-
Journal of the Neurological Sciences Jun 2024Pineal cysts are frequently encountered as incidental findings in magnetic resonance imaging, usually devoid of symptoms, yet some patients exhibit symptomatic...
Pineal cysts are frequently encountered as incidental findings in magnetic resonance imaging, usually devoid of symptoms, yet some patients exhibit symptomatic manifestations possibly associated with the cyst, even in the absence of hydrocephalus. The etiology of these symptoms remains contentious. This study aims to investigate the presence of lymphatic endothelial cell (LEC) markers and indications of inflammation or immune response within the pineal cysts of patients experiencing symptomatic non-hydrocephalic presentations. Eight patients who underwent surgical excision of their cysts were included in the study. Immunohistochemistry was utilized to assess the expression of LYVE-1, PDPN, and VEGFR3 as LEC markers, alongside IL-6 and CD3 for indications of inflammation or immune activity. Our analysis revealed an absence of inflammatory markers or immune response. However, a distinct expression of VEGFR3 was observed, likely localized to neurons within the pineal cyst tissue. We propose that these VEGFR3+ neurons within the pineal cyst may contribute to the headache symptoms reported by these patients. Further investigations are warranted to substantiate this hypothesis.
PubMed: 38943895
DOI: 10.1016/j.jns.2024.123111 -
ESMO Open Jun 2024The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone...
Unraveling the clinicopathological and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-low and HER2-0 breast cancer.
BACKGROUND
The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT.
METHODS
We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples.
RESULTS
The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS.
CONCLUSIONS
HER2-low and HER2-0 status change after NAT in ∼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.
PubMed: 38943737
DOI: 10.1016/j.esmoop.2024.103619 -
STAR Protocols Jun 2024Super-resolution imaging provides unprecedented visualization of sub-cellular structures, but the two main techniques used, single-molecule localization microscopy...
Super-resolution imaging provides unprecedented visualization of sub-cellular structures, but the two main techniques used, single-molecule localization microscopy (SMLM) and stimulated emission depletion (STED), are not easily reconciled. We present a protocol to super-impose nanoscale protein distribution reconstructed with SMLM to sub-cellular morphology obtained in STED. We describe steps for tracking cells on etched coverslips and registering images from two different microscopes with 30-nm accuracy. In this protocol, synaptic proteins are mapped in the dendritic spines of primary neurons. For complete details on the use and execution of this protocol, please refer to Inavalli et al..
PubMed: 38943646
DOI: 10.1016/j.xpro.2024.103160 -
STAR Protocols Jun 2024Tumor acidosis is one of the hallmarks indicating the initiation and progression of various cancers. Here, we present a protocol for preparing a hyperpolarized (HP)...
Tumor acidosis is one of the hallmarks indicating the initiation and progression of various cancers. Here, we present a protocol for preparing a hyperpolarized (HP) C-bicarbonate tissue pH MRI imaging contrast agent to detect aggressive tumors. We describe the steps for the formulation and polarization of a precursor molecule C-glycerol carbonate (C-GLC), the post-dissolution reaction, and converting HP C-GLC to an injectable HP C-bicarbonate solution. We then detail procedures for MRI data acquisition to generate tumor pH maps for assessing tumor aggressiveness. For complete details on the use and execution of this protocol, please refer to Mu et al..
PubMed: 38943645
DOI: 10.1016/j.xpro.2024.103091 -
Journal of the American Chemical Society Jun 2024Manipulating single electrons at the atomic scale is vital for mastering complex surface processes governed by the transfer of individual electrons. Polarons, composed...
Manipulating single electrons at the atomic scale is vital for mastering complex surface processes governed by the transfer of individual electrons. Polarons, composed of electrons stabilized by electron-phonon coupling, offer a pivotal medium for such manipulation. Here, using scanning tunneling microscopy and spectroscopy (STM/STS) and density functional theory (DFT) calculations, we report the identification and manipulation of a new type of polaron, dubbed van der Waals (vdW) polaron, within mono- to trilayer ultrathin films composed of SbO molecules that are bonded via vdW attractions. The SbO films were grown on a graphene-covered SiC(0001) substrate via molecular beam epitaxy. Unlike prior molecular polarons, STM imaging observed polarons at the interstitial sites of the molecular film, presenting unique electronic states and localized band bending. DFT calculations revealed the lowest conduction band as an intermolecular bonding state, capable of ensnaring an extra electron through locally diminished intermolecular distances, thereby forming an intermolecular vdW polaron. We also demonstrated the ability to generate, move, and erase such vdW polarons using an STM tip. Our work uncovers a new type of polaron stabilized by coupling with intermolecular vibrations where vdW interactions dominate, paving the way for designing atomic-scale electron transfer processes and enabling precise tailoring of electron-related properties and functionalities.
PubMed: 38943576
DOI: 10.1021/jacs.4c04450 -
Pigment Cell & Melanoma Research Jun 2024Most melanomas progress from radial to vertical growth phase before spreading locoregionally and distally. Much is still unknown about the metabolic changes in the tumor...
Most melanomas progress from radial to vertical growth phase before spreading locoregionally and distally. Much is still unknown about the metabolic changes in the tumor cells and their microenvironment during this metastatic progression. We aimed to gain new insight into the molecular characteristics of melanoma in regard to spatial lipidomics to deliver new knowledge regarding tumor metastatic progression. We included 10 fresh tumor samples from 10 patients including two in situ melanomas, two invasive primary melanomas, and six metastatic melanomas (four in-transit metastases and two distant metastases). In addition, we analyzed four healthy skin controls from the same patients. Time-of-flight imaging secondary ion mass spectrometry (ToF-SIMS) enabled detailed spatial-lipidomics that could be directly correlated with conventional histopathological analysis of consecutive H&E-stained tissue sections. Significant differences in the lipid profiles were found in primary compared to metastatic melanomas, notably an increase in phosphatidylethanolamine lipids relative to phosphatidylinositol lipids and an increase in GM3 gangliosides in the metastatic samples. Furthermore, analysis of the data from in transit versus distant metastases samples highlighted that specific phospholipids, and a difference in the long versus shorter chain GM3 gangliosides, discriminated the metastatic routes. Further studies are warranted to verify these preliminary findings. Lipidomic changes could serve as a novel biomarker for tumor progression and even serve as a target for novel treatments. Furthermore, analyzing the lipid profiles could help to differentiate between primary and metastatic melanomas in challenging cases.
PubMed: 38943376
DOI: 10.1111/pcmr.13182 -
The American Journal of Case Reports Jun 2024BACKGROUND SARS-CoV-2 infection can persist in immunocompromised patients with hematological malignancies, despite antiviral treatment. This report is of a 67-year-old...
BACKGROUND SARS-CoV-2 infection can persist in immunocompromised patients with hematological malignancies, despite antiviral treatment. This report is of a 67-year-old man with chronic lymphocytic leukemia (CLL), secondary hypogammaglobulinemia, and thrombocytopenia on maintenance therapy with ibrutinib, with persistent SARS-CoV-2 infection unresponsive to antiviral treatment, including remdesivir, nirmatrelvir/ritonavir (Paxlovid), and tixagevimab/cilgavimab (Evusheld). CASE REPORT The patient was admitted to our hospital 3 times. During his first hospitalization, he was treated with 5-day course of remdesivir and intravenous steroids; however, antigen and molecular nasopharyngeal swabs were persistently positive, and he was discharged home. Due to respiratory worsening, he was rehospitalized, and despite being treated initially with tixagevimab/cilgavimab, and subsequently with a remdesivir course of 5 days, SARS-CoV-2 tests remained persistently positive. During his third hospital stay, our patient was subjected to combined therapy with remdesivir and nirmatrelvir/ritonavir for 5 days, obtaining a significant reduction of viral load at both antigen and molecular testing. As an ultimate attempt to achieve a negative status before discharge, a 10-day course of combined remdesivir and nirmatrelvir/ritonavir was administered, with a temporary reduction of viral load, followed by a sudden increase immediately after the discontinuation of Paxlovid. Due to worsening hematological disease and bacterial over-infections, the patient gradually worsened until death. CONCLUSIONS This is an emblematic case of correlation between persistent SARS-CoV-2 infection and immunosuppression status in hematological hosts. In these patients, the viral load remains high, favoring the evolution of the virus, and the immunodeficiency makes it difficult to identify the appropriate therapeutic approach.
Topics: Humans; Male; Aged; Leukemia, Lymphocytic, Chronic, B-Cell; Adenine; COVID-19; Piperidines; Antiviral Agents; COVID-19 Drug Treatment; SARS-CoV-2; Adenosine Monophosphate; Alanine; Immunocompromised Host; Maintenance Chemotherapy
PubMed: 38943241
DOI: 10.12659/AJCR.941165 -
Journal of Biomedical Science Jun 2024Enterovirus 71 (EV-A71) causes Hand, Foot and Mouth Disease (HFMD) in children and has been associated with neurological complications. The molecular mechanisms involved...
BACKGROUND
Enterovirus 71 (EV-A71) causes Hand, Foot and Mouth Disease (HFMD) in children and has been associated with neurological complications. The molecular mechanisms involved in EV-A71 pathogenesis have remained elusive.
METHODS
A siRNA screen in EV-A71 infected-motor neurons was performed targeting 112 genes involved in intracellular membrane trafficking, followed by validation of the top four hits using deconvoluted siRNA. Downstream approaches including viral entry by-pass, intracellular viral genome quantification by qPCR, Western blot analyses, and Luciferase reporter assays allowed determine the stage of the infection cycle the top candidate, RAB11A was involved in. Proximity ligation assay, co-immunoprecipitation and multiplex confocal imaging were employed to study interactions between viral components and RAB11A. Dominant negative and constitutively active RAB11A constructs were used to determine the importance of the protein's GTPase activity during EV-A71 infection. Mass spectrometry and protein interaction analyses were employed for the identification of RAB11A's host interacting partners during infection.
RESULTS
Small GTPase RAB11A was identified as a novel pro-viral host factor during EV-A71 infection. RAB11A and RAB11B isoforms were interchangeably exploited by strains from major EV-A71 genogroups and by Coxsackievirus A16, another major causative agent of HFMD. We showed that RAB11A was not involved in viral entry, IRES-mediated protein translation, viral genome replication, and virus exit. RAB11A co-localized with replication organelles where it interacted with structural and non-structural viral components. Over-expression of dominant negative (S25N; GDP-bound) and constitutively active (Q70L; GTP-bound) RAB11A mutants had no effect on EV-A71 infection outcome, ruling out RAB11A's involvement in intracellular trafficking of viral or host components. Instead, decreased ratio of intracellular mature viral particles to viral RNA copies and increased VP0:VP2 ratio in siRAB11-treated cells supported a role in provirion maturation hallmarked by VP0 cleavage into VP2 and VP4. Finally, chaperones, not trafficking and transporter proteins, were found to be RAB11A's top interacting partners during EV-A71 infection. Among which, CCT8 subunit from the chaperone complex TRiC/CCT was further validated and shown to interact with viral structural proteins specifically, representing yet another novel pro-viral host factor during EV-A71 infection.
CONCLUSIONS
This study describes a novel, unconventional role for RAB11A during viral infection where it participates in the complex process of virus morphogenesis by recruiting essential chaperone proteins.
Topics: rab GTP-Binding Proteins; Enterovirus A, Human; Humans; Molecular Chaperones; Virus Replication
PubMed: 38943128
DOI: 10.1186/s12929-024-01053-2 -
Clinical Proteomics Jun 2024The development of breast cancer has been mainly reported in women who have reached the post-menopausal stage; therefore, it is the primary factor responsible for death... (Review)
Review
The development of breast cancer has been mainly reported in women who have reached the post-menopausal stage; therefore, it is the primary factor responsible for death amongst postmenopausal women. However, if treated on time it has shown a survival rate of 20 years in about two-thirds of women. Cases of breast cancer have also been reported in younger women and the leading cause in them is their lifestyle pattern or they may be carriers of high penetrance mutated genes. Premenopausal women who have breast cancer have been diagnosed with aggressive build-up of tumors and are therefore at more risk of loss of life. Mammography is an effective way to test for breast cancer in women after menopause but is not so effective for premenopausal women or younger females. Imaging techniques like contrast-enhanced MRI can up to some extent indicate the presence of a tumor but it cannot adequately differentiate between benign and malignant tumors. Although the 'omics' strategies continuing for the last 20 years have been helpful at the molecular level in enabling the characteristics and proper understanding of such tumors over long-term longitudinal monitoring. Classification, diagnosis, and prediction of the outcomes have been made through tissue and serum biomarkers but these also fail to diagnose the disease at an early stage. Considerably there is no adequate detection technique present globally that can help early detection and provide adequate specificity, safety, sensitivity, and convenience for the younger and premenopausal women, thereby it becomes necessary to take early measures and build efficient tools and techniques for the same. Through biopsies of nipple aspirate fluid (NAF) biomarker profiling can be performed. It is a naturally secreted fluid from the cells of epithelium found in the breast. Nowadays, home-based liquid biopsy collection kits are also available through which a routine check on breast health can be performed with the help of NAF. Herein, we will review the biomarker screening liquid biopsy, and the new emerging technologies for the examination of cancer at an early stage, especially in premenopausal women.
PubMed: 38943056
DOI: 10.1186/s12014-024-09495-4 -
International Journal of Emergency... Jun 2024Mesenteric arterial thrombosis is an extremely rare thrombotic event, especially during pregnancy, that can cause rapid fatal consequences unless the patient receives...
BACKGROUND
Mesenteric arterial thrombosis is an extremely rare thrombotic event, especially during pregnancy, that can cause rapid fatal consequences unless the patient receives early definitive treatment.
CASE PRESENTATION
We report the case of a 34-year-old female presenting in her seventh week of gestation with severe abdominal pain who was promptly diagnosed with mesenteric artery occlusion amidst incipient miscarriage. The patient underwent a successful mesentery artery embolectomy, recovered and was later diagnosed with elevated factor VIII activity.
CONCLUSION
The diagnosis of mesenteric ischemia should be considered in pregnant women presenting with severe abdominal pain and any prior predisposing factors. Our case highlights the pivotal role of the emergency physician in maintaining a high index of suspicion coupled with timely and determined action. The prognosis of this high mortality condition depends on prompt diagnosis, early definite management and successful multidisciplinary cooperation.
PubMed: 38943051
DOI: 10.1186/s12245-024-00661-x