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Background: The dysregulation of gene expression is one of the key molecular features of colorectal cancer (CRC) development. This study aimed to investigate whether such dysregulation is reflected in rectal swab specimens of CRC patients and to evaluate its potential as a non-invasive approach for screening. Methods: We compared the expression level of 14 CRC-associated genes in tumor and adjacent non-tumor tissue of CRC patients and examined the correlation of their levels in tissue with paired rectal swab specimens. The level of these 14 genes in rectal swab specimens was compared among patients with CRC or polyp and control subjects, and the diagnostic potential of each dysregulated gene and the gene panel were evaluated. Results: The expression of CXCR2, SAA, COX1, PPARδ, PPARγ, Groγ, IL8, p21, c-myc, CD44 and CSF1 was significantly higher in CRC, and there was a significant correlation in the levels of most of them between the CRC and rectal swab specimens. In the training study, we showed that CD44, IL8, CXCR2 and c-myc levels were significantly higher in the rectal swab specimens of the CRC patients. Such result was confirmed in the validation study. A panel of these four genes was developed, and ROC analysis showed that this four-gene panel could identify CRC patients with an AUC value of 0.83 and identify overall polyp and precancerous adenoma patients with AUC values of 0.6522 and 0.7322, respectively. Finally, the predictive study showed that the four-gene panel demonstrated sensitivities of 63.6%, 76.9% and 88.9% in identifying overall polyp, precancerous adenoma and CRC patients, respectively, whereas the specificity for normal subjects was 72.2%. Conclusion: The expression of CRC-associated genes in rectal swab specimens reflects the dysregulation status in colorectal tissue, and the four-gene panel is a potential non-invasive biomarker for early precancerous adenoma and CRC screening. [ABSTRACT FROM AUTHOR]

Objective: To estimate the impact on clinical outcomes and healthcare resource use from recommending that patients with 1–2 low-risk adenomas (LRAs) return to routine fecal immunochemical test (FIT) screening instead of surveillance colonoscopy, from a Canadian provincial healthcare system perspective. Methods: The OncoSim-Colorectal microsimulation model simulated average-risk individuals eligible for FIT-based colorectal cancer (CRC) screening in Alberta, Canada. We simulated two surveillance strategies that applied to individuals with 1–2 LRAs (<10 mm) removed as part of the average risk CRC screening program: (a) Surveillance colonoscopy (status quo) and (b) return to FIT screening (new strategy); both at 5 years after polypectomy. A 75 ng/mL FIT positivity threshold was used in the base case. The simulations projected average annual CRC outcomes and healthcare resource use from 2023 to 2042. We conducted alternative scenarios and sensitivity analyses on key variables. Results: Returning to FIT screening (versus surveillance colonoscopy) after polypectomy was projected to have minimal impact on long-term CRC incidence and deaths (not statistically significant). There was a projected decrease of one (4%) major bleeding event and seven (5%) perforation events per year. There was a projected increase of 4800 (1.5%) FIT screens, decrease of 3900 (5.1%) colonoscopies, and a decrease of $3.4 million (1.2%) in total healthcare costs per year, on average. The annual colonoscopies averted and healthcare cost savings increased over time. Results were similar in the alternative scenarios and sensitivity analyses. Conclusions: Returning to FIT screening would have similar clinical outcomes as surveillance colonoscopy but could reduce colonoscopy demand and healthcare costs. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) stands as the third most common cancer globally and the second leading cause of cancer-related deaths, imposing a substantial health burden. Recent studies highlight a concerning rise in CRC rates among individuals below 50 years old, prompting the American Cancer Society (ACS) to recommend screening starting at age 45 for average-risk individuals. Dr. Aasma Shaukat's Keynote Conference stresses the urgent need for updated screening strategies to tackle suboptimal adherence rates and effectively manage the increasing burden of CRC. Lowering the adenoma detection screening age could aid in early identification of adenomas in asymptomatic younger patients, potentially reshaping disease epidemiology. Current screening options encompass stool-based tests like multitarget stool DNA (mtDNA) tests, fecal immunochemical testing (FIT), and imaging-based tests. Moreover, blood-based tests are emerging as promising tools for early CRC detection, utilizing innovative techniques and AI algorithms. Medicare mandates specific criteria for national coverage of blood-based tests. Ongoing clinical trials, such as Freenome, Guardant, and CancerSEEK, offer hope for further advancements in blood-based CRC screening. Despite breakthroughs, accessibility and affordability challenges persist. Adapting healthcare systems to accommodate changing CRC epidemiology is imperative. Lowering the screening age and integrating blood-based tests hold the potential to alleviate the CRC-related burden amidst evolving epidemiology. Colorectal cancer (CRC) currently ranks as the third most common cancer and the second leading cause of cancer-related deaths worldwide, posing a significant global health burden to the population. Recent studies have reported the emergence of a new clinical picture of the disease, with a notable increase in CRC rates in younger populations of <50 years of age. The American Cancer Society (ACS) now recommends CRC screening starting at age 45 for average-risk individuals. Dr. Aasma Shaukat's Keynote Conference highlights the critical need for updated screening strategies, with an emphasis on addressing the suboptimal adherence rates and the effective management of the growing burden of CRC. Lowering the adenoma detection screening age can facilitate early identification of adenomas in younger asymptomatic patients, altering the epidemiologic landscape. However, its implications may not be as profound unless a drastic shift in the age distribution of CRC is observed. Currently, various screening options are available in practice, including stool-based tests like multitarget stool DNA (mtDNA) tests, fecal immunochemical testing (FIT), and imaging-based tests. In addition to existing screening methods, blood-based tests are now emerging as promising tools for early CRC detection. These tests leverage innovative techniques along with AI and machine learning algorithms, aiding in tumor detection at a significantly earlier stage, which was not possible before. Medicare mandates specific criteria for national coverage of blood-based tests, including sensitivity ≥ 74%, specificity ≥ 90%, FDA approval, and inclusion in professional society guidelines. Ongoing clinical trials, such as Freenome, Guardant, and CancerSEEK, offer hope for further advancements in blood-based CRC screening. The development of multicancer early detection tests like GRAIL demonstrates a tremendous potential for detecting various solid tumors and hematologic malignancies. Despite these breakthroughs, the question of accessibility and affordability still stands. The ever-evolving landscape of CRC screening reflects the strength of the scientific field in light of an altered disease epidemiology. Lowering screening age along with the integration of blood-based tests with existing screening methods holds great potential in reducing the CRC-related burden. At the same time, it is increasingly important to address the challenges of adaptation of the healthcare system to this change in the epidemiologic paradigm. [ABSTRACT FROM AUTHOR]

Asymmetric transport of cargo across axonal branches is a field of active research. Mechanisms contributing to preferential cargo transport along specific branches in vivo in wild type neurons are poorly understood. We find that anterograde synaptic vesicles preferentially enter the synaptic branch or pause at the branch point in Caenorhabditis elegans Posterior Lateral Mechanosensory neurons. The synaptic vesicle anterograde kinesin motor UNC-104 /KIF1A regulates this vesicle behavior at the branch point. Reduced levels of functional UNC-104 cause vesicles to predominantly pause at the branch point and lose their preference for turning into the synaptic branch. SAM-4 /Myrlysin, which aids in recruitment/activation of UNC-104 on synaptic vesicles, regulates vesicle behavior at the branch point similar to UNC-104. Increasing the levels of UNC-104 increases the preference of vesicles to go straight toward the asynaptic end. This suggests that the neuron optimizes UNC-104 levels on the cargo surface to maximize the fraction of vesicles entering the branch and minimize the fraction going to the asynaptic end. [ABSTRACT FROM AUTHOR]

Background Post-colonoscopy colorectal cancers (PCCRCs) decrease the effect of colorectal cancer (CRC) screening programs. To enable PCCRC incidence reduction in the long-term, we classified PCCRCs diagnosed after colonoscopies performed in a fecal immunochemical test (FIT)-based screening program. Methods PCCRCs diagnosed after colonoscopies performed between 2014–2016 for a positive FIT in the Dutch CRC screening program were included. PCCRCs were categorized according to the World Endoscopy Organization consensus statement into (a) interval PCCRC (diagnosed before the recommended surveillance); (b) non-interval type A (diagnosed at the recommended surveillance interval); (c) non-interval type B (diagnosed after the recommended surveillance interval); or (d) non-interval type C (diagnosed after the intended recommended surveillance interval, with surveillance not implemented owing to co-morbidity). The most probable etiology was determined by root-cause analysis. Tumor stage distributions were compared between categories. Results 116362 colonoscopies were performed after a positive FIT with 9978 screen-detected CRCs. During follow-up, 432 PCCRCs were diagnosed. The 3-year PCCRC rate was 2.7%. PCCRCs were categorized as interval (53.5%), non-interval type A (14.6%), non-interval type B (30.6%), and non-interval type C (1.4%). The most common etiology for interval PCCRCs was possible missed lesion with adequate examination (73.6%); they were more often diagnosed at an advanced stage (stage III/IV; 53.2%) compared with non-interval type A (15.9%; P <0.001) and non-interval type B (40.9%; P =0.03) PCCRCs. Conclusions The 3-year PCCRC rate was low in this FIT-based CRC screening program. Approximately half of PCCRCs were interval PCCRCs. These were mostly caused by missed lesions and were diagnosed at a more advanced stage. This emphasizes the importance of high quality colonoscopy with optimal polyp detection. [ABSTRACT FROM AUTHOR]

Objectives: ACE2, known as a host receptor involved with SARS‐CoV‐2 infection, binds to viral spike proteins for host cell entry. However, details regarding its induction and function in oral mucosal cells remain unknown. Materials and Methods: We examined ACE2 expression and its induction by transfected mimic nucleotides and pro‐inflammatory cytokines in oral keratinocytes (RT7) and fibroblasts (GT1). Subsequently, the effects of viral spike S1 protein via ACE2 on CXCL10 expression induced by pro‐inflammatory cytokines in both cells were examined. Results: ACE2 was constitutively expressed in RT7 and GT1. Transfected Poly(I:C) and Poly(dA:dT) increased ACE2 expression in those cells, while knockdown of RIG‐I decreased ACE2 expression induced by those transfected ds nucleotides. IFN‐γ and TNF‐α enhanced transfected ds nucleotides‐induced ACE2 expression in RT7 but not GT1. S1 protein alone did not affect CXCL10 expression in either cell type, whereas it enhanced IFN‐β‐induced CXCL10 in both, while immune responses of IFN‐γ‐ and TNF‐α‐induced CXCL10 enhanced by S1 protein were different between RT7 and GT1. Finally, knockdown of ACE2 decreased cytokines and S1 protein mediated‐CXCL10 levels in both cells. Conclusions: ACE2 in oral mucosal cells may contribute to development of infection and inflammation in cooperation with pro‐inflammatory cytokines following SARS‐CoV‐2 invasion. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the effect of mammalian‐enabled (Mena) on tongue squamous cell carcinoma (TSCC) metastasis and its mechanism. Materials and Methods: Immunochemistry was performed to investigate the Mena and tumor‐related markers expression, and its clinicopathological characteristics in 46 TSCC specimens. TSCC cell SCC9 and Cal27 untransfected or stable transfected with Mena overexpression and small interfering RNA were used to determine the role of Mena in cell proliferation, cell migration, invasion and metastasis, and EMT‐related markers in vitro, and the effect of Mena on TSCC growth and metastasis through tumor‐bearing and tumor metastasis immunodeficient mice models in vivo. Results: Immunochemistry showed that the expression of Mena was significantly correlated with lymphatic metastasis and TNM stage, E‐cadherin, Vimentin, and MMP2. Mena did not affect cell proliferation and colony formation in vitro, and tumor growth in vivo. However, it promoted cell migration and invasion in vitro, and TSCC metastasis in vivo. Conclusions: Mena expression is associated with lymphatic metastasis and tumor stage and promotes TSCC invasion and metastasis by inducing the EMT process. Thus, Mena may be a biomarker for prognosis and targeted therapy in TSCC patients. [ABSTRACT FROM AUTHOR]

Veillonella parvula, prototypical member of the oral and gut microbiota, is at times commensal yet also potentially pathogenic. The definition of the molecular basis tailoring this contrasting behavior is key for broadening our understanding of the microbiota‐driven pathogenic and/or tolerogenic mechanisms that take place within our body. In this study, we focused on the chemistry of the main constituent of the outer membrane of V. parvula, the lipopolysaccharide (LPS). LPS molecules indeed elicit pro‐inflammatory and immunomodulatory responses depending on their chemical structures. Herein we report the structural elucidation of the LPS from two strains of V. parvula and show important and unprecedented differences in both the lipid and carbohydrate moieties, including the identification of a novel galactofuranose and mannitol‐containing O‐antigen repeating unit for one of the two strains. Furthermore, by harnessing computational studies, in vitro human cell models, as well as lectin binding solid‐phase assays, we discovered that the two chemically diverse LPS immunologically behave differently and have attempted to identify the molecular determinant(s) governing this phenomenon. Whereas pro‐inflammatory potential has been evidenced for the lipid A moiety, by contrast a plausible "immune modulating" action has been proposed for the peculiar O‐antigen portion. [ABSTRACT FROM AUTHOR]

Veillonella parvula, prototypical member of the oral and gut microbiota, is at times commensal yet also potentially pathogenic. The definition of the molecular basis tailoring this contrasting behavior is key for broadening our understanding of the microbiota‐driven pathogenic and/or tolerogenic mechanisms that take place within our body. In this study, we focused on the chemistry of the main constituent of the outer membrane of V. parvula, the lipopolysaccharide (LPS). LPS molecules indeed elicit pro‐inflammatory and immunomodulatory responses depending on their chemical structures. Herein we report the structural elucidation of the LPS from two strains of V. parvula and show important and unprecedented differences in both the lipid and carbohydrate moieties, including the identification of a novel galactofuranose and mannitol‐containing O‐antigen repeating unit for one of the two strains. Furthermore, by harnessing computational studies, in vitro human cell models, as well as lectin binding solid‐phase assays, we discovered that the two chemically diverse LPS immunologically behave differently and have attempted to identify the molecular determinant(s) governing this phenomenon. Whereas pro‐inflammatory potential has been evidenced for the lipid A moiety, by contrast a plausible "immune modulating" action has been proposed for the peculiar O‐antigen portion. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastomas are the most aggressive brain tumors, and affected patients still only have an extremely poor prognosis with today's therapeutic options. Further developments are still necessary, particularly in therapeutic approaches. Orlistat can act as an antitumor agent as it inhibits fatty acid synthase, decreases tumor cell proliferation, and stimulates tumor cell apoptosis. Investigations conducted on breast, pancreatic, hepatic, and colorectal tumors showed that FASN—fatty acid synthase, a protein that catalyzes the de novo synthesis of long-chain fatty acids—is strongly upregulated. Using an animal model, we tested whether the drug's effects could be demonstrated visually, quantitatively, and by texture analysis based on MR studies. Histology and immunochemistry were used as references. The key results of the present study are as follows: Firstly, a significant difference was found between orlistat-treated and untreated tumors in MRI studies based on morphology and texture analyses. Secondly, the expression of FASN was reduced in the orlistat group, which, however, did not result in a higher apoptosis rate in the treatment group. Our findings suggest that some effects of orlistat on tumor cell proliferation must have taken place during therapy. Further studies should investigate the effects of FASN inhibition when combined with targeted therapies. Background: This study aimed to investigate the effects of tetrahydrolipstatin (orlistat) on heterotopic glioblastoma in mice by applying MRI and correlating the results with histopathology and immunochemistry. Methods: Human glioblastoma cells were injected subcutaneously into the groins of immunodeficient mice. After tumor growth of >150 mm3, the animals were assigned into a treatment group (n = 6), which received daily intraperitoneal injections of orlistat, and a control group (n = 7). MRI was performed at the time of randomization and before euthanizing the animals. Tumor volumes were calculated, and signal intensities were analyzed. The internal tumor structure was evaluated visually and with texture analysis. Western blotting and protein expression analysis were performed. Results: At histology, all tumors showed high mitotic and proliferative activity (Ki67 ≥ 10%). Reduced fatty acid synthetase expression was measured in the orlistat group (p < 0.05). Based on the results of morphologic MRI-based analysis, tumor growth remained concentric in the control group and changed to eccentric in the treatment group (p < 0.05). The largest area under the receiver operating curve of the predictors derived from the texture analysis of T2w images was for wavelet transform parameters WavEnHL_s3 and WavEnLH_s4 at 0.96 and 1.00, respectively. Conclusions: Orlistat showed effects on heterotopically implanted glioblastoma multiforme in MRI studies of mice based on morphologic and texture analysis. [ABSTRACT FROM AUTHOR]

* Context.--Breast cancer with low (1%-10%) estrogen receptor (ER) expression (ER--low positive) constitutes a small portion of invasive breast cancers, and the treatment strategy for these tumors remains debatable. Objective.--To characterize the features and outcomes of ER--low positive patients, and clarify the clinical significance of FOXC1 and SOX10 expression in ER--low positive/HER2-negative tumors. Design.--Among 9082 patients diagnosed with primary invasive breast cancer, the clinicopathologic features of those with ER--low positive breast cancer were characterized. FOXC1 and SOX10 mRNA levels were analyzed in ER--low positive/HER2-negative cases from public data sets. The expression of FOXC1 and SOX10 in ER--low positive/HER2-negative tumors was evaluated by immunohistochemistry. Results.--The clinicopathologic study of ER--low positive tumors indicated more aggressive characteristics compared with those tumors with ER .10%, while they had more overlapping features with ER-negative tumors irrespective of the HER2 status. The intrinsic molecular subtype of ER--low positive cases with high FOXC1 and SOX10 mRNA expression was more likely to be nonluminal. Among the ER--low positive/HER2-negative tumors, 56.67% (51 of 90) and 36.67% (33 of 90) were positive for FOXC1 and SOX10, respectively, which was significantly positively correlated with CK5/6 expression. In addition, the survival analysis demonstrated no significant difference between patients who received and who did not receive endocrine therapy. Conclusions.--ER--low positive breast cancers biologically overlap more with ER-negative tumors. ER--low positive/HER2-negative cases demonstrate a high rate of FOXC1 or SOX10 expression, and these cases might be better categorized as a basal-like phenotype/subtype. FOXC1 and SOX10 testing may be used for the intrinsic phenotype prediction for ER--low positive/HER2-negative patients. [ABSTRACT FROM AUTHOR]

Primary Mucinous eccrine carcinoma (MEC) is a rare malignant neoplasm of skin believed to arise from eccrine sweat gland commonly with periocular involvement. Here we report a case of 60-year male with a recurrence of unilateral nasomaxillary mass and epiphora. Imaging suggested nasolacrimal duct as probable site of origin. Histopathology and immunochemistry confirmed the diagnosis and managed surgically. This case report emphasizes the significance of including primary MEC in the differential diagnosis of nasomaxillary mass for its recurrence nature and histological similarity with metastasis from other viscera. [ABSTRACT FROM AUTHOR]

In the fruit fly Drosophila melanogaster, two cells in a cyst of 16 interconnected cells have the potential to become the oocyte, but only one of these will assume an oocyte fate as the cysts transition through regions 2a and 2b of the germarium. The mechanism of specification depends on a polarized microtubule network, a dynein dependent Egl:BicD mRNA cargo complex, a special membranous structure called the fusome and its associated proteins, and the translational regulator orb. In this work, we have investigated the role of orb and the fusome in oocyte specification. We show here that specification is a stepwise process. Initially, orb mRNAs accumulate in the two pro-oocytes in close association with the fusome. This association is accompanied by the activation of the orb autoregulatory loop, generating high levels of Orb. Subsequently, orb mRNAs become enriched in only one of the pro-oocytes, the presumptive oocyte, and this is followed, with a delay, by Orb localization to the oocyte. We find that fusome association of orb mRNAs is essential for oocyte specification in the germarium, is mediated by the orb 3′ UTR, and requires Orb protein. We also show that the microtubule minus end binding protein Patronin functions downstream of orb in oocyte specification. Finally, in contrast to a previously proposed model for oocyte selection, we find that the choice of which pro-oocyte becomes the oocyte does not seem to be predetermined by the amount of fusome material in these two cells, but instead depends upon a competition for orb gene products. [ABSTRACT FROM AUTHOR]

Objective: To compare interval cancer proportions (ICP) in the faecal immunochemical test (FIT)-based Scottish Bowel Screening Programme (SBoSP) with the former guaiac faecal occult blood test (gFOBT)-based SBoSP and investigate associations between interval cancer (IC) and faecal haemoglobin concentration (f-Hb) threshold, sex, age, deprivation, site, and stage. Methods: The ICP data from first year of the FIT-based SBoSP and the penultimate year of the gFOBT-based SBoSP were compared in a prospective cohort design. Results: With FIT, 801 colorectal cancers (CRCs) were screen detected (SDC), 802 were in non-participants, 548 were ICs, 39 were colonoscopy missed and 72 were diagnosed after incomplete screening; with gFOBT: 540, 904, 556, 45, and 13, respectively. FIT had a significantly higher proportion of SDC compared to IC than gFOBT. For FIT and gFOBT, ICP was significantly higher in women than men. As f-Hb threshold increased, ICP increased and, for any f-Hb threshold for men, a lower threshold was required for comparable ICP in women. In Scotland, the current threshold of ≥80 µg Hb/g faeces would have to be lowered to ≥40 µg Hb/g faeces for women to achieve sex equality for ICP. In the FIT-based SBoSP, there were four times as many stage I SDC than IC. This was reversed in advanced stages, with twice as many stage IV CRC diagnosed as IC versus SDC. Conclusions: Reducing the numbers of IC requires lowering the f-Hb threshold. Using different f-Hb thresholds for women and men could eliminate the sex disparity, but with additional colonoscopy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate participation and participation patterns in a population-based screening programme for colorectal cancer (CRC) using the faecal immunochemical test (FIT). Methods: All individuals invited to three consecutive screening rounds in the population-based CRC screening between October 2015 and December 2020 in the Stockholm–Gotland Region, Sweden were included. Patterns of participation were assessed. Results: The study included 26 541 individuals which resulted in 79 623 screening events. The overall uptake rate was 71.5% and women had a significantly higher participation rate. The participation rate increased significantly between the first and third screening round for both men and women, and the increase was larger among men than women (66.1 to 70.7% vs. 73.1 to 75.4%). In total, 80.9% participated at least once. Consistent participation was the most common participation pattern (61.0%). The probability of attending all three consecutive rounds after initial participation was 87.7%. Over the three rounds, 17.4% participated after a reminder letter. Screening individuals attending after a reminder letter had a higher proportion of drop-outs in the following screening round compared to initial participants (15.4% vs 6.2%). Conclusion: A constant and high participation rate was observed in population-based FIT-screening for CRC. Initial participation was a strong predictor for continuous participation. The need for a reminder letter before participation was a risk factor for subsequent drop-out. [ABSTRACT FROM AUTHOR]

Objective: To evaluate interval cancer (IC) after two screening rounds of the Swedish population-based screening program of Stockholm–Gotland applying gender-specific cut-off levels in the fecal immunochemical test (FIT). Methods: All 60- to 69-year-olds invited to screening 2015–2019 were included. The cut-off level for a positive test was 40 µg/g in women and 80 µg/g in men. Screening-detected colorectal cancers (SD CRCs) and ICs were verified in the Swedish Colorectal Cancer Register, and the follow-up time was two years from invitation. The test sensitivity, the IC rate (ICs per 10,000 screening negatives) and the IC incidence (ICs per 100,000 person-years) relative to the background CRC incidence were assessed by gender and age. The FIT levels were compared in men and women for CRCs diagnosed within one year of the sample. Results: In the second screening round, 229,187 were invited, and SD CRCs and ICs were diagnosed in 193 and 144, respectively. The IC rate was 8.9 (7.4–10.3) and test sensitivity 0.61 (0.55–0.66), and was similar in men and women. For two screening rounds, the IC rate was significantly higher in men than in women, but the IC incidence/ background CRC incidence was similar in both genders. The FIT levels in female participants with CRC were significantly lower overall, and in early-staged CRCs as compared to men, and proximal localization was more common in women. In multivariable analysis, FIT levels were significantly lower in proximal CRCs. Conclusion: Over two rounds, the IC incidence relative to the background CRC incidence was similar in men and women supporting a gender-specific screening strategy. The results could be explained by lower FIT levels in women due to proximal CRC localization. [ABSTRACT FROM AUTHOR]

Simple Summary: Penile cancer is a rare but aggressive cancer. After it metastasizes, the median survival time is less than 12 months. The overall response rate to common first-line combination chemotherapy treatments is approximately 50%. There is an urgent need in advanced-penile-cancer treatment to find novel therapies that would generate better response rates than standard chemotherapy thus far and have less toxicity. Partially due to its rarity, there are few animal models and cell lines of penile cancer. We report on the generation of seven penile cancer animal models that were created by directly implanting human tumor tissue into immunocompromised mice. Metastatic penile squamous cell carcinoma (PSCC) has only a 50% response rate to first-line combination chemotherapies and there are currently no targeted-therapy approaches. Therefore, we have an urgent need in advanced-PSCC treatment to find novel therapies. Approximately half of all PSCC cases are positive for high-risk human papillomavirus (HR-HPV). Our objective was to generate HPV-positive (HPV+) and HPV-negative (HPV−) patient-derived xenograft (PDX) models and to determine the biological differences between HPV+ and HPV− disease. We generated four HPV+ and three HPV− PSCC PDX animal models by directly implanting resected patient tumor tissue into immunocompromised mice. PDX tumor tissue was found to be similar to patient tumor tissue (donor tissue) by histology and short tandem repeat fingerprinting. DNA mutations were mostly preserved in PDX tissues and similar APOBEC (apolipoprotein B mRNA editing catalytic polypeptide) mutational fractions in donor tissue and PDX tissues were noted. A higher APOBEC mutational fraction was found in HPV+ versus HPV− PDX tissues (p = 0.044), and significant transcriptomic and proteomic expression differences based on HPV status included p16 (CDKN2A), RRM2, and CDC25C. These models will allow for the direct testing of targeted therapies in PSCC and determine their response in correlation to HPV status. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1, resulting from dominantly inherited mutations affecting neurofibromin, is among the most common human genetic syndromes associated with many neurocutaneous manifestations. Neoplasms, neurogenic and non-neurogenic, are frequent, as are the gastrointestinal manifestations. Gastrointestinal tumors and vasculopathy are well-reported in individuals with neurofibromatosis type 1. A combination of somatostatioma and gastrointestinal stromal tumor is considered pathognomonic. We here report a case of neurofibromatosis type 1 with a triad of distinct neoplasms: gastrointestinal stromal tumor, neuroendoscrine tumor, and intra-ampullary papillary-tubular neoplasm. The trilogy of these neoplasms is unique and, to our knowledge, has never been reported in the literature. The report also emphasizes the role of advanced immunochemical staining in day-to-day practice, which has improved diagnostic accuracy and yield. [ABSTRACT FROM AUTHOR]

The International System for Reporting Serous Fluid Cytology (TIS) has been proposed by an expert working team composed of the International Academy of Cytology and the American Society of Cytopathology, following an international survey. Since its introduction, the TIS has gained worldwide acceptance, and this review aims to assess its global impact. A literature search revealed 25 studies which have presented data on the impact of the TIS. Most of them provide data, including risk of malignancy (ROM) for each diagnostic category, separately for pleural, peritoneal and pericardial effusions, while a few do not separate them. A few studies focus on specific diagnoses like mesothelioma on specific types of fluids or more specific issues like the optimal fluid volume for cytology or interobserver variability. A synopsis of the data from the literature search is presented in four tables. The ROM assessment is discussed, as well as interobserver variability and the use of ancillary diagnostic immunochemistry. In conclusion, our review of the published data suggests that the TIS is a valid classification scheme that has been widely accepted by pathologists globally, is highly reproducible and makes a valuable contribution to clinical therapeutic management. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a disease specific to pregnancy that causes 9–10 % of maternal deaths. Early-onset PE (<34 weeks' gestation) is the most dangerous category of PE. Wnt7a and GPR124 (G protein-coupled receptor 124) are widely expressed in the human reproductive process. Especially during embryogenesis and tumorigenesis, Wnt7a plays a crucial role. However, few studies have examined the association between Wnt7a-GPR124 and early-onset PE. The aim of this study was to examine the significance of Wnt7a and GPR124 in early-onset PE as well as Wnt7a's role in trophoblast cells. Immunohistochemistry (IHC), real-time PCR, and western blotting (WB) were used to investigate Wnt7a and GPR124 expression in normal and early-onset PE placentas. Additionally, FACS, Transwell, and CCK-8 assays were used to diagnose Wnt7a involvement in migration, invasion, and proliferation. In the early-onset PE group, Wnt7a and GPR124 expression was significantly lower than in the normal group, especially in the area of syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). A negative correlation was found between Wnt7a RNA and GPR124 expression (r=−0.42, p<0.01). However, the Wnt7a RNA expression level was positive correlated with PE severity. In further cellular functional experiments, knockdown of Wnt7a inhibits HTR8/SVeno cells invasion and migration but has little effect on proliferation and apoptosis. Through the Wnt pathway, Wnt7a regulates trophoblast cell invasion and migration, and may contribute to early-onset preeclampsia pathogenesis. A molecular level study of Wnt7a will be needed to find downstream proteins and mechanisms of interaction. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects as many as 50 million people worldwide. It is neurochemically characterized by an aggregation of β-amyloid plaques and tau neurofibrillary tangles that result in neuronal dysfunction, cognitive decline, and a progressive loss of brain function. TgSwDI is a well-studied transgenic mouse model of AD, but no longitudinal studies have been performed to characterize cognitive deficits or β-amyloid plaque accumulation for use as a baseline reference in future research. Thus, we use behavioral tests (T-Maze, Novel Object Recognition (NOR), Novel Object Location (NOL)) to study long-term and working memory, and immunostaining to study β-amyloid plaque deposits, as well as brain size, in hippocampal, cerebellum, and cortical slices in TgSwDI and wild-type (WT) mice at 3, 5, 8, and 12 months old. The behavioral results show that TgSwDI mice exhibit deficits in their long-term spatial memory starting at 8 months old and in long-term recognition memory at all ages, but no deficits in their working memory. Immunohistochemistry showed an exponential increase in β-amyloid plaque in the hippocampus and cortex of TgSwDI mice over time, whereas there was no significant accumulation of plaque in WT mice at any age. Staining showed a smaller hippocampus and cerebellum starting at 8 months old for the TgSwDI compared to WT mice. Our data show how TgSwDI mice differ from WT mice in their baseline levels of cognitive function and β-amyloid plaque load throughout their lives. [ABSTRACT FROM AUTHOR]

Background: Intracranial schwannomas are benign lesions, expected to exhibit characteristic ultrastructural features and immunophenotypic profile, typically being S-100, SOX10 and collagen-IV positive, while other markers, including CD34, are not usually expressed and are employed in the diagnostic elimination process. Case presentation: A 51-year-old female presented with a rapidly deteriorating neurological status. MRI showed a heterogeneous enhancing neoplasm of the anterior fossa. Preoperative differential diagnosis predilected an esthesioneuroblastoma. A bifrontal craniotomy with total excision of the lesion was performed. Dural infiltration was present. There was no association with the olfactory system. Microscopic examination revealed a uniform population of spindled to slightly epithelioid cellular proliferation with no significant atypia, low mitotic activity, and foci of necrosis. Upon immunohistochemical investigation the tumor was consistent with cellular schwannoma. Diffuse positivity for CD34 was an unusual finding. Discussion: Cellular schwannoma should be considered in the presence of an anterior fossa tumefaction. Olfactory nerve is not directly associated with these lesions. Various theories have been proposed, with the meningeal trigeminal branches' origin being the most probable. The characteristic ultrastructural Antoni formations may be scarce or even absent in cellular schwannomas creating potential diagnostic difficulties. Unusual diffuse CD34 positivity should not be employed for excluding the diagnosis. [ABSTRACT FROM AUTHOR]

Background & Methods: The aim of the study is to study Characterizing of Early Leprosy by routine histopathology Immunochemistry and by methods of Molecular Biological. Results: The lesions were found to be mostly in the extremities (44/50, 88%) with the upper extremities being more frequently involved. Nerve thickening was observed to be present in 26% of the cases, with cutaneous nerve involvement being seen in 5 (10%) and peripheral nerve trunk involvement in 8 (16%). The skin smear was negative for AFB in all, and the Mitsuda lepromin reaction was positive in 18/30 (60%) of the cases studied. Conclusion: The present study, 100 cases of clinically diagnosed early leprosy (Idt leprosy, early TT/BT) and, 90 cases of clinically suspect leprosy were studied from the viewpoint of histological diagnosis. Homogeneity within the two groups was achieved by selecting only untreated cases and by defining the features required to make the clinical diagnosis. Biopsies were taken from the lesion peripheries, fixed in 10% buffered formalin, and, processed for routine histopathological examination. The histological diagnosis of leprosy, using specific defined criteria was made in (36%) in the clinical category of early leprosy, and in (24.44%) in the clinical category of suspect leprosy. These findings are consistent with the low (and variable) degree of histological confirmation reported in several studies in the chosen categories of cases. [ABSTRACT FROM AUTHOR]

The cellulose-enriched tertiary cell walls present in many plant fibers have specific composition, architecture, machinery of formation, and function. To better understand the mechanisms underlying their mode of action and to reveal the peculiarities of fibers from different plant species, it is necessary to more deeply characterize the major components. Next to overwhelming cellulose, rhamnogalacturonan I (RG-I) is considered to be the key polymer of the tertiary cell wall; however, it has been isolated and biochemically characterized in very few plant species. Here, we add RG-I to the list from the phloem fibers of the Phaseolus vulgaris stem that was isolated and analyzed by nuclear magnetic resonance (NMR), dynamic light scattering, and immunolabeling, both within tissue and as an isolated polymer. Additionally, fibers with tertiary cell walls from nine species of dicotyledonous plants from the orders Malphigiales, Fabales, and Rosales were labeled with RG-I-related antibodies to check the presence of the polymer and compare the in situ presentation of its backbone and side chains. The obtained results confirm that RG-I is an obligatory polymer of the tertiary cell wall. However, there are differences in the structure of this polymer from various plant sources, and these peculiarities may be taxonomically related. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastric cancer (GC) has a poor prognosis, as it has often grown into an advanced stage when diagnosed. Genetic testing is crucial for establishing a treatment plan. In this study, next-generation sequencing (NGS) was performed to discover that LRP1B mutation was associated with a poor prognosis in GC. Through layer-by-layer research, it was found that LRP1B expression in GC was accompanied by a higher-level infiltration of CD4+ T, CD8+ T cells, and CD86/CD163. It is concluded that LRP1B expression can stimulate tumor immune cell infiltration, thus bringing clinical benefits to GC patients. Background: Recent studies have shown that low-density lipoprotein receptor-related protein 1b (LRP1B), as a potential tumor suppressor, is implicated in the response to immunotherapy. The frequency of LRP1B mutation gene is high in many cancers, but its role in gastric cancer (GC) has not been determined. Methods: The prognostic value of LRP1B mutation in a cohort containing 100 patients having received radical gastrectomy for stage II–III GC was explored. By analyzing the data of LRP1B mRNA, the risk score of differentially expressed genes (DEGs) between LRP1B mutation-type and wild-type was constructed based on the TCGA-STAD cohort. The infiltration of tumor immune cells was evaluated by the CYBERSORT algorithm and verified by immunohistochemistry. Results: LRP1B gene mutation was an independent risk factor for disease-free survival (DFS) in GC patients (HR = 2.57, 95% CI: 1.28–5.14, p = 0.008). The Kaplan–Meier curve demonstrated a shorter survival time in high-risk patients stratified according to risk score (p < 0.0001). CYBERSORT analysis showed that the DEGs were mainly concentrated in CD4+ T cells and macrophages. TIMER analysis suggested that LRP1B expression was associated with the infiltration of CD4+ T cells and macrophages. Immunohistochemistry demonstrated that LRP1B was expressed in the tumor cells (TCs) and immune cells in 16/89 and 26/89 of the cohort, respectively. LRP1B-positive TCs were associated with higher levels of CD4+ T cells, CD8+ T cells, and CD86/CD163 (p < 0.05). Multivariate analysis showed that LRP1B-positive TCs represented an independent protective factor of DFS in GC patients (HR = 0.43, 95% CI: 0.10–0.93, p = 0.042). Conclusions: LRP1B has a high prognostic value in GC. LRP1B may stimulate tumor immune cell infiltration to provide GC patients with survival benefits. [ABSTRACT FROM AUTHOR]

Simple Summary: Many cancers, especially those most common in adolescents and young adults, are initiated by a single change in the DNA sequence of a gene. The particular change creates a new gene through the fusing of the beginning of one gene to the end of a second gene. This new fusion gene will be expressed as a fusion protein that combines the functions of the two parent genes, but in new ways. Because many of the cancers that are driven by these fusion genes are rare, study of the precise function of the fusion proteins can be difficult. This article reports on the study of a particular fusion protein that drives the rare, but deadly, pediatric cancer clear cell sarcoma. The fusion protein was expressed in mice, leading to the formation of similar tumors to those it causes in humans. This permitted the study of fusion protein function in these tumors. Clear cell sarcoma (CCS) is a rare, aggressive malignancy that most frequently arises in the soft tissues of the extremities. It is defined and driven by expression of one member of a family of related translocation-generated fusion oncogenes, the most common of which is EWSR1::ATF1. The EWSR1::ATF1 fusion oncoprotein reprograms transcription. However, the binding distribution of EWSR1::ATF1 across the genome and its target genes remain unclear. Here, we interrogated the genomic distribution of V5-tagged EWSR1::ATF1 in tumors it had induced upon expression in mice that also recapitulated the transcriptome of human CCS. ChIP-sequencing of V5-EWSR1::ATF1 identified previously unreported motifs including the AP1 motif and motif comprised of TGA repeats that resemble GGAA-repeating microsatellites bound by EWSR1::FLI1 in Ewing sarcoma. ChIP-sequencing of H3K27ac identified super enhancers in the mouse model and human contexts of CCS, which showed a shared super enhancer structure that associates with activated genes. [ABSTRACT FROM AUTHOR]

Background. Iron deficiency (ID) is a common micronutrient deficiency and the leading cause of anemia worldwide. ID can be caused by chronic occult blood loss from colorectal neoplasia including colorectal cancer (CRC) and advanced precancerous colorectal lesions. Current guidelines recommend colonoscopy in both men and postmenopausal women presenting with ID anemia (IDA). However, there is controversy on the investigation of patients presenting with a lower risk of CRC including younger women with ID and those with nonanemic ID (NAID). There is a need for a triaging tool to identify which ID patients may benefit from colonoscopy. The fecal immunochemical test (FIT) is sensitive for CRC screening in an asymptomatic population, but its role in ID patients is unclear. The aim of this study is to conduct a systematic review to determine the diagnostic accuracy of FIT for detecting CRC and advanced precancerous neoplasia in individuals presenting with ID with or without anemia. Methods and Analysis. This protocol conforms with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols and Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. A comprehensive search of the MEDLINE, Embase, and Web of Science databases will be undertaken for studies published after 2010 which involve patients with ID, who completed a FIT in the 6 months prior to colonoscopy, with FIT sensitivity and specificity calculated against the reference standard colonoscopy. The search will be limited to studies conducted after 2010 to reduce variability in colonoscopy quality. Risk of bias assessment will be conducted using the Quality Assessment of Diagnostic Accuracy Studies version 2. FIT sensitivity and specificity will be the primary measure of diagnostic accuracy, and data will be analysed using a random effects meta-analysis. Discussion. This review and meta-analysis will be the first to systematically explore the value of the FIT as a triaging tool for patients with ID. This trial is registered with CRD42022367162. [ABSTRACT FROM AUTHOR]

The article focuses on ulcerative lymphomatoid papulosis (LyP) as a rare immune-related adverse event following immune checkpoint inhibitor (ICI) therapy and autologous stem cell transplant (autoSCT) in a patient with recurrent Hodgkin lymphoma. Topics include the rarity of LyP as an ICI-induced adverse event, the clinical presentation and histopathological features of ulcerative LyP, and the challenges in diagnosis and management of LyP in patients treated with ICIs and autoSCT.

Objectives: To explore the perceptions of patients and healthcare professionals on Raman‐faecal immunochemical test (FIT) as an alternative test for colorectal cancer exclusion in primary care. Design: Semi‐structured interviews within a feasibility study. Setting: Patients presenting to primary care with colorectal symptoms and healthcare professionals working in primary and secondary care. Participants: A total of 23 patients and 12 healthcare professionals. Methods: Patient participants were asked to complete a novel combined Raman‐FIT test before being seen in secondary care. This study sought their opinions about the test. We also sought the views of healthcare professionals. Findings: Patients and healthcare professionals agreed that Raman‐FIT was a suitable test to be given in primary care. It aligned with routine practice and was a simple test for most patients to complete. Conclusions: Patients are willing and able to complete the Raman‐FIT test in primary care. Raman‐FIT may accelerate access to diagnosis with the potential to improve cancer outcomes. Patient and Public Involvement: Lay members (J. H. and I. H.) with experience and knowledge of colorectal cancer and screening contributed to developing, undertaking, and disseminating all aspects of the research. They were supported to collaborate as equal members of the research team. They were involved in developing the study as coapplicants, using personal experience to ensure that the research and its methods were relevant to the patient and public needs. Both prepared participant information sheets, coanalysed data, and contributed to study reporting and dissemination through papers, conference presentations and a lay summary. [ABSTRACT FROM AUTHOR]

* Context.--Nonsalivary primary adenocarcinomas of the base of the tongue (PABOTs) are extremely rare and worth reporting. Objective.--To study the detailed clinicopathologic features of PABOT. Design.--Cases of PABOT diagnosed on pathology material were retrieved from the archived electronic surgical pathology records. Results.--Six cases in 4 men and 2 women (M:F ratio, 2:1), with an age range of 31 to 76 years, satisfied the criteria. The tumor epicenter was the base of the tongue in all (6 of 6; 100%), with extension to the epiglottis in 50% (3 of 6), nodal metastasis in 66.7% (4 of 6), and distant metastasis in 33.3% (2 of 6). On histology, all but one were pure adenocarcinoma. Five of 6 cases (83.3%) had a gastrointestinal (GI) phenotype, of which 2 (40%) had a colonic/lower-GI--type (small groups of cells floating in mucin, CK20+, SATB2+, and CDX2+) and 3 (60%) had an upper-GI--like adenocarcinoma (UGI-LA; malignant glands with intracellular mucin, CK7+) histology. Cystic structure suggestive of teratomatous origin was identified in 2 of 5 cases (40%), both with UGI-LA phenotype. The non--GItype case had a unique histology with squamous differentiation in addition to adenocarcinoma areas, diffuse nuclear β-catenin on immunohistochemistry, and a corresponding exon 3 CTNNB1 mutation. One patient succumbed to disease, and 4 are alive with disease (follow-up of 1-9 months after completion of therapy). Conclusions.--We suggest using the broad term primary adenocarcinomas of the base of tongue (PABOTs), which can be further subdivided into colonic-type adenocarcinoma of the tongue and oral cavity, UGI-LA, and not otherwise specified categories, and reiterate a need for recognition and distinction of PABOT from salivary gland tumors. A subset originates from teratoid/duplication cysts, necessitating extensive sampling. Multicentric studies are essential to clinically and biologically prognosticate each of these categories. [ABSTRACT FROM AUTHOR]

Simple Summary: IgY antibodies are used in research and in the development of solutions for immunotherapy and the immunodiagnosis of human and animal diseases. Affinity and avidity are forces that describe the interaction between an antigen and antibody and are important characteristics for the biological function of IgY antibodies. Therefore, these measures are fundamental variables for the development of immunodiagnostic methodologies and immunotherapy based on IgY antibodies. In this review, we address factors that influence the affinity and avidity of IgY antibodies and the methodologies used for the determination of these strengths. We observed a low number of studies on the factors influencing the maturation of IgY affinity and avidity and a wide variation in the methodologies used to determine these variables. The development of studies characterising the factors that influence the maturation of IgY antibody affinity and avidity, with standardised methodologies for the determination of these forces, is of utmost importance. IgY antibodies are found in the blood and yolk of eggs. Several studies show the feasibility of utilising IgY for immunotherapy and immunodiagnosis. These antibodies have been studied because they fulfil the current needs for reducing, replacing, and improving the use of animals. Affinity and avidity represent the strength of the antigen–antibody interaction and directly influence antibody action. The aim of this review was to examine the factors that influence the affinity and avidity of IgY antibodies and the methodologies used to determine these variables. In birds, there are few studies on the maturation of antibody affinity and avidity, and these studies suggest that the use of an adjuvant-type of antigen, the animal lineage, the number of immunisations, and the time interfered with the affinity and avidity of IgY antibodies. Regarding the methodologies, most studies use chaotropic agents to determine the avidity index. Studies involving the solution phase and equilibrium titration reactions are also described. These results demonstrate the need for the standardisation of methodologies for the determination of affinity and avidity so that further studies can be performed to optimise the production of high avidity IgY antibodies. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is the most prevalent cancer with high mortality worldwide. We aimed to evaluate the incidence of CRC based on the positive fecal immunochemical test (FIT) result in the Iranian population. Methods: The present study was conducted on the health assessment data recorded in the SINA (Integrated Health Information System) in 2018 and 2019 from individuals who had participated in the national program, including asymptomatic people aged 50-69 years or had risk factors of CRC such as family or past personal history of CRC as well as symptomatic individuals, for the early detection and prevention of CRC in Mashhad, Iran. Results: The study participants included 140,463 eligible individuals, of whom 8258 (5.88%) and 145 (2.21%) were positive for FIT and diagnosed with colon cancer, respectively. Unfortunately, only 654 people had undergone colonoscopy. Our results indicated that age, fast food intake (≥ two units per day), family history of CRC in first or second-degree relatives, some gastrointestinal diseases such as inflammatory bowel disease (IBD) and CRC, as well as bleeding per anus, constipation, abdominal cramp, and losing body weight were associated with increased risk of positive FIT. However, some other factors, including having a hard job, physical activity, and Iranian nationality (compared to non-Iranians), were associated with a low risk of positive FIT screening tests for CRC. Conclusion: A high number of high-risk persons in Mashhad were positive for the FIT test in 2018-2019, and many of them were diagnosed with CRC, according to the colonoscopy results. Therefore, screening is highly recommended as the first step in the early detection of CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Fast-track pathways to detect colorectal cancer have been implemented in several European countries, using different entry criteria. We analyzed 2539 fast-track colonoscopies including referrals in detail, in order to calculate the predictive values and odds ratios of different red flags with respect to the risk for colorectal cancer. Interestingly, we observed that a number of red flags were not at all associated with an increased risk for colorectal cancer. On the other hand, the variable with the highest predictive value: a positive fecal occult blood test (FOBT), is not always part of colorectal cancer fast tracks. These findings are important when selecting patients for fast-track colonoscopy. We propose that the entry criteria should be limited to the following signs/symptoms: patients > 40 years with one or more of the following signs/symptoms: positive FOBT, abnormal radiology, abnormal rectal examination, visible blood in stool, in the absence of hemorrhoids and unexplained iron-deficiency anemia. Background: Fast-track pathways for diagnosing colorectal cancer (CRC) have been implemented in several European countries. In Sweden, a substantial number of CRC are diagnosed via the Swedish Standardized Course of Care for colorectal cancer (SCC-CRC). We evaluated the SCC-CRC in terms of CRC yield, and predictive values and odds ratios (OR) for the entry criteria. Methods: We retrospectively analyzed all 2539 patients referred for SCC-CRC colonoscopy between September 2016 and December 2020. Entry criteria and colonoscopy outcomes were analyzed. Results: CRC yield was 16.4%. Highest positive predictive values (PPVs) were seen for abnormal radiology (PPV 30.5%, OR 4.7 (95% CI 3.4–6.4) p < 0.001), abnormal rectal examination (PPV 28%, OR 3.6 (95% CI 2.7–4.8) p < 0.001), and anemia (PPV 24.8%, OR 2.2 (95% CI 1.5–3.1) p < 0.001). Some entry criteria showed no significant risk increase, i.e., visible blood in stool/rectal bleeding, change in bowel habits, and the combination of changed bowel habits plus anemia. A positive fecal immunochemical test (FIT), although not part of the SCC-CRC, showed the highest OR: 9.9 (95% CI 4.5–21.7) p < 0.001) and PPV of 18.8%. Conclusions: CRC yield from the SCC-CRC is slightly higher compared to other European fast tracks. A number of entry criteria showed no benefit towards assessing CRC risk. FIT testing should be included in CRC fast tracks to increase diagnostic efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian tumors mobilize a heterogenous population of myeloid cells. While these cells initially contribute to anti-tumor immunity, as cancer progresses, they switch from immunostimulatory to immunosuppressive. Ovarian cancer is most frequently restricted to the peritoneal cavity, negating the need for systemic delivery of therapeutics. With a goal of targeting and activating myeloid cells in the tumor microenvironment, this study sought to determine which nanoparticle characteristics enhance uptake by myeloid cells in vitro and in vivo using an animal model of ovarian cancer. Lipids coating a mesoporous silica core were optimized for surface charge, formulation, and inclusion of immunogenic monophosphoryl lipid A. Benefits of a mesoporous core include opportunities for loading with additional therapeutics, such as antigens to direct immune responses or other therapeutic payloads that facilitate anti-cancer immune responses. Immunogenic lipid-coated mesoporous silica nanoparticles (ILM) present pathogen-associated molecular patterns (PAMPs) on the nanoparticle surface to engage pathogen-associated receptors on immune cells. The mesoporous core is capable of loading additional immunogens, antigens or drugs. In this study, the impact of lipid composition, surface potential and intercalation of lipophilic monophosphoryl lipid A (MPL-A) in the lipid coat on nanoparticle properties and cellular interactions is presented. Loading and retention of the model antigen ovalbumin into the mesoporous silica core were found to be similar for all nanoparticle formulations, with presentation of ova peptide (SIINFEKL) by major histocompatibility complex (MHC) evaluated to facilitate the selection of an anionic nanoparticle composition. ILM were able to induce lysosomal tubulation and streaming of lysosomes towards the cell surface in dendritic cells, leading to an enhanced surface presentation of MHC. Myeloid cells robustly internalized all ILM formulations; however, non-myeloid cells selectively internalized cationic ILM in vitro in the presence of 20% serum. Interestingly, ILM administration to the peritoneal cavity of mice with disseminated ovarian cancer resulted in selective accumulation of ILM in tumor-associated tissues (>80%), regardless of nanoparticle surface charge or the presence of MPL-A. Immunofluorescence analysis of the omental tumor showed that ILMs, regardless of surface charge, were localized within clusters of CD11b+ myeloid cells 24 h post administration. Selective uptake of ILMs by myeloid cells in vivo indicates that these cells outcompete other cell populations in the ovarian tumor microenvironment, making them a strong target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: This study found that high levels of STMN1 expression in neuroblastoma indicate malignant potential, proliferation potency, and poor prognosis. STMN1 knockdown inhibited neuroblastoma cell growth regardless of MYCN overexpression. The study suggests that assessing STMN1 expression could be a powerful indicator of prognosis and a promising therapeutic candidate against refractory neuroblastoma. Background. Stathmin 1 (STMN1), a marker for immature neurons and tumors, controls microtubule dynamics by destabilizing tubulin. It plays an essential role in cancer progression and indicates poor prognosis in several cancers. This potential protein has not been clarified in clinical patients with neuroblastoma. Therefore, this study aimed to assess the clinical significance and STMN1 function in neuroblastoma with and without MYCN amplification. Methods. Using immunohistochemical staining, STMN1 expression was examined in 81 neuroblastoma samples. Functional analysis revealed the association among STMN1 suppression, cellular viability, and endogenous or exogenous MYCN expression in neuroblastoma cell lines. Result. High levels of STMN1 expression were associated with malignant potential, proliferation potency, and poor prognosis in neuroblastoma. STMN1 expression was an independent prognostic factor in patients with neuroblastoma. Furthermore, STMN1 knockdown inhibited neuroblastoma cell growth regardless of endogenous and exogenous MYCN overexpression. Conclusion. Our data suggest that assessing STMN1 expression in neuroblastoma could be a powerful indicator of prognosis and that STMN1 might be a promising therapeutic candidate against refractory neuroblastoma with and without MYCN amplification. [ABSTRACT FROM AUTHOR]

Introduction: SOX2 plays a crucial role in tumor development, cancer stem cell maintenance, and cancer progression. Mechanisms of SOX2 gene regulation in human breast and prostate cancers are not established yet. Methods: SOX2 expression in prostate and breast cancer tissues and cell lines was determined by qRT-PCR, Western blot, and immunochemistry, followed by the investigation of pro-tumorigenic properties like cell proliferation, migration, and apoptosis by gene knockdown and treatment with epigenetic modulators and ChIP. Results: Prostate and breast cancer tissues showed very high expression of SOX2. All cancer cell lines DU145 and PC3 (prostate) and MCF7 and MDA-MB-231 (breast) exhibited high expression of SOX2. Inhibition of SOX2 drastically decreased cell proliferation and migration. Epigenetic modulators enhanced SOX2 gene expression in both cancer types. DNA methylation pattern in SOX2 promoter could not be appreciably counted for SOX2 overexpression. Activation of SOX2 gene promoter was due to very high deposition of H3K4me3 and H3K9acS10p and drastic decrease of H3K9me3 and H3K27me3. Conclusion: Histone modification is crucial for the overexpression of SOX2 during tumor development and cancer progression. These findings show the avenue of co-targeting SOX2 and its active epigenetic modifier enzymes to effectively treat aggressive prostate and breast cancers. [ABSTRACT FROM AUTHOR]

Today, the home pregnancy test is the most frequently performed laboratory test for self-diagnosis (home diagnostic test). It is also the first laboratory test that has been adapted for self-use at home. This is probably because women have always wanted to know the answer to the question: "Am I pregnant or not?" and always preferred to know the answer to this question intimately and in a discreet way. The history of the pregnancy test is also an interesting example of how the discovery of antibodies and the development of in vitro diagnostic methods based on the antigen–antibody reaction were important for the development of laboratory and clinical diagnostics. Immunodiagnostic techniques (based on the antigen–antibody reaction) are currently the basis of modern specialist laboratory diagnostics, which is essential in clinical diagnosis. The history of the pregnancy test is an interesting one and dates back to ancient times. A pregnancy test is defined as a procedure intended to reveal the presence or absence of pregnancy. Nowadays, every pregnancy test is based on the detection of human chorionic gonadotropin (hCG) in urine or blood. Human chorionic gonadotropin is secreted by the placenta right after a fertilized egg cell implants in the uterus and can be detected in both the urine and blood of pregnant women. Urine pregnancy tests are convenient for self-use at home. Blood tests are performed in medical laboratories. Specialized laboratory methods not only detect hCG but also determine the concentration of this hormone. However, both of these methods are highly accurate and common. Throughout the ages, many different methods were used to detect pregnancy at the earliest stage. Grain, wine, and various small animals were used as research tools. These were both long-term and often unreliable; most were based on folk beliefs and superstitions. Animal pregnancy tests were the first biological tests used in this field. This was a significant advance in the accurate detection of relatively early pregnancy. Animal tests in modern times are considered cruel and inhumane, no matter how reliable their results can be. Their place is now taken by much more specific, more sensitive, and definitely more ethical immunochemical tests. The pregnancy test and the methods to find out whether a woman is pregnant have gone through massive transformations, from bioassays using plants to bioassays on animals to advanced immunochemical techniques and biosensors. Modern pregnancy tests are not invasive and are very sensitive. Nowadays, it takes only about 3 min to know the answer to the question: "Am I pregnant or not?". However, it was not always as simple as it is today. This manuscript aims to show the important role played by antibodies in the development of laboratory and clinical diagnostics in the example of the interesting history of the pregnancy test. [ABSTRACT FROM AUTHOR]

The fecal immunochemical test (FIT) has been implemented in colorectal cancer (CRC) screening programs, but effect evaluations are lacking. We evaluated the effect of a positive FIT on all-cause and CRC mortality using the regression discontinuity design. The Danish CRC screening program invites all residents 50–74 years old, using a 20-μg hemoglobin/g feces cutoff for colonoscopy referral. In this cohort study, we followed all first-time screening participants from 2014–2019 until 2020. We estimated the local effect of screening results, of just above the cutoff vs. just below, as hazard ratios (HRs) between models fitted at each side of the cutoff. We conducted the analysis within a narrow hemoglobin range (≥17 and <23, n  = 16,428) and a wider range (≥14 and <26, n  = 35,353). Those screened just above the cutoff had lower all-cause mortality compared with below (HR = 0.87, 95% confidence interval: 0.69; 1.10), estimated from the narrow range. The CRC mortality analysis had few outcomes. In the wider range, those with a FIT just above the cutoff had a lower hazard of CRC mortality compared with just below the cutoff (HR = 0.49, 95% confidence interval: 0.17; 1.41). A FIT result just above the cutoff, leading to referral to colonoscopy, pointed towards reduced all-cause and CRC mortality compared with just below the cutoff. [ABSTRACT FROM AUTHOR]

Using Anticalin technology, a lipocalin protein dubbed Colchicalin, with the ability to bind the toxic plant alkaloid colchicine with picomolar affinity, has previously been engineered, thus offering a potential antidote in vivo and also allowing its sensitive detection in biological samples. To further analyze the mode of ligand recognition, the crystal structure of Colchicalin is now reported in its unliganded form and is compared with the colchicine complex. A superposition of the protein structures revealed major rearrangements in the four structurally variable loops of the engineered lipocalin. Notably, the binding pocket in the unbound protein is largely occupied by the inward‐bent loop #3, in particular Ile97, as well as by the phenylalanine side chain at position 71 in loop #2. Upon binding of colchicine, a dramatic shift of loop #3 by up to 11.1 Å occurs, in combination with a side‐chain flip of Phe71, thus liberating the necessary space within the ligand pocket. Interestingly, the proline residue at the neighboring position 72, which arose during the combinatorial engineering of Colchicalin, remained in a cis configuration in both structures. These findings provide a striking example of a conformational adaptation mechanism, which is a long‐known phenomenon for antibodies in immunochemistry, during the recognition of a small ligand by an engineered lipocalin, thus illustrating the general similarity between the mode of antigen/ligand binding by immunoglobulins and lipocalins. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is an increasing usage of noninvasive screening modalities for colorectal cancer (CRC), primarily the fecal immunochemical test (FIT) and multi-target stool DNA test (Cologuard [CG]). The aim of this study was to determine the comprehensive, long-term cost implications of these noninvasive screening modalities. STUDY DESIGN: Using a national insurer-based administrative dataset, patients screened for CRC from January 1, 2019 to December 31, 2019 were analyzed. A hierarchical logic system was used to determine the primary screening modality for each patient. The total annual costs in US dollars ($) were extrapolated using number of patients screened, costs per test, screening intervals, and costs incurred from false results. Patients within our tumor registry diagnosed with CRC were matched to their claims data, and cancer stage distribution was compared. RESULTS: Of 119,334 members who underwent noninvasive screening, 38.1% underwent screening with FIT and 40.0% with CG. The combined annual cost for these 2 screening modalities was $13.7 million. By transitioning to FIT alone for all noninvasive screening, the total annual cost would decrease to $7.9 million, resulting in a savings of approximately $5.8 million per year. Additionally, by combining data from the network cancer registry and insurer-based claims dataset, we were able to match 533 individuals who underwent screening and were later diagnosed with CRC. The rate of early-stage (stage 0 to II) disease was found to be similar between those screened with FIT and CG (59.5% FIT vs 63.2% CG; p = 0.77). CONCLUSIONS: The adoption of FIT as the primary noninvasive CRC screening method has the potential to generate significant cost savings, and therefore, carries significant value implications for a large population health system. [ABSTRACT FROM AUTHOR]

Background: There is sparse evidence in the literature in relation to indications and outcomes among adult indigenous patients requiring a flexible bronchoscopy (FB). In this study, FB indications and outcomes between indigenous and non‐indigenous patients were assessed. Aim: To assess the similarities and differences of FB indications and outcomes between indigenous and non‐indigenous patients. Methods: Self‐reported indigenous status, resident locality and the primary indication for FB were assessed. The FB procedures details, results of microbiology, cytology and histopathology were compared between indigenous and non‐indigenous patients. Chest computed tomography (CT) was also analysed for its relationship to FB outcomes. Results: Of the 403 patients, 111 (28%) were indigenous, and indigenous patients were younger (mean difference 11 years) and had a higher proportion of remote residence (70% vs 13%). Malignancy (40%) and infection (31%) were the most common indications for FB, although indigenous patients reported significantly more haemoptysis (15% vs 9%). No differences were noted in findings of the preceding chest CT scans. For positive microbiology, indigenous patients had a higher presence of Streptococcus pneumoniae (30% vs 9%), while non‐indigenous patients had a higher presence of Pseudomonas aeruginosa (43% vs 11%) and mycobacteria (15% vs 4%). There was no significant difference between indigenous and non‐indigenous patients for a positive histopathology, particularly for a diagnosis of lung malignancy (58% vs 54%). Conclusions: This study has demonstrated that adult indigenous patients requiring a FB are significantly younger, tend to reside in remote communities and demonstrate differing microbiology with no significant difference in the diagnostic outcomes for lung malignancy. Ethnic status or remoteness should not preclude indigenous patients to undergo a FB if clinically indicated. [ABSTRACT FROM AUTHOR]

Background: The association between programed cell death‐ligand 1 (PD‐L1) and tumor‐infiltrating lymphocytes (TILs) in vestibular schwannoma (VS) has been investigated in a few studies. These published studies report a difference in the PD‐L1 positivity rate in malignant peripheral nerve sheath tumors. We examined PD‐L1 expression and lymphocyte infiltration in patients with VS who had undergone surgical resection and investigated the association between PD‐L1 expression and clinicopathological features. Methods: The expression of PD‐L1, CD8, and Ki‐67 in 40 VS tissue specimens was investigated using immunohistochemistry, and a clinical review of the patients was performed. Results: Of the 40 VS samples, 23 (57.5%) were positive for PD‐L1 and 22 (55%) were positive for CD8. No significant differences in age, tumor size, pure‐tone audiometry, speech discrimination, or Ki‐67 expression were observed between patients in the PD‐L1‐positive and PD‐L1‐negative groups. A higher level of CD8‐positive cell infiltration was observed in PD‐L1‐positive tumors than in PD‐L1‐negative tumors. Conclusion: We demonstrated that PD‐L1 was expressed in VS tissues. Although no correlation was identified between clinical characteristics and PD‐L1 expression, the association between PD‐L1 and CD8 was confirmed. Thus, additional research on targeting PD‐L1 is necessary to improve immunotherapy for VS in the future. [ABSTRACT FROM AUTHOR]

We conducted a research study to create the groundwork for personalized solutions within a skin aging segment. This test utilizes genetic and general laboratory data to predict individual susceptibility to weak skin characteristics, leveraging the research on genetic polymorphisms related to skin functional properties. A cross-sectional study was conducted in a collaboration between the Private Clinic Medicina Practica Laboratory (Vilnius, Lithuania) and the Public Institution Lithuanian University of Health Sciences (Kaunas, Lithuania). A total of 370 participants agreed to participate in the project. The median age of the respondents was 40, with a range of 19 to 74 years. After the literature search, we selected 15 polymorphisms of the genes related to skin aging, which were subsequently categorized in terms of different skin functions: SOD2 (rs4880), GPX1 (rs1050450), NQO1 (rs1800566), CAT (rs1001179), TYR (rs1126809), SLC45A2 (rs26722), SLC45A2 (rs16891982), MMP1 (rs1799750), ELN (rs7787362), COL1A1 (rs1800012), AHR (rs2066853), IL6 (rs1800795), IL1Beta (rs1143634), TNF-α (rs1800629), and AQP3 (rs17553719). RT genotyping, blood count, and immunochemistry results were analyzed using statistical methods. The obtained results show significant associations between genotyping models and routine blood screens. These findings demonstrate the personalized medicine approach for the aging segment and further add to the growing literature. Further investigation is warranted to fully understand the complex interplay between genetic factors, environmental influences, and skin aging. [ABSTRACT FROM AUTHOR]

Simple Summary: Mitochondrial dysfunction and respiratory function changes have been associated with the initiation and progression of cancer. However, no study has comprehensively investigated the relationship between these mitochondrial-related factors and prognosis in a large number of patients with oral squamous cell carcinoma (OSCC). Here, we retrospectively investigated the expression of mitochondrial tumor-suppressor and DNA-repair proteins (PGC-1α, TFAM, OGG1, MTUS1, and SIRT3) in patients with OSCC and evaluated the relationship between their expression and prognosis. The expression levels of the five proteins were associated with patient outcomes. The 3-year disease-specific survival (DSS) rates of patients showing positive expression of all selected proteins were significantly higher than those of patients showing a lack of expression. Particularly, based on the results of multivariate analysis, negative expression of PGC-1α is related to a poor prognosis of OSCC. Low PGC-1α expression and vascular invasion may be clinically effective predictors of oral cancer prognosis. Mitochondrial dysfunction and respiratory function changes have been consistently associated with the initiation and progression of cancer. The purpose of this study was to retrospectively investigate the expression of mitochondrial tumor-suppressor and DNA-repair proteins in patients with oral squamous cell carcinoma (OSCC) and to evaluate the relationship between their expression and prognosis. We enrolled 197 patients with OSCC who underwent surgical resection between August 2013 and October 2018. Clinical, pathological, and epidemiological data were retrospectively collected from hospital records. The expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A, mitochondrial tumor suppressor gene 1, silent information regulator 3, and 8-hydroxyguanine DNA glycosylase was investigated using immunochemistry. The 3-year disease-specific survival (DSS) rates of patients showing positive expression of all selected proteins were significantly higher than those of patients showing a lack of expression. Multivariate analysis revealed that the expression of PGC-1α (hazard ratio, 4.684) and vascular invasion (hazard ratio, 5.690) can predict the DSS rate (p < 0.001). Low PGC-1α expression and vascular invasion are potential clinically effective predictors of the prognosis of OSCC. [ABSTRACT FROM AUTHOR]

The analysis of secreted protein biomarkers can be a useful non-invasive method of predicting or monitoring cancer therapeutic response. The increased level of soluble programmed cell death protein ligand 1 (sPD-L1) is a promising predictive biomarker for selecting patients who are likely to respond to immune checkpoint immunotherapy. The current established immunoassay for secreted protein analysis is enzyme-linked immunosorbent assay (ELISA). Yet, ELISA is generally still liable to limited detection sensitivity and restricted to bulky chromogenic readout equipment. Herein, we present a designed nanophotonic immunoarray sensor which achieved sPD-L1 analysis at high-throughput, enhanced detection sensitivity and portability. The key benefits of our nanophotonic immunoarray sensor are (i) high-throughput surface-enhanced Raman scattering (SERS) analysis of multiple samples on a singular platform; (ii) improved sPD-L1 detection sensitivity at 1 pg mL−1 (by two orders of magnitude as compared to ELISA) via electrochemically roughened gold sensor surfaces; (iii) fit for handheld SERS detection with miniaturized equipment footprint. We evaluated the analytical performance of the nanophotonic immunoarray sensor and successfully demonstrated quantitative sPD-L1 detection in a cohort of contrived human plasma samples. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Colorectal cancer (CRC) screening rates continue to be low among safety-net populations. We sought to elucidate the impact of social determinants of health (SDOH) on the noncompletion of fecal immunochemical tests (FITs) and colonoscopies at the Providence Community Health Centers (PCHC). STUDY DESIGN: This was a retrospective cohort review of PCHC patients with associated SDOH profiles between December 1, 2018, and December 1, 2019. METHODS: We analyzed fulfilled and unfulfilled CRC screening orders (FITs and colonoscopies) and examined associations and odds ratios between order noncompletion and the presence of SDOH variables. The study sample consisted of a total of 517 orders (fulfilled and unfulfilled; FIT, n = 348; colonoscopy, n = 169). RESULTS: FITs were completed more often than colonoscopies (81.3% vs 65.7%, respectively; P < .001). Colonoscopy noncompletion was associated with patientreported social determinants of "housing insecurity/ homelessness" (P = .0083) and "living conditions" (P = .048) and staff-reported "behavioral health problem" (P = .048). The presence of housing insecurity/homelessness increased the likelihood of an unfulfilled colonoscopy order (odds ratio, 7.5; 95% CI, 1.3-75.0). Patients who reported any SDOH need had a statistically significant increase in colonoscopy noncompletion (P = .0022), whereas FIT noncompletion was not associated with the presence of SDOH needs (P = .81). CONCLUSIONS: Providers should consider FITs as a strategic real-world modality for patients with SDOH needs. [ABSTRACT FROM AUTHOR]

Background: the association between ovarian endometriosis (OE) and endometriosis-associated ovarian cancer (EAOC) is extensively documented, and misfunction of the immune system might be involved. The primary objective of this study was to identify and compare the spatial distribution of tumour-infiltrating lymphocytes (TILs) and tumour-associated macrophages (TAMs) in OE and EAOC. Secondary objectives included the analysis of the relationship between immunosuppressive populations and T-cell exhaustion markers in both groups. Methods: TILs (CD3, CD4, and CD8) and macrophages (CD163) were assessed by immunochemistry. Exhaustion markers (PD-1, TIM3, CD39, and FOXP3) and their relationship with tumour-associated macrophages (CD163) were assessed by immunofluorescence on paraffin-embedded samples from n = 43 OE and n = 54 EAOC patients. Results: we observed a predominantly intraepithelial CD3+ distribution in OE but both an intraepithelial and stromal pattern in EAOC (p < 0.001). TILs were more abundant in OE (p < 0.001), but higher TILs significantly correlated with a longer overall survival and disease-free survival in EAOC (p < 0.05). CD39 and FOXP3 significantly correlated with each other and CD163 (p < 0.05) at the epithelial level in moderate/intense CD4 EAOC, whereas in moderate/intense CD8+, PD-1+ and TIM3+ significantly correlated (p = 0.009). Finally, T-cell exhaustion markers FOXP3-CD39 were decreased and PD-1-TIM3 were significantly increased in EAOC (p < 0.05). Conclusions: the dysregulation of TILs, TAMs, and T-cell exhaustion might play a role in the malignization of OE to EAOC. [ABSTRACT FROM AUTHOR]

Purpose: Polyamine modulating factor 1 binding protein (PMFBP1) acts as a scaffold protein for the maintenance of sperm structure. The aim of this study was further to identify the new role and molecular mechanism of PMFBP1 during mouse spermatogenesis. Methods and Results: We identified a profile of proteins interacting with PMFBP1 by immunoprecipitation combined with mass spectrometry and demonstrated that class I histone deacetylases, particularly HDAC3 and chaperonin-containing TCP1 subunit 3 (CCT3), were potential interaction partners of PMFBP1 based on network analysis of protein-protein interactions and co-immunoprecipitation. Immunoblotting and immunochemistry assays showed that loss of Pmfbp1 would result in a decline in HDACs and change the proteomic profile of mouse testis, in which differently expressed proteins are associated with spermatogenesis and assembly of flagella, which was proved by proteomic analysis of testis tissue obtained from Pmfbp1−/− mice. After integrating with transcriptome data for Hdac3−/− and Sox30−/− round sperm obtained from a public database, RT-qPCR confirmed ring finger protein 151 (Rnf151) and ring finger protein 133 (Rnf133) were key downstream response factors of the Pmfbp1-Hdac axis affecting mouse spermatogenesis. Conclusion: Taken together, this study indicates a previously unidentified molecular mechanism of PMFBP1 in spermatogenesis whereby PMFBP1 interacts with CCT3, affecting the expression of HDAC3, followed by the downregulation of RNF151 and RNF133, resulting in an abnormal phenotype of sperm beyond the headless sperm tails. These findings not only advance our understanding of the function of Pmfbp1 in mouse spermatogenesis but also provide a typical case for multi-omics analysis used in the functional annotation of specific genes. [ABSTRACT FROM AUTHOR]

Middle ear adenomatous neuroendocrine tumors (MEANT) are rare, mainly benign neoplasms and account for less than 2% of the middle and inner ear neoplasms. There are no specific radiological or clinical findings; therefore, the diagnosis is often difficult. Biopsy prior to surgery is often proposed. The definite treatment is the complete surgical resection. We present an uncommon clinical report of a MEANT, which was treated successfully with surgical excision. [ABSTRACT FROM AUTHOR]