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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.

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.)

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.)

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.)

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.)

[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.

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.)

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.

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.

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.)

Despite the advancement in research methodologies and technologies for cancer research, there is a high rate of anti-cancer drug attrition. In this review, we discuss different conventional and modern approaches in cancer research and how human-centric models can improve on the voids conferred by more traditional animal-centric models, thereby offering a more reliable platform for drug discovery. Advanced three-dimensional cell culture methodologies, along with in silico computational analysis form the core of human-centric cancer research. This can provide a holistic understanding of the research problems and help design specific and accurate experiments that could lead to the development of better cancer therapeutics. Here, we propose a new human-centric research roadmap that promises to provide a better platform for cancer research and drug discovery., 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 © 2022 Parekh, Das, Das and Mandal.)

Abstract: Nivolumab, a fully human immunoglobulin G4 anti-programmed cell death 1 antibody, provides a novel therapy option for patients with metastatic cancers. Immunotherapy agents have been associated with immune-related adverse events (irAEs), which may be detected on 18F-FDG PET/CT. Cutaneous toxicities are one of the most common irAEs in the form of maculopapular rash (eczema-like spongiotic dermatitis) and pruritus. These irAEs may lead to false-positive findings on PET/CT done during the treatment. One should be aware of the potential irAEs while interpreting PET/CT to avoid misinterpretation., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Amol Patel Background  In India, breast cancer patients' post-treatment follow-up practices are not known. We did this survey to understand how the breast cancer patients are followed-up and tried to explore the challenges associated with it. Methods  We conducted a survey-based study among Indian oncologists. Seven questions were framed pertaining to follow-up practices. Answers were provided in the form of multiple options. Google forms platform was used. Survey was circulated through social media apps and through mail. We sought suggestions and opinions to address the challenges from participants. Results  A total of 158 medical oncologists responded to this survey. 10% were not aware that only history and clinical examination are the scientific recommendations for follow-up. Ninety percent of the medical oncologists felt clinical breast examination as an uncomfortable practice for patients and physicians and 39% ordered a chest X-ray and an ultrasound abdomen. Annual mammogram was ordered by 83%, and blood investigations were recommended by 14% routinely. The majority (49.6%) felt that the absence of a female attendant, physician and patient factors were responsible for nonadherence to clinical breast examination. The DEXA scan was recommended by 84 (53%) medical oncologists regularly for patients on aromatase inhibitors, while 23 (14%) did not recommend it. Conclusion  There is a disparity between scientific recommendations and real-world follow-up practices. A large number of medical oncologists relied on chest X-ray and ultrasound abdomen. There is an unmet need to address this issue., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Aim of the Study: To investigate computed tomography (CT) texture parameters in suspected gallbladder cancer (GBC) and assess its utility in predicting histopathological grade and overall survival., Material and Methods: This retrospective pilot study included consecutive patients with clinically suspected GBC. CT images, clinical, and histological or cytological data were retrieved from the database. CT images were reviewed by two radiologists. A single axial CT section in the portal venous phase was selected for texture analysis. Radiomic feature extraction was done using commercially available research software., Results: Thirty-eight patients (31 females, mean age 53.1 years) were included. Malignancy was confirmed in 29 patients in histopathology or cytology analysis, and the rest had no features of malignancy. Exophytic gallbladder mass with associated gallbladder wall thickening was present in 22 (58%) patients. Lymph nodal, liver, and omental metastases were present in 10, 1, and 3 patients, respectively. The mean overall survival was 9.7 months. There were significant differences in mean and kurtosis at medium texture scales to differentiate moderately differentiated and poorly differentiated adenocarcinoma ( p < 0.05). The only texture parameter that was significantly associated with survival was kurtosis ( p = 0.020) at medium texture scales. In multivariate analysis, factors found to be significantly associated with length of overall survival were mean number of positive pixels ( p = 0.02), skewness ( p = -0.046), kurtosis (0.018), and standard deviation ( p = 0.045)., Conclusions: Our preliminary results highlight the potential utility of CT texture-based radiomics analysis in patients with GBC. Medium texture scale parameters including both mean and kurtosis, or kurtosis alone, may help predict the histological grade and survival, respectively., (Copyright © 2021 Clinical and Experimental Hepatology.)

ParB-like CTPases mediate the segregation of bacterial chromosomes and low-copy number plasmids. They act as DNA-sliding clamps that are loaded at parS motifs in the centromere of target DNA molecules and spread laterally to form large nucleoprotein complexes serving as docking points for the DNA segregation machinery. Here, we solve crystal structures of ParB in the pre- and post-hydrolysis state and illuminate the catalytic mechanism of nucleotide hydrolysis. Moreover, we identify conformational changes that underlie the CTP- and parS-dependent closure of ParB clamps. The study of CTPase-deficient ParB variants reveals that CTP hydrolysis serves to limit the sliding time of ParB clamps and thus drives the establishment of a well-defined ParB diffusion gradient across the centromere whose dynamics are critical for DNA segregation. These findings clarify the role of the ParB CTPase cycle in partition complex assembly and function and thus advance our understanding of this prototypic CTP-dependent molecular switch., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The sensitivity of single abdominal paracentesis for diagnosis of peritoneal carcinomatosis in patients with malignant ascites is 40-70%. Tumor cells shed from the peritoneum settle preferentially in certain recesses of the peritoneum. We aim to compare the standard technique of abdominal paracentesis versus a rollover technique in a randomized crossover study to assess the cytological yield in patients suspected to have peritoneal carcinomatosis. Each patient will serve as their own control and the outcome assessor (cytopathologist) will be blinded to the method of paracentesis performed. The primary objective will be to compare the tumor cell positivity between the standard paracentesis group and the rollover group among enrolled patients. Clinical Trial registration: CTRI/2020/06/025887 and NCT04232384.

A major challenge in understanding ligand binding to biomacromolecules lies in dissecting the underlying thermodynamic driving forces at the atomic level. Quantifying the contributions of water molecules is often especially demanding, although they can play important roles in biomolecular recognition and binding processes. One example is human carbonic anhydrase II, whose active site harbors a conserved network of structural water molecules that are essential for enzymatic catalysis. Inhibitor binding disrupts this water network and changes the hydrogen-bonding patterns in the active site. Here, we use atomistic molecular dynamics simulations to compute the absolute entropy of the individual water molecules confined in the active site of hCAII using a spectrally resolved estimation (SRE) approach. The entropy decrease of water molecules that remain in the active site upon binding of a dorzolamide inhibitor is caused by changes in hydrogen bonding and stiffening of the hydrogen-bonding network. Overall, this entropy decrease is overcompensated by the gain due to the release of three water molecules from the active site upon inhibitor binding. The spectral density calculations enable the assignment of the changes to certain vibrational modes. In addition, the range of applicability of the SRE approximation is systematically explored by exploiting the gradually changing degree of immobilization of water molecules as a function of the distance to a phospholipid bilayer surface, which defines an "entropy ruler". These results demonstrate the applicability of SRE to biomolecular solvation, and we expect it to become a useful method for entropy calculations in biomolecular systems.

Abstract: 68Ga-PSMA PET/CT is a commonly performed procedure in the staging of intermediate- and high-risk prostate cancer after biochemical recurrence. Uptake of 68Ga-PSMA in benign conditions is also reported in the literature. Docetaxel is the mainstay of treatment in high-volume hormone-sensitive prostate cancer and castration-resistant prostate cancer. The major treatment-emergent adverse drug reactions attributed to docetaxel include myelosuppression, alopecia, and asthenia. Interstitial pneumonitis is seen in less than 2% of docetaxel-treated patients. We present a case of metastatic castration-resistant prostate cancer, wherein docetaxel-induced interstitial pneumonitis was detected on 68Ga-PSMA PET/CT, after docetaxel treatment., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Drug discovery, in particular optimization of candidates using medicinal chemistry, is generally guided by structural biology. However, for optimizing binding kinetics, relevant for efficacy and off-target effects, information on protein motion is important. Herein, we demonstrate for the prototypical textbook example of an allegedly "rigid protein" that substantial active-site dynamics have generally remained unrecognized, despite thousands of medicinal-chemistry studies on this model over decades. Comparing cryogenic X-ray structures, solid-state NMR on micro-crystalline protein at room temperature, and solution NMR structure and dynamics, supported by MD simulations, we show that under physiologically relevant conditions the pocket is in fact shaped by pronounced open/close conformational-exchange dynamics. The study, which is of general significance for pharmacological research, evinces a generic pitfall in drug discovery routines., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

Protein-water interactions have widespread effects on protein structure and dynamics. As such, the function of many biomacromolecules can be directly related to the presence and exchange of water molecules. While the presence of structural water sites can be easily detected by X-ray crystallography, the dynamics within functional water-protein network architectures is largely elusive. Here we use solid-state NMR relaxation dispersion measurements with a focus on those active-site residues in the enzyme human carbonic anhydrase II (hCAII) that constitute the evolutionarily conserved water pocket, key for CAs' enzymatic catalysis. Together with chemical shifts, peak broadening, and results of molecular dynamics (MD) and DFT shift calculations, the relaxation dispersion data suggest the presence of a widespread fast μs-time-scale dynamics in the pocket throughout the protein-water network. This process is abrogated in the presence of an inhibitor which partially disrupts the network. The time scale of the protein-water pocket motion coincides both with the estimated residence time of Zn-bound water/OH - in the pocket showing the longest lifetimes in earlier magnetic relaxation dispersion experiments as well as with the rate-limiting step of catalytic turnover. As such, the reorganization of the water pocket:enzyme architecture might constitute an element of importance for enzymatic activity of this and possibly other proteins.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma. We conducted a retrospective study to analyze the clinicopathological characteristics, cell of origin, response to therapy, and the outcome of patients with DLBCL., Materials and Methods: This was a retrospective study which included all patients with DLBCL registered at our center, between May 1, 2013, and July 31, 2015. The data regarding demography, clinical presentation, histopathology, stage, prognostic index, treatment, and treatment-related outcome were collected from prospectively maintained clinical case records of the patients., Results: In the study, we included 267 patients. The median age is 49 (20-81) years with male: female ratio of 2:1. B symptoms were seen in 124 (45%) of patients. Early Stages (I and II) were seen in 130 (52%) patients, while advanced Stages (III and 1V) were seen in 119 (48%) patients. Bulky disease (>7.5 cm) was seen in 30% of cases, and bone marrow was involved in 12%. Extranodal involvement is present in 35% of cases. Cell of origin data was available in 160 (60%) of cases, of which 88 (55%) were germinal center and 72 (45%) were activated B cell in origin. The distribution according to the international prognostic index (IPI) was as follows: low risk 40%, intermediate risk 45%, and high risk in 15%. Rituximab was used in 45% of cases. The overall response rate was 84% with a complete response (CR) rate of 70.5%. The CR rates were better with RCHOP compared with CHOP (77% vs. 61.5%, P = 0.001) and good-risk IPI (83.3% vs. 65.2%, P < 0.001) compared with intermediate- and high-risk IPI. Median follow-up period was 24 months, and 2-year event-free survival (EFS) was 70%. The presence of B symptoms, high IPI, failure to attain CR, poor PS, and nonrituximab-based chemotherapy were significantly associated with lower EFS., Conclusions: This is the first study from India, which investigated the impact of chemotherapy with or without rituximab in context of cell of origin. Adding rituximab to CHOP showed better response rate and EFS irrespective of cell of origin., Competing Interests: There are no conflicts of interest.

Competing Interests: There are no conflicts of interest.

Background: Information on prevalence of Pneumocystis jirovecii pneumonia (PCP) in immunocompromised children with pneumonia in Southeast Asia is limited., Methods: Immunocompromised children hospitalized with radiographic pneumonia were investigated for PCP by testing induced sputum by using polymerase chain reaction (PCR)., Results: Ninety-four immunocompromised children (mean age 74.5 ± 43.7 months, boys 69) with pneumonia were investigated for PCP. Underlying disease included solid tumors and hematological malignancy in 57, HIV infection in 14, primary immune deficiency in 11 and other immune deficiency disorders in 12 children. PCR could detect P. jirovecii in 14 children. Prevalence of PCP in HIV-infected children was 43% (6 of 14), renal disease on immunosuppressants 45% (4 of 9), primary immune deficiency 19% (2 of 11) and malignancies on chemotherapy 4% (2 of 57). Three of 14 children died from PCP., Conclusions: PCP is responsible for pneumonia in 14% of children with underlying immunocompromised state; PCR on induced sputum improves diagnosis., (© The Author [2014]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Three-stage pseudo-supercritical transformation path and multiple-histogram reweighting technique are employed for the determination of solid-liquid coexistence of the Lennard-Jones (12-6) fluid, in a structureless cylindrical pore of radius, R, ranging from 4 to 20 molecular diameters. The Gibbs free energy difference is evaluated using thermodynamic integration method by connecting solid and liquid phases under confinement via one or more intermediate states without any first order phase transition among them. The thermodynamic melting temperature, Tm, is found to oscillate for pore size, R < 8, which is in agreement with the behavior observed for the melting temperature in slit pores. However, Tm for almost all pore sizes is less than the bulk case, which is contrary to the behavior seen for the slit pore. The oscillation in Tm decays at around pore radius R = 8, and beyond that shift in the melting temperature with respect to the bulk case is in line with the prediction of the Gibbs-Thomson equation.

The solid-liquid coexistence of a Lennard-Jones fluid confined in slit pores of variable pore size, H, is studied using molecular dynamics simulations. Three-stage pseudo-supercritical transformation path of Grochola [J. Chem. Phys. 120(5), 2122 (2004)] and multiple histogram reweighting are employed for the confined system, for various pore sizes ranging from 20 to 5 molecular diameters, to compute the solid-liquid coexistence. The Gibbs free energy difference is evaluated using thermodynamic integration method by connecting solid-liquid phases under confinement via one or more intermediate states without any first order phase transition among them. Thermodynamic melting temperature is found to oscillate with wall separation, which is in agreement with the behavior seen for kinetic melting temperature evaluated in an earlier study. However, thermodynamic melting temperature for almost all wall separations is higher than the bulk case, which is contrary to the behavior seen for the kinetic melting temperature. The oscillation founds to decay at around H = 12, and beyond that pore size dependency of the shift in melting point is well represented by the Gibbs-Thompson equation.

Modeling tumor growth in vitro is essential for cost-effective testing of hypotheses in preclinical cancer research. 3-D cell culture offers an improvement over monolayer culture for studying cellular processes in cancer biology because of the preservation of cell-cell and cell-ECM interactions. Oxygen transport poses a major barrier to mimicking in vivo environments and is not replicated in conventional cell culture systems. We hypothesized that we can better mimic the tumor microenvironment using a bioreactor system for controlling gas exchange in cancer cell cultures with silicone hydrogel synthetic vessels. Soft-lithography techniques were used to fabricate oxygen-permeable silicone hydrogel membranes containing arrays of micropillars. These membranes were inserted into a bioreactor and surrounded by basement membrane extract (BME) within which fluorescent ovarian cancer (OVCAR8) cells were cultured. Cell clusters oxygenated by synthetic vessels showed a ∼100μm drop-off to anoxia, consistent with in vivo studies of tumor nodules fed by the microvasculature. Oxygen transport in the bioreactor system was characterized by experimental testing with a dissolved oxygen probe and finite element modeling of convective flow. Our study demonstrates differing growth patterns associated with controlling gas distributions to better mimic in vivo conditions., (Published by Elsevier Ltd.)

Growing myocardial cells from human stem cells and stem cell transplantation to repair injured myocardium are new frontiers in cardiovascular research. The 1st stage of this study was conducted to determine whether transplantation of autologous bone marrow stem cells into infarcted myocardium of sheep could differentiate into beating cardiomyocytes. The 2nd stage was to demonstrate transdifferentiation of human bone marrow mesenchymal stem cells to precursor cardiomyocytes in vitro, using a novel conditioning medium. In the 3rd stage, a clinical trial of stem cell implantation in patients with severe myocardial dysfunction involved injection of peripheral blood-derived endothelial precursor cells in 11 patients and autologous bone marrow mononuclear cells in 29. A marginal improvement in myocardial function was noted at 3 months (mean increase in ejection fraction, 6% +/- 1%), although it plateaued at 6 months. The trial proved to be safe because there was no procedure-related mortality. There is growing optimism that stem cell therapy may delay heart transplantation.

Curcumin (diferuloylmethane) is a major component of food flavoring turmeric (Curcuma longa), and has been reported to be anticarcinogenic and anti-inflammatory. Although curcumin was shown to have antioxidant properties, its exact antioxidant nature has not been fully investigated. In this report we have investigated the possible antioxidant properties of curcumin using EPR spectroscopic techniques. Curcumin was found to inhibit the (1)O(2)-dependent 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) formation in a dose-dependent manner. (1)O(2) was produced in a photosensitizing system using rose bengal as sensitizer, and was detected as TEMP-(1)O(2) adducts by electron paramagnetic resonance (EPR) spectroscopic techniques using TEMP as a spin-trap. Curcumin at 2.75 microM caused 50% inhibition of TEMP-(1)O(2) adduct formation. However, curcumin only marginally inhibited (24% maximum at 80 microM) reduction of ferricytochrome c in a xanthine-xanthine oxidase system demonstrating that it is not an effective superoxide radical scavenger. Additionally, there was minor inhibition of DMPO-OH adduct formation by curcumin (solubilized in ethanol) when an ethanol control was included in the EPR spin-trapping study, suggesting that curcumin may not be an effective hydroxyl radical scavenger. Together these data demonstrate that curcumin is able only to effectively quench singlet oxygen at very low concentration in aqueous systems., ((c) 2002 Elsevier Science (USA).)