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Lysyl oxidase (LOX) is upregulated in highly stiff aggressive tumors, correlating with metastasis, resistance, and worse survival; however, there are currently no potent, safe, and orally bioavailable small molecule LOX inhibitors to treat these aggressive desmoplastic solid tumors in clinics. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by robust screening of drug-like molecules combined with cell/recombinant protein-based assays. Structure-activity relationship analysis identified a potent lead compound (LXG6403) with ∼3.5-fold specificity for LOX compared to LOXL2 while not inhibiting LOXL1 with a competitive, time- and concentration-dependent irreversible mode of inhibition. LXG6403 shows favorable pharmacokinetic properties, globally changes ECM/collagen architecture, and reduces tumor stiffness. This leads to better drug penetration, inhibits FAK signaling, and induces ROS/DNA damage, G1 arrest, and apoptosis in chemoresistant triple-negative breast cancer (TNBC) cell lines, PDX organoids, and in vivo. Overall, our potent and tolerable bi-thiazole LOX inhibitor enhances chemoresponse in TNBC, the deadliest breast cancer subtype., Competing Interests: Declaration of interests O. Sahin is the co-founder and manager of OncoCube Therapeutics LLC, founder and president of LoxiGen, and member of scientific advisory board of A2A Pharmaceuticals Inc. M.C., O. Saatci, A.-H.R., C.B., C.M., and O.S. are inventors on patent US 11,712,437., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor β receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce β-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3 + regulatory T cells and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4 -/- were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sevoflurane, a common pediatric anesthetic, has been linked to neurodegeneration, raising safety concerns. This study explored N-acetylcysteine's protective potential against sevoflurane-induced neurotoxicity in rat hippocampi. Four groups were examined: Control: Received 6 hours of 3 l/min gas (air and 30 % O2) and intraperitoneal saline. NAC: Received 6 hours of 3 l/min gas and 150 mg/kg NAC intraperitoneally. Sev: Exposed to 6 hours of 3 l/min gas and 3 % sevoflurane. Sev+NAC: Received 6 hours of 3 l/min gas, 3 % sevoflurane, and 150 mg/kg NAC. Protein levels of NRF-2, NLRP3, IL-1β, caspase-1, Beclin 1, p62, LC3A, and apoptosis markers were assessed. Sevoflurane and NAC alone reduced autophagy, while Sev+NAC group maintained autophagy levels. Sev group had elevated NRF-2, NLRP3, pNRF2, Caspase-1, and IL-1β, which were reduced in Sev+NAC. Apoptosis was higher in Sev, but Sev+NAC showed reduced apoptosis compared to the control. In summary, sevoflurane induced neurotoxicity in developing hippocampus, which was mitigated by N-acetylcysteine administration., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Esra adiyeke reports financial support was provided by University of Health Sciences. If there are other authors, they 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 © 2024 Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is one of the deadliest forms of cancer with limited therapy options. Overexpression of the heat shock protein 70 (HSP70) is a hallmark of cancer that is strongly associated with aggressive disease and worse clinical outcomes. However, the underlying mechanisms by which HSP70 allows tumor cells to thrive under conditions of continuous stress have not been fully described. Here, we report that PDAC has the highest expression of HSP70 relative to normal tissue across all cancers analyzed. Furthermore, HSP70 expression is associated with tumor grade and is further enhanced in metastatic PDAC. We show that genetic or therapeutic ablation of HSP70 alters mitochondrial subcellular localization, impairs mitochondrial dynamics, and promotes mitochondrial swelling to induce apoptosis. Mechanistically, we find that targeting HSP70 suppresses the PTEN-induced kinase 1 (PINK1) mediated phosphorylation of dynamin-related protein 1 (DRP1). Treatment with the HSP70 inhibitor AP-4-139B was efficacious as a single agent in primary and metastatic mouse models of PDAC. In addition, we demonstrate that HSP70 inhibition promotes the AMP-activated protein kinase (AMPK) mediated phosphorylation of Beclin-1, a key regulator of autophagic flux. Accordingly, we find that the autophagy inhibitor hydroxychloroquine (HCQ) enhances the ability of AP-4-139B to mediate anti-tumor activity in vivo. Collectively, our results suggest that HSP70 is a multi-functional driver of tumorigenesis that orchestrates mitochondrial dynamics and autophagy. Moreover, these findings support the rationale for concurrent inhibition of HSP70 and autophagy as a novel therapeutic approach for HSP70-driven PDAC., (© 2024. The Author(s).)

Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca 2+ channel. This causes cytosolic Ca 2+ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe 2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death which are reversed upon chelating Ca 2+ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca 2+ /ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca 2+ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer., (© 2024. The Author(s).)

Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells, T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pretreatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of antitumor CD8+ T cells in posttreatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1-resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression whereas nonresponders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacologic inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the antitumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance., Significance: Loss of induction of immunogenic cell death in response to T-DM1 leads to resistance that can be overcome by targeting TACC3, providing an attractive strategy to improve the efficacy of T-DM1., (©2024 The Authors; Published by the American Association for Cancer Research.)

Polyploid giant cancer cells (PGCC) are frequently detected in tumors and are increasingly recognized for their roles in chromosomal instability and associated genome evolution that leads to cancer recurrence. We previously reported that therapy stress promotes polyploidy, and that acid ceramidase plays a role in depolyploidization. In this study, we used an RNA-seq approach to gain a better understanding of the underlying transcriptomic changes that occur as cancer cells progress through polyploidization and depolyploidization. Our results revealed gene signatures that are associated with disease-free and/or overall survival in several cancers and identified the cell cycle inhibitor CDKN1A/p21 as the major hub in PGCC and early progeny. Increased expression of p21 in PGCC was limited to the cytoplasm. We previously demonstrated that the sphingolipid enzyme acid ceramidase is dispensable for polyploidization upon therapy stress but plays a crucial role in depolyploidization. The current study demonstrates that treatment of cells with ceramide is not sufficient for p53-independent induction of p21 and that knockdown of acid ceramidase, which hydrolyzes ceramide, does not interfere with upregulation of p21. In contrast, blocking the expression of p21 with UC2288 prevented the induction of acid ceramidase and inhibited both the formation of PGCC from parental cells as well as the generation of progeny from PGCC. Taken together, our data suggest that p21 functions upstream of acid ceramidase and plays an important role in polyploidization and depolyploidization., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

TACC3 is the most oncogenic member of the transforming acidic coiled-coil domain-containing protein (TACC) family. It is one of the major recruitment factors of distinct multi-protein complexes. TACC3 is localized to spindles, centrosomes, and nucleus, and regulates key oncogenic processes, including cell proliferation, migration, invasion, and stemness. Recently, TACC3 inhibition has been identified as a vulnerability in highly aggressive cancers, such as cancers with centrosome amplification (CA). TACC3 has spatiotemporal functions throughout the cell cycle; therefore, targeting TACC3 causes cell death in mitosis and interphase in cancer cells with CA. In the clinics, TACC3 is highly expressed and associated with worse survival in multiple cancers. Furthermore, TACC3 is a part of one of the most common fusions of FGFR, FGFR3-TACC3 and is important for the oncogenicity of the fusion. A detailed understanding of the regulation of TACC3 expression, its key partners, and molecular functions in cancer cells is vital for uncovering the most vulnerable tumors and maximizing the therapeutic potential of targeting this highly oncogenic protein. In this review, we summarize the established and emerging interactors and spatiotemporal functions of TACC3 in cancer cells, discuss the potential of TACC3 as a biomarker in cancer, and therapeutic potential of its inhibition.

Resistance to endocrine therapy and CDK4/6 inhibitors, the standard of care (SOC) in estrogen receptor-positive (ER+) breast cancer, greatly reduces patient survival. Therefore, elucidating the mechanisms of sensitivity and resistance to SOC therapy and identifying actionable targets are urgently needed. Here, we show that SOC therapy causes DNA damage and toxic PARP1 trapping upon generation of a functional BRCAness (i.e., BRCA1/2 deficiency) phenotype, leading to increased histone parylation and reduced H3K9 acetylation, resulting in transcriptional blockage and cell death. Mechanistically, SOC therapy downregulates phosphodiesterase 4D (PDE4D), a novel ER target gene in a feedforward loop with ER, resulting in increased cAMP, PKA-dependent phosphorylation of mitochondrial COXIV-I, ROS generation and DNA damage. However, during SOC resistance, an ER-to-EGFR switch induces PDE4D overexpression via c-Jun. Notably, combining SOC with inhibitors of PDE4D, EGFR or PARP1 overcomes SOC resistance irrespective of the BRCA1/2 status, providing actionable targets for restoring SOC efficacy., (© 2023. The Author(s).)

Centrosome amplification (CA) is a hallmark of cancer that is strongly associated with highly aggressive disease and worse clinical outcome. Clustering extra centrosomes is a major coping mechanism required for faithful mitosis of cancer cells with CA that would otherwise undergo mitotic catastrophe and cell death. However, its underlying molecular mechanisms have not been fully described. Furthermore, little is known about the processes and players triggering aggressiveness of cells with CA beyond mitosis. Here, we identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) to be overexpressed in tumors with CA, and its high expression is associated with dramatically worse clinical outcome. We demonstrated, for the first time, that TACC3 forms distinct functional interactomes regulating different processes in mitosis and interphase to ensure proliferation and survival of cancer cells with CA. Mitotic TACC3 interacts with the Kinesin Family Member C1 (KIFC1) to cluster extra centrosomes for mitotic progression, and inhibition of this interaction leads to mitotic cell death via multipolar spindle formation. Interphase TACC3 interacts with the nucleosome remodeling and deacetylase (NuRD) complex (HDAC2 and MBD2) in nucleus to inhibit the expression of key tumor suppressors (e.g., p21, p16 and APAF1) driving G1/S progression, and its inhibition blocks these interactions and causes p53-independent G1 arrest and apoptosis. Notably, inducing CA by p53 loss/mutation increases the expression of TACC3 and KIFC1 via FOXM1 and renders cancer cells highly sensitive to TACC3 inhibition. Targeting TACC3 by guide RNAs or small molecule inhibitors strongly inhibits growth of organoids and breast cancer cell line- and patient-derived xenografts with CA by induction of multipolar spindles, mitotic and G1 arrest. Altogether, our results show that TACC3 is a multifunctional driver of highly aggressive breast tumors with CA and that targeting TACC3 is a promising approach to tackle this disease., (© 2023. The Author(s).)

Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α' 2 is associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-α' 2 to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis is highly associated with human metastatic melanoma tissues and patient-derived xenografts. Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and pharmacologic tools prevents lung colonization/metastasis of various murine cancer cell lines using WT and C3a-receptor1 knockout (C3aR1 -/- ) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.

Purpose: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that is frequently treated with chemotherapy. However, many patients exhibit either de novo chemoresistance or ultimately develop resistance to chemotherapy, leading to significantly high mortality rates. Therefore, increasing the efficacy of chemotherapy has potential to improve patient outcomes., Methods: Here, we performed whole transcriptome sequencing (both RNA and small RNA-sequencing), coupled with network simulations and patient survival data analyses to build a novel miRNA-mRNA interaction network governing chemoresistance in TNBC. We performed cell proliferation assay, Western blotting, RNAi/miRNA mimic experiments, FN coating, 3D cultures, and ChIP assays to validate the interactions in the network, and their functional roles in chemoresistance. We developed xenograft models to test the therapeutic potential of the identified key miRNA/proteins in potentiating chemoresponse in vivo. We also analyzed several patient datasets to evaluate the clinical relevance of our findings., Results: We identified fibronectin (FN1) as a central chemoresistance driver gene. Overexpressing miR-326 reversed FN1-driven chemoresistance by targeting FN1 receptor, ITGA5. miR-326 was downregulated by increased hypoxia/HIF1A and ECM stiffness in chemoresistant tumors, leading to upregulation of ITGA5 and activation of the downstream FAK/Src signaling pathways. Overexpression of miR-326 or inhibition of ITGA5 overcame FN1-driven chemotherapy resistance in vitro by inhibiting FAK/Src pathway and potentiated the efficacy of chemotherapy in vivo. Importantly, lower expression of miR-326 or higher levels of predicted miR-326 target genes was significantly associated with worse overall survival in chemotherapy-treated TNBC patients., Conclusion: FN1 is central in chemoresistance. In chemoresistant tumors, hypoxia and resulting ECM stiffness repress the expression of the tumor suppressor miRNA, miR-326. Hence, re-expression of miR-326 or inhibition of its target ITGA5 reverses FN1-driven chemoresistance making them attractive therapeutic approaches to enhance chemotherapy response in TNBCs., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Estrogen receptor-positive (ER +) breast cancer accounts for approximately 75% of all breast cancers. Endocrine therapies, including selective ER modulators (SERMs), aromatase inhibitors (AIs), and selective ER down-regulators (SERDs) provide substantial clinical benefit by reducing the risk of disease recurrence and mortality. However, resistance to endocrine therapies represents a major challenge, limiting the success of ER + breast cancer treatment. Mechanisms of endocrine resistance involve alterations in ER signaling via modulation of ER (e.g., ER downregulation, ESR1 mutations or fusions); alterations in ER coactivators/corepressors, transcription factors (TFs), nuclear receptors and epigenetic modulators; regulation of signaling pathways; modulation of cell cycle regulators; stress signaling; and alterations in tumor microenvironment, nutrient stress, and metabolic regulation. Current therapeutic strategies to improve outcome of endocrine-resistant patients in clinics include inhibitors against mechanistic target of rapamycin (mTOR), cyclin-dependent kinase (CDK) 4/6, and the phosphoinositide 3-kinase (PI3K) subunit, p110α. Preclinical studies reveal novel therapeutic targets, some of which are currently tested in clinical trials as single agents or in combination with endocrine therapies, such as ER partial agonists, ER proteolysis targeting chimeras (PROTACs), next-generation SERDs, AKT inhibitors, epidermal growth factor receptor 1 and 2 (EGFR/HER2) dual inhibitors, HER2 targeting antibody-drug conjugates (ADCs) and histone deacetylase (HDAC) inhibitors. In this review, we summarize the established and emerging mechanisms of endocrine resistance, alterations during metastatic recurrence, and discuss the approved therapies and ongoing clinical trials testing the combination of novel targeted therapies with endocrine therapy in endocrine-resistant ER + breast cancer patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives/hypothesis: Prognosis of post-traumatic olfactory dysfunction is poor, with medical treatment options showing limited success rates. Olfactory training (OT) has been introduced as a potential therapeutic option in olfactory dysfunction. We aimed to identify the imaging features that would predict a better response to OT and create an imaging-based prognostic scale., Methods: We retrospectively reviewed 52 patients that underwent OT at our center for post-traumatic olfactory dysfunction. Olfactory functions at the time of initial presentation and at completion of OT were evaluated using Sniffin' Sticks test and threshold discrimination identification (TDI) scores were calculated. Patients were divided into responders (ROT group: 16 cases) and non-responders (n-ROT group: 36 cases) to OT based on TDI score change (cut-off 5.5 point). Morphological measurements of olfactory fossa, olfactory bulb volume and signal abnormalities, olfactory nerve filia integrity, siderosis, encephalomalacic changes in olfactory cortex, and other cortical regions were reviewed., Results: There was no significant difference between the two groups in terms of age, gender distribution, olfactory dysfunction duration, head-trauma severity, and initial TDI scores. A model incorporating five variables: cribriform plate fracture, olfactory fossa depth (cut-off: 4.9 mm), olfactory bulb encephalomalacia, olfactory bulb volume (cut-off: 27.1 mm 3 ), and siderosis was developed. This model had an area under the curve (AUC) of 0.950, and a cut-off value of 1 had 76.5% sensitivity and 97.1% specificity in prediction of response to OT., Conclusions: We developed an imaging-based scoring system with good specificity that can be used as an adjunctive tool for patient counseling, and optimal selection of management options., Level of Evidence: 4 Laryngoscope, 131:E2243-E2250, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Extracellular adenosine in tumors can suppress immune responses and promote tumor growth. Adenosine deaminase 2 (ADA2) converts adenosine into inosine. The role of ADA2 in cancer and whether it can target adenosine for cancer therapy has not been investigated. Here we show that increased ADA2 expression is associated with increased patient survival and enrichment of adaptive immune response pathways in several solid tumor types. Several ADA2 variants were created to improve catalytic efficiency, and PEGylation was used to prolong systemic exposure. In mice, PEGylated ADA2 (PEGADA2) inhibited tumor growth by targeting adenosine in an enzyme activity-dependent manner and thereby modulating immune responses. These findings introduce endogenous ADA2 expression as a prognostic factor and PEGADA2 as a novel immunotherapy for cancer. SIGNIFICANCE: This study identifies ADA2 as a prognostic factor associated with prolonged cancer patient survival and introduces the potential of enzymatic removal of adenosine with engineered ADA2 for cancer immunotherapy., (©2021 American Association for Cancer Research.)

Objective: This study aimed to investigate the differences in olfactory cleft (OC) morphology in coronavirus disease 2019 (COVID-19) anosmia compared to control subjects and postviral anosmia related to infection other than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Study Design: Prospective., Setting: This study comprises 91 cases, including 24 cases with anosmia due to SARS-CoV-2, 38 patients with olfactory dysfunction (OD) due to viral infection other than SARS-CoV-2, and a control group of 29 normosmic cases., Methods: All cases had paranasal sinus computed tomography (CT), and cases with OD had magnetic resonance imaging (MRI) dedicated to the olfactory nerve. The OC width and volumes were measured on CT, and T2-weighted signal intensity (SI), olfactory bulb volumes, and olfactory sulcus depths were assessed on MRI., Results: This study showed 3 major findings: the right and left OC widths were significantly wider in anosmic patients due to SARS-CoV-2 (group 1) or OD due to non-SARS-CoV-2 viral infection (group 2) when compared to healthy controls. OC volumes were significantly higher in group 1 or 2 than in healthy controls, and T2 SI of OC area was higher in groups 1 and 2 than in healthy controls. There was no significant difference in olfactory bulb volumes and olfactory sulcus depths on MRI among groups 1 and 2., Conclusion: In this study, patients with COVID-19 anosmia had higher OC widths and volumes compared to control subjects. In addition, there was higher T2 SI of the olfactory bulb in COVID-19 anosmia compared to control subjects, suggesting underlying inflammatory changes. There was a significant negative correlation between these morphological findings and threshold discrimination identification scores., Level of Evidence: Level 4.

Objective: This study aimed to define the clinical course of anosmia in relation to other clinical symptoms., Methods: 135 patients with COVID-19 were reached by phone and subsequently included in the study. Olfactory functions were evaluated using a questionnaire for assessment of self-reported olfactory function. Patients were divided into four subgroups according to the presence of olfactory symptoms and temporal relationship with the other symptoms: group1 had only olfactory complaints (isolated, sudden-onset loss of smell); group2 had sudden-onset loss of smell, followed by COVID-19 related complaints; group3 initially had COVID-19 related complaints, then gradually developed olfactory complaints; and group4 had no olfactory complaints., Results: In total, 59.3% of the patients interviewed had olfactory complaints during the disease course. The olfactory dysfunction severity during COVID-19 infection was significantly higher in group1 compared to groups 2 and 3. In groups1-3, the odor scores after recovery from COVID-19 disease were significantly lower compared to the status prior to disease onset. The residual olfactory dysfunction was similar between groups1 and 2, but was more evident than group3. Mean duration for loss of smell was 7.8 ± 3.1 (2-15) days. Duration of loss of smell was longer in groups1 and 2 than in group3. Odor scores completely returned back to the pre-disease values in 41 (51.2%) patients with olfactory dysfunction. Rate of complete olfactory dysfunction recovery was higher in group3 compared to groups1 and 2., Conclusion: In isolated anosmia cases, anosmia is more severe, and complete recovery rates are lower compared to the patients who have other clinical symptoms., Level of Evidence: Level 4.

Background and Purpose: There is limited literature consisting of case reports or series on olfactory bulb imaging in COVID-19 olfactory dysfunction. An imaging study with objective clinical correlation is needed in COVID-19 anosmia in order to better understand underlying pathogenesis., Material and Methods: We evaluated 23 patients with persistent COVID-19 olfactory dysfunction. Patients included in this study had a minimum 1-month duration between onset of olfactory dysfunction and evaluation. Olfactory functions were evaluated with Sniffin' Sticks Test. Paranasal sinus CTs and MRI dedicated to olfactory nerves were acquired. On MRI, quantitative measurements of olfactory bulb volumes and olfactory sulcus depth and qualitative assessment of olfactory bulb morphology, signal intensity, and olfactory nerve filia architecture were performed., Results: All patients were anosmic at the time of imaging based on olfactory test results. On CT, Olfactory cleft opacification was seen in 73.9% of cases with a mid and posterior segment dominance. 43.5% of cases had below normal olfactory bulb volumes and 60.9% of cases had shallow olfactory sulci. Of all, 54.2% of cases had changes in normal inverted J shape of the bulb. 91.3% of cases had abnormality in olfactory bulb signal intensity in the forms of diffusely increased signal intensity, scattered hyperintense foci or microhemorrhages. Evident clumping of olfactory filia was seen in 34.8% of cases and thinning with scarcity of filia in 17.4%. Primary olfactory cortical signal abnormality was seen in 21.7% of cases., Conclusion: Our findings indicate olfactory cleft and olfactory bulb abnormalities are seen in COVID-19 anosmia. There was a relatively high percentage of olfactory bulb degeneration. Further longitudinal imaging studies could shed light on the mechanism of olfactory neuronal pathway injury in COVID-19 anosmia., Competing Interests: Conflicts of Interest None to declare., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Epithelial-to-mesenchymal transition (EMT) enhances motility, stemness, chemoresistance and metastasis. Little is known about how various pathways coordinate to elicit EMT's different functional aspects in non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) has been previously correlated with EMT transcription factor ZEB1 in NSCLC and imparts resistance against anti-folate chemotherapy. In this study, we establish a functional correlation between TS, EMT, chemotherapy and metastasis and propose a network for TS mediated EMT., Methods: Published datasets were analysed to evaluate the significance of TS in NSCLC fitness and prognosis. Promoter reporter assay was used to sort NSCLC cell lines in TS HIGH and TS LOW . Metastasis was assayed in a syngeneic mouse model., Results: TS levels were prognostic and predicted chemotherapy response. Cell lines with higher TS promoter activity were more mesenchymal-like. RNA-seq identified EMT as one of the most differentially regulated pathways in connection to TS expression. EMT transcription factors HOXC6 and HMGA2 were identified as upstream regulator of TS, and AXL, SPARC and FOSL1 as downstream effectors. TS knock-down reduced the metastatic colonisation in vivo., Conclusion: These results establish TS as a theranostic NSCLC marker integrating survival, chemo-resistance and EMT, and identifies a regulatory network that could be targeted in EMT-driven NSCLC.

Background: Multiple Sclerosis (MS) is a neuroinflammatory, neurodegenerative, demyelinating disease that causes cognitive, olfactory, and other neurological dysfunctions. Radiologically Isolated Syndrome (RIS), in which only radiological findings are monitored, is accepted as the preclinical stage of demyelinating disease and is considered an important period for disease pathology. Therefore, in this study, we aimed to evaluate the olfactory and cognitive functions and their clinical correlation in RIS and Relapsing-Remitting MS (RRMS) patients and a healthy control group., Methods: Our study included 10 RRMS patients, 10 RIS patients, and 10 healthy controls. We conducted an olfactor evaluation via the "Sniffin' Sticks" test. The subjects underwent a neuropsychometric test battery to evaluate cognitive functions, including memory, visuospatial, and executive functions. Depression was evaluated using the Beck depression scale. Fatigue and daily life activity were evaluated using the Fatigue Severity Scale (FSS) and the 36-Item Short Form Survey (SF-36), respectively. Disability assessment was done with the Expanded Disability Status Scale (EDSS)., Results: RRMS and RIS patients' olfactory test scores were significantly different from those in the control group (p < 0.05). There was a significant difference between the odor threshold scores of patients in the RRMS and RIS groups. There was a significant correlation between memory-oriented cognitive tests and olfactory tests in the RRMS and RIS groups., Conclusion: Olfactory dysfunction can be seen in RIS patients, like in RRMS patients. Cognitive and olfactory dysfunction may be together a sign of degeneration in demyelinating diseases., (© 2021 S. Karger AG, Basel.)

Background: An association between IL-6 levels and cytokine storm syndrome in COVID-19 patients has been suggested. Cases with higher IL-6 levels have more rapid progression and a higher complication rate. On the other hand, COVID-19 cases with anosmia have a milder course of the disease., Objective: We aimed to investigate whether there is a relationship between serum IL-6 levels and presence of anosmia in COVID-19 patients., Methods: Patients with a confirmed diagnosis of COVID-19 based on laboratory (PCR) were stratified into two groups based on presence of olfactory dysfunction (OD). In all cases with and without anosmia; psychophysical test (Sniffin' Sticks test) and a survey on olfactory symptoms were obtained. Threshold (t) - discrimination (d) - identification (i), and total (TDI) scores reflecting olfactory function were calculated. Clinical symptoms, serum IL-6 levels, other laboratory parameters, and chest computed tomography (CT) findings were recorded., Results: A total of 59 patients were included, comprising 23 patients with anosmia and 36 patients without OD based on TDI scores. Patients with anosmia (41.39 ± 15.04) were significantly younger compared to cases without anosmia (52.19 ± 18.50). There was no significant difference between the groups in terms of comorbidities, smoking history, and symptoms including nasal congestion and rhinorrhea. Although serum IL-6 levels of all patients were above normal values (7 pg/mL), patients with anosmia had significantly lower serum IL-6 levels (16.72 ± 14.28 pg/mL) compared to patients without OD (60.95 ± 89.33 pg/mL) (p = 0.026)., Conclusion: Patients with COVID-19 related anosmia tend to have significantly lower serum levels of IL-6 compared to patients without OD, and the lower IL-6 levels is related to milder course of the disease. With the effect of low cytokine storm and IL-6 level, it may be said that anosmic cases have a milder disease in COVID-19., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Oxygen therapy provided via high-flow nasal cannula (HFNC) improves gas exchange lung compliance and results in increased lung expiratory volumes. Previous data indicate that hyperbaric and humid states improve the olfactory thresholds compared to hypobaric and dry conditions. This prospective, observational study aimed to determine the impact of oxygen delivery through HFNC on olfactory function in subjects admitted to the ICU for acute respiratory failure (ARF)., Methods: 30 subjects who were admitted to the ICU for ARF underwent an olfactory sniff test before and after oxygen therapy with HFNC. Baseline olfactory function of subjects with ARF was also compared against 30 healthy controls. Odor threshold (OT), odor discrimination (OD), odor identification (OI) and global olfactory score (TDI) were recorded for all subjects., Results: The OT, OD, OI, and TDI scores were significantly higher in the control group compared to the baseline scores of the subjects with ARF ( P < .001 for all comparisons). In subjects with ARF, administration of oxygen with HFNC led to significant improvements in OT ( P = .02), OD ( P = .001), OI ( P = .02), and TDI (25.5 ± 3.8 vs 27.1 ± 3.5, P < .001) scores., Conclusions: Our results indicate that subjects with ARF had relative olfactory dysfunction compared to healthy controls. These results also suggest that implementation of HFNC to relieve hypoxemia in subjects presenting with ARF can lead to a significant improvement in olfactory function., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2020 by Daedalus Enterprises.)

Introduction: Although previous evidence suggest that paracetamol decreases psychological reactivity in healthy subjects, there is still no confirmed correlation between the empathy scores and brain activity in healthy and headache patients after paracetamol treatment., Material and Methods: The study group included 16 patients with tension-type headache, and 12 healthy age-and sex-matched controls. After a detailed neurological examination Positive and Negative Affect Schedule (PANAS) and Empathy for Pain Scale (EPS) were applied to all subjects. Next, 1000 mg paracetamol tablet was administered orally, after administration of paracetamol, EPS were repeated, and fMRI was performed to all subjects., Results: We have revealed increased empathy scores in the headache group after the paracetamol treatment which were associated with significant alterations in brain regions which play a critical role in the processing of empathy., Discussion: The observed neuroimaging and clinical difference between healthy and headache subjects could be related to the fact that pain perception in healthy subjects might differ in some aspects from the mechanisms of empathy in headache-experienced patients., Conclusion: To the best of our knowledge, this is the first study that evaluated the paracetamol treatment and neural networks' correlation with pain empathy in healthy and headache individuals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: In an effort to make olfactory training (OT) simpler, we designed an 'olfactory training ball' (OTB)-a baseball-size ball with four odor-containing tubes to use in OT. The study aimed to investigate the effects of OT with the OTB in comparison to classical OT with special attention to the effects of adherence to OT on olfactory outcome measures., Methods: Sixty patients with olfactory dysfunction following infections of the upper respiratory tract received OT either with classical methods-sniffing odors from jars (COT)-or the OTB for 12 weeks. Patients exposed themselves to the odors for 5 min twice daily. Adherence was measured with a modified version of the Morisky scale. Before and after OT, all patients underwent extensive olfactory testing using the Sniffin' Sticks test., Results: At the end of the 12 weeks of OT, TDI composite score (22.1 ± 2.8 vs. 19.9 ± 4.7, P = 0.044) and odor discrimination subtest scores (9.1 ± 1.8 vs.7.6 ± 2.5, P = 0.013) of the OTB group were significantly higher than that of the COT group. Adequate adherence to OT was significantly higher in patients receiving OTB when compared to those receiving COT (63% vs. 30%, P = 0.019)., Conclusion: The present study shows that a novel OT device, the OTB, provides better adherence to the training process compared to COT. Moreover, findings of the current study show that better adherence to the OT process is associated with better olfactory outcomes.

TACC3, a transforming acidic coiled-coil (TACC) family member, is frequently upregulated in a broad spectrum of cancers, including breast cancer. It plays critical roles in protecting microtubule stability and centrosome integrity that is often dysregulated in cancers; therefore, making TACC3 a highly attractive therapeutic target. Here, we identified a new TACC3-targeting chemotype, BO-264, through the screening of in-house compound collection. Direct interaction between BO-264 and TACC3 was validated by using several biochemical methods, including drug affinity responsive target stability, cellular thermal shift assay, and isothermal titration calorimetry. BO-264 demonstrated superior antiproliferative activity to the two currently reported TACC3 inhibitors, especially in aggressive breast cancer subtypes, basal and HER2+, via spindle assembly checkpoint-dependent mitotic arrest, DNA damage, and apoptosis, while the cytotoxicity against normal breast cells was negligible. Furthermore, BO-264 significantly decreased centrosomal TACC3 during both mitosis and interphase. BO-264 displayed potent antiproliferative activity (∼90% have less than 1 μmol/L GI 50 value) in the NCI-60 cell line panel compromising of nine different cancer types. Noteworthy, BO-264 significantly inhibited the growth of cells harboring FGFR3-TACC3 fusion, an oncogenic driver in diverse malignancies. Importantly, its oral administration significantly impaired tumor growth in immunocompromised and immunocompetent breast and colon cancer mouse models, and increased survival without any major toxicity. Finally, TACC3 expression has been identified as strong independent prognostic factor in breast cancer and strongly prognostic in several different cancers. Overall, we identified a novel and highly potent TACC3 inhibitor as a novel potential anticancer agent, inducing spindle abnormalities and mitotic cell death., (©2020 American Association for Cancer Research.)

Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.

Background and Aim: Recent data have shown that olfactory dysfunction is strongly related to Alzheimer's Disease (AD) that is often preceded by olfactory deficits suggesting that olfactory dysfunction might represent an early indicator of future cognitive in prediabetes., Methods: We have applied to a group of normal (n=15), prediabetic (n=16) and type 2 diabetic outpatients (n=15) olfactory testing, 1.5-T MRI scanner and detailed cognitive evaluation including the standard Mini-Mental State Examination (MMSE) form, Short Blessed Test (SBT), Letter Fluency Test (LFT) and the category fluency test with animal, Fruit and Vegetable Naming (CFT)., Results: We have shown that Odour Threshold (OT), Discrimination (OD), and Identification (OI) scores and most cognitive test results were significantly different in the prediabetes and diabetes group compared to those in the control group. OD and OT were significantly different between the prediabetes and diabetes group, although the cognitive test results were only significantly different in the prediabetes and diabetes group compared to those in the control group. In evaluating the association between OI, OT, OD scores and specific cognitive tests, we have found, that impaired olfactory identification was the only parameter that correlated significantly with the SBT both in the pre-diabetes and diabetes group. Although spot glucose values were only correlated with OT, HbA1c levels were correlated with OT, OD, and OI, as well as results of the letter fluency test suggesting that HbA1c levels rather than the spot glucose values play a critical role in specific cognitive dysfunction., Conclusion: To the best of our knowledge, this is the first prospective study to demonstrate a strong association between olfactory dysfunction and specific memory impairment in a population with prediabetes and diabetes suggesting that impaired olfactory identification might play an important role as a specific predictor of memory decline., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cancer cells frequently boost nucleotide metabolism (NM) to support their increased proliferation, but the consequences of elevated NM on tumor de-differentiation are mostly unexplored. Here, we identified a role for thymidylate synthase (TS), a NM enzyme and established drug target, in cancer cell de-differentiation and investigated its clinical significance in breast cancer (BC). In vitro, TS knockdown increased the population of CD24 + differentiated cells, and attenuated migration and sphere-formation. RNA-seq profiling indicated repression of epithelial-to-mesenchymal transition (EMT) signature genes upon TS knockdown, and TS-deficient cells showed an increased ability to invade and metastasize in vivo, consistent with the occurrence of a partial EMT phenotype. Mechanistically, TS enzymatic activity was found essential for maintenance of the EMT/stem-like state by fueling a dihydropyrimidine dehydrogenase-dependent pyrimidine catabolism. In patient tissues, TS levels were found significantly higher in poorly differentiated and in triple negative BC, and strongly correlated with worse prognosis. The present study provides the rationale to study in-depth the role of NM at the crossroads of proliferation and differentiation, and depicts new avenues for the design of novel drug combinations for the treatment of BC.

Background: It is known that complementary and integrative medicine (CIM) methods are especially used by patients with chronic headaches. The aim of our study is to increase the knowledge on this topic, to provide objective data about use in Turkish headache patients., Methods: This study included 425 patients with headache. The survey form prepared was filled in under the supervision of a health professional. The questionnaire included 2 items, about CIM methods and finance., Results: Among the patients evaluated, 316 were female, and 109 were male. All of 52% answered yes to the question "did you ever use any CIM treatment method for headaches during your life?". The most frequently used methods were combined (herbal+one or more other method) (29.6%), herbal (9.4%) and cupping therapy (4.2%). Among the patients that used combined methods, 26.9% had spent 30-100TL (5-25euro), 20.6% had spent 100-300TL (25-70euro), 26.9% had spent 300-500TL (70-120euro) and the last two groups that formed 12.6% had spent 500-1000 (120-250euro) and >1000TL (>250euro)., Conclusion: Half of the patients that applied to outpatient clinic with headaches use one or more of these methods and make budgets in accordance with their income levels. Physicians should have sufficient knowledge and clinical opinions about the CIM methods used by headache patients., (Copyright © 2017 Polish Neurological Society. Published by Elsevier Sp. z o.o. All rights reserved.)