO 2 link and the covalent character of the bonds have both been calculated using the atoms in molecule (AIM) method. The electronic structure calculations have been recovered at DFT method with aug-cc-pVDZ basis set using the Gaussian-16 quantum chemistry programme., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The prostate-specific membrane antigen (PSMA) inhibitor [ 177 Lu]Lu-PSMA-617 has been previously demonstrated to be noninferior to docetaxel in achieving a biochemical response in chemotherapy-naïve metastatic castration-resistant prostate cancer patients. Here, we report the final analysis of overall survival (OS) for a phase 2 randomized, controlled trial. Methods: Forty chemotherapy-naïve, PSMA-positive metastatic castration-resistant prostate cancer patients were randomly assigned to [ 177 Lu]Lu-PSMA-617 ( n = 20) or docetaxel ( n = 20). Thirty-five patients received treatment per the protocol. Survival analysis was done using Kaplan-Meier curves and the Cox regression model. Results: The mean follow-up duration was 33.4 mo. In intention-to-treat analysis, the median OS for the [ 177 Lu]Lu-PSMA-617 and docetaxel arms was 15.0 mo (95% CI, 9.5-20.5 mo) and 15.0 mo (95% CI, 8.1-21.9 mo), respectively ( P = 0.905). In per-protocol analysis, the median OS was 19.0 mo (95% CI, 12.3-25.7 mo) versus 15.0 mo (95% CI, 8.1-21.9 mo), respectively ( P = 0.712). No significant difference in OS was observed between the 2 arms across the analyzed subgroups. Conclusion: Long-term outcomes with [ 177 Lu]Lu-PSMA-617 administered earlier in the prechemotherapy setting are comparable to those with docetaxel., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The differentiation of benign and malignant gallbladder wall thickening is challenging. The purpose of this study is to evaluate a new sonographic sign, "cervix sign" for differentiation of benign and malignant gallbladder neck thickening., Methods: This retrospective study comprised consecutive patients with gallbladder neck thickening who underwent sonography between August 2019 and December 2021. The presence of "cervix sign" was assessed by two radiologists independently., Results: Sixty-five patients had gallbladder neck thickening (28 malignant and 37 benign). The sonographic "cervix sign" was present in 18 (64%) patients with malignant thickening and in only one (2.7%) patient with benign thickening ( P  = 0.0001). The mean wall thickness was greater, and symmetric wall thickening and liver metastases were more common in malignant thickening with "cervix sign" (without reaching statistical significance). There was substantial agreement (kappa = 0.78) between the two observers for the cervix sign., Conclusion: Sonographic "cervix sign" is a useful ancillary feature of gallbladder neck cancer., (© 2023 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: There is relatively scarce data on the computed tomography (CT) detection of gastrointestinal (GI) involvement in gallbladder cancer (GBC). We aim to assess the GI involvement in GBC on CT and propose a CT-based classification., Methods: This retrospective study comprized consecutive patients with GBC who underwent contrast-enhanced computed tomography (CECT) for staging between January 2019 and April 2022. Two radiologists evaluated the CT images independently for the morphological type of GBC and the presence of GI involvement. GI involvement was classified into probable involvement, definite involvement and GI fistulization. The incidence of GI involvement and the association of GI involvement with the morphological type of GBC was evaluated. In addition, the inter-observer agreement for GI involvement was assessed., Results: Over the study period, 260 patients with GBC were evaluated. Forty-three (16.5%) patients had GI involvement. Probable GI involvement, definite GI involvement and GI fistulization were seen in 18 (41.9%), 19 (44.2%) and six (13.9%) patients, respectively. Duodenum was the most common site of involvement (55.8%), followed by hepatic flexure (23.3%), antropyloric region (9.3%) and transverse colon (2.3%). There was no association between GI involvement and morphological type of GBC. There was substantial to near-perfect agreement between the two radiologists for the overall GI involvement (k = 0.790), definite GI involvement (k = 0.815) and GI fistulization (k = 0.943). There was moderate agreement (k = 0.567) for probable GI involvement., Conclusion: GBC frequently involves the GI tract and CT can be used to categorize the GI involvement. However, the proposed CT classification needs validation., (© 2023. Indian Society of Gastroenterology.)

Background: Gallbladder cancer (GBC) is highly aggressive. Diagnosis of GBC is challenging as benign gallbladder lesions can have similar imaging features. We aim to develop and validate a deep learning (DL) model for the automatic detection of GBC at abdominal ultrasound (US) and compare its diagnostic performance with that of radiologists., Methods: In this prospective study, a multiscale, second-order pooling-based DL classifier model was trained (training and validation cohorts) using the US data of patients with gallbladder lesions acquired between August 2019 and June 2021 at the Postgraduate Institute of Medical Education and research, a tertiary care hospital in North India. The performance of the DL model to detect GBC was evaluated in a temporally independent test cohort (July 2021-September 2022) and was compared with that of two radiologists., Findings: The study included 233 patients in the training set (mean age, 48 ± (2SD) 23 years; 142 women), 59 patients in the validation set (mean age, 51.4 ± 19.2 years; 38 women), and 273 patients in the test set (mean age, 50.4 ± 22.1 years; 177 women). In the test set, the DL model had sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of 92.3% (95% CI, 88.1-95.6), 74.4% (95% CI, 65.3-79.9), and 0.887 (95% CI, 0.844-0.930), respectively for detecting GBC which was comparable to both the radiologists. The DL-based approach showed high sensitivity (89.8-93%) and AUC (0.810-0.890) for detecting GBC in the presence of stones, contracted gallbladders, lesion size <10 mm, and neck lesions, which was comparable to both the radiologists (p = 0.052-0.738 for sensitivity and p = 0.061-0.745 for AUC). The sensitivity for DL-based detection of mural thickening type of GBC was significantly greater than one of the radiologists (87.8% vs. 72.8%, p = 0.012), despite a reduced specificity., Interpretation: The DL-based approach demonstrated diagnostic performance comparable to experienced radiologists in detecting GBC using US. However, multicentre studies are warranted to explore the potential of DL-based diagnosis of GBC fully., Funding: None., Competing Interests: None., (© 2023 The Author(s).)

Loss of the tumor suppressive activity of the protein phosphatase 2A (PP2A) is associated with cancer, but the underlying molecular mechanisms are unclear. PP2A holoenzyme comprises a heterodimeric core, a scaffolding A subunit and a catalytic C subunit, and one of over 20 distinct substrate-directing regulatory B subunits. Methylation of the C subunit regulates PP2A heterotrimerization, affecting B subunit binding and substrate specificity. Here, we report that the leucine carboxy methyltransferase (LCMT1), which methylates the L309 residue of the C subunit, acts as a suppressor of androgen receptor (AR) addicted prostate cancer (PCa). Decreased methyl-PP2A-C levels in prostate tumors is associated with biochemical recurrence and metastasis. Silencing LCMT1 increases AR activity and promotes castration-resistant prostate cancer growth. LCMT1-dependent methyl-sensitive AB56αCme heterotrimers target AR and its critical coactivator MED1 for dephosphorylation, resulting in the eviction of the AR-MED1 complex from chromatin and loss of target gene expression. Mechanistically, LCMT1 is regulated by S6K1-mediated phosphorylation-induced degradation requiring the β-TRCP, leading to acquired resistance to anti-androgens. Finally, feedforward stabilization of LCMT1 by small molecule activator of phosphatase (SMAP) results in attenuation of AR-signaling and tumor growth inhibition in anti-androgen refractory PCa. These findings highlight methyl-PP2A-C as a prognostic marker and that the loss of LCMT1 is a major determinant in AR-addicted PCa, suggesting therapeutic potential for AR degraders or PP2A modulators in prostate cancer treatment., (© 2023. Springer Nature Limited.)

Targeted delivery of site-specific therapeutic agents is an effective strategy for osteoarthritis treatment. The lack of blood vessels in cartilage makes it difficult to deliver therapeutic agents like peptides to the defect area. Therefore, nucleus-targeting zwitterionic carbon nano-dots (CDs) have immense potential as a delivery vehicle for effective peptide delivery to the cytoplasm as well as nucleus. In the present study, nucleus-targeting zwitterionic CDs have been synthesized as delivery vehicle for peptides while also working as nano-agents towards optical monitoring of cartilage healing. The functional groups of zwitterion CDs were introduced by a single-step microwave assisted oxidation procedure followed by COL II peptide conjugation derived from Capra auricular cartilage through NHS/EDC coupling. The peptide-conjugated CDs (PCDs) allows cytoplasmic uptake within a short period of time (∼30 m) followed by translocation to nucleus after ∼24 h. Moreover, multicolor fluorescence of PCDs improves (blue, green, and read channel) its sensitivity as an optical code providing a compelling solution towards enhanced non-invasive tracking system with multifunctional properties. The PCDs-based delivery system developed in this study has exhibited superior ability to induce ex-vivo chondrogenic differentiation of ADMSCs as compared to bare CDs. For assessment of cartilage regeneration potential, pluronic F-127 based PCDs hydrogel was injected to rabbit auricular cartilage defects and potential healing was observed after 60 days. Therefore, the results confirm that PCDs could be an ideal alternate for multimodal therapeutic agents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Maity, Kapat, Poddar, Bora, Das, Das, Ganguly, Das, Dhara, Mandal, Roy Chowdhury, Mukherjee and Dhara.)

Chemoresistance is a primary cause of breast cancer treatment failure, and protein-protein interactions significantly contribute to chemoresistance during different stages of breast cancer progression. In pursuit of novel biomarkers and relevant protein-protein interactions occurring during the emergence of breast cancer chemoresistance, we used a computational predictive biological (CPB) approach. CPB identified associations of adhesion molecules with proteins connected with different breast cancer proteins associated with chemoresistance. This approach identified an association of Integrin β1 (ITGB1) with chemoresistance and breast cancer stem cell markers. ITGB1 activated the Focal Adhesion Kinase (FAK) pathway promoting invasion, migration, and chemoresistance in breast cancer by upregulating Erk phosphorylation. FAK also activated Wnt/Sox2 signaling, which enhanced self-renewal in breast cancer. Activation of the FAK pathway by ITGB1 represents a novel mechanism linked to breast cancer chemoresistance, which may lead to novel therapies capable of blocking breast cancer progression by intervening in ITGB1-regulated signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

5-methylcytosine (mC) and its TET-oxidized derivatives exist in CpG dyads of mammalian DNA and regulate cell fate, but how their individual combinations in the two strands of a CpG act as distinct regulatory signals is poorly understood. Readers that selectively recognize such novel 'CpG duplex marks' could be versatile tools for studying their biological functions, but their design represents an unprecedented selectivity challenge. By mutational studies, NMR relaxation, and MD simulations, we here show that the selectivity of the first designer reader for an oxidized CpG duplex mark hinges on precisely tempered conformational plasticity of the scaffold adopted during directed evolution. Our observations reveal the critical aspect of defined motional features in this novel reader for affinity and specificity in the DNA/protein interaction, providing unexpected prospects for further design progress in this novel area of DNA recognition., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Perineural invasion (PNI) indicates a worse prognosis for patients with gallbladder cancer (GBC). This preliminary retrospective study included 19 patients with GBC who under-went contrast-enhanced CT in the 4 weeks before undergoing surgical resection. GBC showed PNI on pathologic assessment in eight of 19 patients. On CT, wall thickening morphology had sensitivity of 75.0% and specificity of 81.8% for PNI; soft-tissue stranding around the celiac plexus had sensitivity of 62.5% and specificity of 100.0% for PNI.

Telomerase is an RNA-dependent DNA polymerase that plays a role in the maintenance of the 3' end of the eukaryotic chromosome, known as a telomere, by catalyzing the DNA polymerization reaction in cancer and embryonic stem cells. The detailed molecular details of the DNA polymerization by telomerase, especially the general base for deprotonating the terminal 3'-hydroxyl, which triggers the chemical reaction, remain elusive. We conducted a computational investigation using hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations to probe the detailed mechanism of the reaction. Our simulations started with the telomerase:RNA:DNA:dNTP ternary complex, and by using enhanced sampling QM/MM MD simulations, we probed the general base involved directly in the polymerization. We report the participation of an aspartate (Asp344) coordinated to Mg and an active site water molecule, jointly acting as a base during nucleic acid addition. The Asp344 residue remains transiently protonated during the course of the reaction, and later it deprotonates by transferring its proton to the water at the end of the reaction.

Background: The sensitivity of single abdominal paracentesis for diagnosis of peritoneal carcinomatosis (PC) varies from 40-70%. We hypothesized that rolling-over the patient before paracentesis might improve the cytological yield., Research Design and Methods: This was a single center pilot study with a randomized cross-over design. We compared the cytological yield of fluid obtained by roll-over technique (ROG) with standard paracentesis (SPG) in suspected PC. In the ROG group, patients were rolled side-to-side thrice, and the paracentesis was done within 1 minute. Each patient served as their own control, and the outcome assessor (cytopathologist) was blinded. The primary objective was to compare the tumor cell positivity between SPG and ROG groups., Results: Of 71 patients, 62 were analyzed. Of 53 patients with malignancy-related ascites, 39 had PC. Most of the tumor cells were adenocarcinoma (30, 94%) with one patient each having suspicious cytology and one having lymphoma. The sensitivity for diagnosis of PC was (31/39) 79.49% in SPG group and (32/39) 82.05% in ROG group ( p = 1.00). The cellularity was similar between both the groups (good cellularity in 58% of SPG and 60% of ROG, p = 1.00)., Conclusions: Rollover paracentesis did not improve the cytological yield of abdominal paracentesis., Trial Registration: CTRI/2020/06/025887 and NCT04232384.

Glioma is difficult-to-treat because of its infiltrative nature and the presence of the blood-brain barrier. Temozolomide is the only FDA-approved drug for its management. Therefore, finding a novel chemotherapeutic agent for glioma is of utmost importance. Magnolol, a neolignan, has been known for its apoptotic role in glioma. In this work, we have explored a novel anti-glioma mechanism of Magnolol associated with its role in autophagy modulation. We found increased expression levels of Beclin-1, Atg5-Atg12, and LC3-II and lower p62 expression in Magnolol-treated glioma cells. PI3K/AKT/mTOR pathway proteins were also downregulated in Magnolol-treated glioma cells. Next, we treated the glioma cells with Insulin, a stimulator of PI3K/AKT/mTOR signaling, to confirm that Magnolol induced autophagy by inhibiting this pathway. Insulin reversed the effect on Magnolol-mediated autophagy induction. We also established the same in in vivo glioma model where Magnolol showed an anti-glioma effect by inducing autophagy. To confirm the cytotoxic effect of Magnolol-induced autophagy, we used Chloroquine, a late-stage autophagy inhibitor. Chloroquine efficiently reversed the anti-glioma effects of Magnolol both in vitro and in vivo. Our study revealed the cytotoxic effect of Magnolol-induced autophagy in glioma, which was not previously reported. Additionally, Magnolol showed no toxicity in non-cancerous cell lines as well as rat organs. Thus, we concluded that Magnolol is an excellent candidate for developing new therapeutic strategies for glioma management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Genomic defects in DNA-damage repair (DDR) mechanisms have been proposed to affect the radiosensitivity of prostate cancers. In this study, we intended to evaluate the prevalence of genetic alterations in a cohort of metastatic castration-resistant prostate cancer (mCRPC) patients undergoing radioligand therapy (RLT) with prostate-specific membrane antigen (PSMA)-inhibitors as well as the impact of such mutations on treatment outcomes., Methods: Data of consecutive mCRPC patients from 2017 to 2021 who were treated with PSMA-RLT and underwent next-generation sequencing (NGS) were collected and analyzed for response and survival outcomes., Results: In 95 patients of mCRPC treated with PSMA-RLT, 15 patients (median age: 66 years, range: 50-73 years; [ 177 Lu]Lu-PSMA-617, n = 12; [ 225 Ac]Ac-PSMA-617, n = 3) underwent NGS. The median progression-free survival (PFS) of this cohort was 3 months (95% confidence interval: 1.6-4.4 months). On NGS, 21 genetic alterations were reported in 10/15 (67%) patients, of which 13 were DDR-associated alterations involving the genes: ATM (n = 3), BRCA2 (n = 3), TP53 (n = 2), PTEN (n = 2), FANCD2 (n = 1), FANCM (n = 1), and NBN (n = 1). Overall, 5/15 (33%) patients harbored six pathogenic variants (BRCA2, n = 2; ATM, n = 1; TP53, n = 1; PTEN, n = 2). No significant difference was noted for the biochemical response, radiological response, PFS, and overall survival between the patients with and without genetic alterations., Conclusions: Patients of mCRPC undergoing PSMA-RLT were frequently seen to harbor DDR-associated aberrations, albeit with no significant impact on treatment outcomes. Large prospective trials comparing PSMA-RLT-related outcomes in DDR-deficient and -proficient patients are required to bring out the differences, if any, in a more observable manner., (© 2022 Wiley Periodicals LLC.)

Here we report synthetic monosaccharide channels built with shape-persistent organic cages, porphyrin boxes (PBs), that allow facile transmembrane transport of glucose and fructose through their windows. PBs show a much higher transport rate for glucose and fructose over disaccharides such as sucrose, as evidenced by intravesicular enzyme assays and molecular dynamics simulations. The transport rate can be modulated by changing the length of the alkyl chains decorating the cage windows. Insertion of a linear pillar ligand into the cavity of PBs blocks the monosaccharide transport. In vitro cell experiment shows that PBs transport glucose across the living-cell membrane and enhance cell viability when the natural glucose transporter GLUT1 is blocked. Time-dependent live-cell imaging and MTT assays confirm the cyto-compatibility of PBs. The monosaccharide-selective transport ability of PBs is reminiscent of natural glucose transporters (GLUTs), which are crucial for numerous biological functions., (© 2022 Wiley-VCH GmbH.)

The high turnover rates of [FeFe]-hydrogenases under mild conditions and at low overpotentials provide a natural blueprint for the design of hydrogen catalysts. However, the unique active site (H-cluster) degrades upon contact with oxygen. The [FeFe]-hydrogenase from Clostridium beijerinckii (CbA5H) is characterized by the flexibility of its protein structure, which allows a conserved cysteine to coordinate to the active site under oxidative conditions. Thereby, intrinsic cofactor degradation induced by dioxygen is minimized. However, the protection from O 2 is only partial, and the activity of the enzyme decreases upon each exposure to O 2 . By using site-directed mutagenesis in combination with electrochemistry, ATR-FTIR spectroscopy, and molecular dynamics simulations, we show that the kinetics of the conversion between the oxygen-protected inactive state (cysteine-bound) and the oxygen-sensitive active state can be accelerated by replacing a surface residue that is very distant from the active site. This sole exchange of methionine for a glutamate residue leads to an increased resistance of the hydrogenase to dioxygen. With our study, we aim to understand how local modifications of the protein structure can have a crucial impact on protein dynamics and how they can control the reactivity of inorganic active sites through outer sphere effects., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)