Cytomorphological characteristics of low-grade papillary urothelial carcinoma in voided urine samples: Distinction from benign and high-grade papillary urothelial carcinoma.

OBJECTIVE: Given its frequent recurrence and the potential for high-grade transformation, accurate diagnosis of low-grade papillary urothelial carcinoma (LGPUC) in urine cytology is clinically important. We attempted to identify cytomorphologic features in urine samples, which could be helpful for the identification of LGPUC. METHODS: We conducted a retrospective review of voided urine specimens collected from patients with histopathologic diagnoses of LGPUC. Their cytomorphological features were compared with those from patients with benign conditions and high-grade papillary urothelial carcinoma (HGPUC). RESULTS: A total of 115 voided urine specimens were evaluated, including 30 benign, 41 LGPUC, and 44 HGPUC cases. In LGPUC, 18 cases (44%) were diagnosed as atypical, a proportion significantly higher than that observed in benign cases (4 cases, 13%), while the remaining 23 cases (56%) were diagnosed as negative. LGPUC urine samples tended to have higher cellularity than benign cases, but the difference was not statistically significant. Three cytological features, namely nuclear enlargement, higher nuclear-to-cytoplasmic (N/C) ratio, and presence of small cell clusters, were statistically more prevalent in LGPUC compared to benign cases, although the changes were relatively subtle. In contrast, cytomorphological distinction between LGPUC and HGPUC was evident, as high cellularity, nuclear enlargement, hyperchromasia, high N/C ratio, irregular nuclear membrane, and apoptosis were significantly more prevalent in HGPUC cases. CONCLUSIONS: Several cytomorphologic features in voided urine samples were more prevalent in cases with LGPUC, albeit not observed in all instances. Since these alterations were relatively subtle, meticulous attention to these cytomorphologic details is crucial to suggest the possibility of LGPUC.

[Mechanism of total saponins of Panax japonicus against liver injury induced by acetaminophen in mice based on ERK/NF-κB/COX-2 signaling pathway].

This study investigated the effects and mechanisms of total saponins of Panax japonicus(TSPJ) against liver injury induced by acetaminophen(APAP). Male Kunming mice were randomly divided into a blank control group, TSPJ group(200 mg·kg~(-1), ig), model group, APAP+ TSPJ low-dose group(50 mg·kg~(-1), ig), APAP+ TSPJ medium-dose group(100 mg·kg~(-1), ig), APAP+ TSPJ high-dose group(200 mg·kg~(-1), ig), and APAP+ N-acetyl-L-cysteine group(200 mg·kg~(-1), ip). The administration group received the corresponding medications via ig or ip once a day for 14 consecutive days. After the last administration for one hour, except for the blank control group and TSPJ group, all groups of mice were given 500 mg·kg~(-1) APAP by gavage. After 24 hours, mouse serum and liver tissue were collected for serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), reactive oxygen species(ROS), tumor necrosis factor alpha(TNF-α), interleukin-1 beta(IL-1ß), cyclooxygenase-2(COX-2), IL-6, IL-4, IL-10, as well as lactate dehydrogenase(LDH), glutathione(GSH), superoxide dismutase(SOD), catalase(CAT), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and myeloperoxidase(MPO) liver tissue. Hematoxylin-eosin staining was used to observe the morphological changes of liver tissue. The mRNA expression levels of lymphocyte antigen 6G(Ly6G), galectin 3(Mac-2), TNF-α, IL-1ß, COX-2, IL-6, IL-4, and IL-10 in liver tissue were determined by quantitative real-time polymerase chain reaction(PCR). Western blot was utilized to detect the protein expression levels of Ly6G, Mac-2, extracellular regulated protein kinases(ERK), phosphorylated extracellular regulated protein kinases(p-ERK), COX-2, inhibitor of nuclear factor κB protein α(IκBα), phosphorylated inhibitor of nuclear factor κB protein α(p-IκBα), and nuclear factor-κB subunit p65(NF-κB p65) in cytosol and nucleus in liver tissue. The results manifested that TSPJ dramatically reduced liver coefficient, serum ALT, AST, ROS, TNF-α, IL-1ß, IL-6, and COX-2 levels, LDH, MPO, and MDA contents in liver tissue, and mRNA expressions of TNF-α, IL-1ß, and IL-6 in APAP-induced liver injury mice. It prominently elevated serum IL-4 and IL-10 levels, GSH, CAT, SOD, and T-AOC contents, and mRNA expressions of IL-4 and IL-10 in liver tissue, improved the degree of liver pathological damage, and suppressed neutrophil infiltration and macrophage recruitment in liver tissue. In addition, TSPJ lessened the mRNA and protein expressions of neutrophil marker Ly6G, macrophage marker Mac-2, and COX-2 in liver tissue, protein expressions of p-ERK, p-IκBα, and NF-κB p65 in nuclear, and p-ERK/ERK and p-IκBα/p-IκBα ratios and hoisted protein expression of NF-κB p65 in cytosol. These results suggest that TSPJ has a significant protective effect on APAP-induced liver injury in mice, and it can alleviate APAP-induced oxidative damage and inflammatory response. Its mechanism may be related to suppressing ERK/NF-κB/COX-2 signaling pathway activation, thus inhibiting inflammatory cell infiltration, cytokine production, and liver cell damage.

Adenocarcinoma of anogenital mammary gland type arising from encapsulated papillary carcinoma: A rare vulvar tumor mimicking breast carcinoma.

Anogenital mammary-like glands are normal structures of the anogenital region. Tumors originating from these glands often exhibit a striking resemblance to their mammary gland counterparts. Herein, we present a rare case of adenocarcinoma of mammary gland type in the vulva of a 69-year-old female. Histopathologic examination revealed a complex lesion, which included a large encapsulated papillary carcinoma (EPC) with associated invasive carcinoma of mammary gland type and ductal carcinoma in situ (DCIS). The invasive component consisted mostly of invasive ductal carcinoma of no special type, with a notable focus of invasive mucinous carcinoma. p40 immunostain demonstrated a lack of myoepithelial cells in both the EPC and invasive carcinoma, but such cells expressed p40 around the ducts involved by DCIS. The main component of this lesion, EPC, was characterized by a papillary proliferation within a cystic space surrounded by a fibrous capsule without a myoepithelial layer. The histopathologic features of anogenital EPC closely resemble cutaneous hidradenoma papilliferum. Indeed, there have been a few reports in the literature describing cases where in situ and invasive carcinoma arose from a preexisting hidradenoma papilliferum. As tumors of anogenital mammary-like glands bear a closer resemblance to breast lesions than to skin tumors, we recommend that they be aligned with the classification of well-established breast lesions rather than cutaneous adnexal tumors.

Artificial intelligence-aided steatosis assessment in donor livers according to the Banff consensus recommendations.

OBJECTIVES: Severe macrovesicular steatosis in donor livers is associated with primary graft dysfunction. The Banff Working Group on Liver Allograft Pathology has proposed recommendations for steatosis assessment of donor liver biopsy specimens with a consensus for defining "large droplet fat" (LDF) and a 3-step algorithmic approach. METHODS: We retrieved slides and initial pathology reports from potential liver donor biopsy specimens from 2010 to 2021. Following the Banff approach, we reevaluated LDF steatosis and employed a computer-assisted manual quantification protocol and artificial intelligence (AI) model for analysis. RESULTS: In a total of 113 slides from 88 donors, no to mild (<33%) macrovesicular steatosis was reported in 88.5% (100/113) of slides; 8.8% (10/113) was reported as at least moderate steatosis (≥33%) initially. Subsequent pathology evaluation, following the Banff recommendation, revealed that all slides had LDF below 33%, a finding confirmed through computer-assisted manual quantification and an AI model. Correlation coefficients between pathologist and computer-assisted manual quantification, between computer-assisted manual quantification and the AI model, and between the AI model and pathologist were 0.94, 0.88, and 0.81, respectively (P < .0001 for all). CONCLUSIONS: The 3-step approach proposed by the Banff Working Group on Liver Allograft Pathology may be followed when evaluating steatosis in donor livers. The AI model can provide a rapid and objective assessment of liver steatosis.

Detection of Large-Droplet Macrovesicular Steatosis in Donor Livers Based on Segment-Anything Model.

Liver transplantation is an effective treatment for end-stage liver disease, acute liver failure, and primary hepatic malignancy. However, the limited availability of donor organs remains a challenge. Severe large-droplet fat (LDF) macrovesicular steatosis, characterized by cytoplasmic replacement with large fat vacuoles, can lead to liver transplant complications. Artificial intelligence models, such as segmentation and detection models, are being developed to detect LDF hepatocytes. The Segment-Anything Model, utilizing the DEtection TRansformer architecture, has the ability to segment objects without prior knowledge of size or shape. We investigated the Segment-Anything Model's potential to detect LDF hepatocytes in liver biopsies. Pathologist-annotated specimens were used to evaluate model performance. The model showed high sensitivity but compromised specificity due to similarities with other structures. Filtering algorithms were developed to improve specificity. Integration of the Segment-Anything Model with rule-based algorithms accurately detected LDF hepatocytes. Improved diagnosis and treatment of liver diseases can be achieved through advancements in artificial intelligence algorithms for liver histology analysis.

Folliculotropic Mycosis Fungoides Is Associated with Decreased PD1 Staining Compared with Classic Mycosis Fungoides.

Programmed cell death protein 1 (PD-1) plays a pivotal role in immune system regulation, with its expression levels linked to malignancy prognosis. However, existing reports on PD-1 staining in mycosis fungoides (MF) present conflicting findings, and little attention has been given to PD-1 staining in different MF variants. To address this, we conducted a retrospective study, employing immunohistochemistry to examine PD-1 expression in cases of folliculotropic MF and non-folliculotropic MF. We analyzed 24 cases of folliculotropic MF and 18 cases of non-folliculotropic MF, and recorded both the percentage of PD-1-labeled tumor cells and the intensity score (negative, weak, medium, or strong). Our results revealed significant disparity in PD-1 labeling between patch/plaque MF and folliculotropic MF (p = 0.028). Non-folliculotropic MF exhibited higher PD-1 labeling in tumor cells (58.3%) compared to folliculotropic MF (40.2%). Notably, there was no significant difference in PD-1 staining between folliculotropic MF and non-folliculotropic MF when both were in the early stage/indolent disease category. However, when considering the tumor stage, folliculotropic MF exhibited PD-1 staining in tumor cells at a rate of 21.1%, while non-folliculotropic MF showed PD-1 staining in tumor cells at a rate of 46.6% (p = 0.005). Additionally, among folliculotropic MF cases, 13 out of 24 cases displayed differing PD-1 expression patterns between epidermal and dermal components, with preserved PD-1 staining in the epidermal component and loss of staining in the dermal component. Furthermore, consistent with the prior literature, tumor cells with large cell transformations exhibited significantly lower PD-1 labeling (p = 0.017). Our findings showcase the unique PD-1 staining patterns in MF.

Prognostic impact of reduced HER2 protein expression in post-neoadjuvant therapy resection specimens: A single institution experience and review of the literature.

BACKGROUND: Retesting for Human epidermal growth factor receptor-2 (HER2) in post-neoadjuvant therapy resection is variable, and data is conflicting regarding the prognostic significance of changes in HER2 expression pre and post therapy. METHODS: We identified 104 patients with localized HER2 IHC 3+ breast cancer who received neoadjuvant trastuzumab(T)/pertuzumab(P) containing chemotherapy at Yale Cancer Center between 2012 and 2022. Patients were divided into 3 cohorts by response and HER2 IHC in the residual disease: Cohort 1 pathologic complete response (pCR), Cohort 2 pre-treatment IHC 3+/post treatment IHC 1+/2+, and Cohort 3 pre-treatment IHC 3+/post-treatment IHC 3+. Kaplan-Meier survival analysis was performed to assess recurrence free survival at 36 months. RESULTS: The overall pCR rate was 62.5% (65/104), while 37.5% (39/104) of patients had residual disease (RD). Among patients with RD, 58.9% (23/39) remained IHC 3+ and 41.1% (16/39) had reduced HER2 expression IHC1+ or 2+. In patients with HER2 IHC 3+ RD, 26% (6/23) developed local recurrence or distant metastasis while none of patients with post NAT HER2 IHC 1+ or 2+ RD had relapse (p = 0.0309). In patients with pCR, 6.15% (4/65) had recurrence. Kaplan-Meier survival analysis revealed superior disease-free survival in patients with reduced HER2 IHC expression compared to those with remained IHC 3+ (log rank p = 0.004). CONCLUSION: We conclude that reduced HER2 expression by IHC following neoadjuvant treatment was associated with lower recurrence rates in HER2 IHC 3+ breast cancer. If confirmed, RD HER2 IHC expression could be used as a prognostic biomarker to stratify patients in adjuvant trials and identify patients who may benefit from more intensive adjuvant therapy and post therapy surveillance.

Clinicopathologic Features of Cutaneous T-Cell Lymphomas With Extracutaneous Metastasis: A Case Series.

BACKGROUND: In advanced stages, Cutaneous T-cell lymphomas (CTCL) can metastasize to extracutaneous regions. CTCL with metastasis exhibits unique clinicopathologic characteristics. PATIENTS AND METHODS: This study collected 35 cases of primary CTCL with extracutaneous metastasis from a single institution over a period of 20 years. Clinicopathologic features including demographics, CD30 expression, large cell transformation, metastatic sites, T-cell receptor clonality studies and survival data were analyzed. RESULTS: The study identified various CTCL entities including mycosis fungoides (MF), Sezary syndrome (SS), cutaneous anaplastic large cell lymphoma (C-ALCL), and primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS). Limited data showed that metastasis can be independent of large cell transformation and/or CD30 expression. Lymph nodes were the most common site of metastasis, followed by the bone marrow. Oropharyngeal metastasis is likely to accompany visceral organ or brain metastasis (P = .049). MF had a longer interval to metastasis than SS (P = .038). Patients with lymph node only metastasis have better survival than patients with metastasis to other sites (P = .012). CONCLUSION: To the best of our knowledge, there are limited studies analyzing the clinicopathologic features of different CTCL entities with metastasis as a single population. This research provides valuable insights into the unique characteristics of metastatic CTCL.

PRAME-negativity in sclerosing nevi with pseudomelanomatous features supports classification as an indolent lesion.

BACKGROUND: Some dysplastic nevi, termed sclerosing nevi with pseudomelanomatous features, may have florid fibroplasia associated with features that cause melanoma to be a prominent consideration in the differential diagnosis. PRAME (PReferentially expressed Antigen in MElanoma) immunohistochemistry (IHC) has been shown to be a useful marker in the distinction of melanoma and nevus. PRAME expression in such sclerosing nevi with pseudomelanomatous features has not been evaluated to our knowledge. METHODS: Thirty-two sclerosing nevi with pseudomelanomatous features were stained with PRAME IHC, with positive labeling defined as staining of >75% of the cytomorphologically atypical lesional cells. RESULTS: All 32 cases had variable cytologic atypia, bridging of elongated rete, fibroplasia, and a vertically oriented trizonal appearance. Some cases (23/32) had centrally located flattening of the rete ridge pattern bilaterally flanked by fibroplasia associated with elongated rete. PRAME labeling was negative (<1% labeling) in 28/32 cases. Four cases, also interpreted as having negative labeling with PRAME, showed only weak nuclear positivity of <50% of the melanocytes within the pseudomelanomatous foci. p16 staining was positive in 28/28 lesions. CONCLUSIONS: Rare sclerosing nevi with pseudomelanomatous features (4/32; ~13%) had weak PRAME labeling of 25%-50% of atypical foci. Twenty-eight of 32 lesions had virtually no labeling with PRAME. PRAME results support classifying sclerosing nevi with pseudomelanomatous features as indolent lesions.

IRF8 may be a useful marker for blastic plasmacytoid dendritic cell neoplasm, especially with weak CD123 expression.

We highlight the utility of interferon regulatory factor 8 (IRF8), a novel marker of monocytic and dendritic cell lineages, in the diagnosis of a case of blastic plasmacytoid dendritic cell neoplasm (BPDCN) presenting initially in the skin. A 60-year-old male with a previous history of myelodysplastic syndrome presented with cutaneous nodules on chest and scalp. A punch biopsy specimen of a skin nodule showed a diffuse dermal infiltrate of atypical mononuclear cells. The neoplastic cells expressed CD4, CD56, CD43, and TdT but showed minimal reaction for TCL-1 and CD123, and were negative for CD34, CD117, and MPO, confounding the diagnosis. IRF8 performed in retrospect was strongly positive. A new punch biopsy specimen of a chest nodule showed the blastoid tumor cells were positive for TCL-1, CD4, and CD56, but dim CD123. Subsequent bone marrow involvement showed blastoid tumor cells with intense positivity for CD123, CD4, and CD56, which was supportive of the BPDCN diagnosis. BPDCN cases with weak or variable CD123 and TCL-1 expression represent a potential diagnostic pitfall. In a recent study, 15 cases of BPDCN showed uniformly strong staining for IRF8, while CD123 was dim or negative in 4 of these 15 cases. We suggest IRF8 may be a useful marker for BPDCN, especially in cases with weak or variable expression of CD123 and TCL1.

Squamous carcinogenesis: potential truncal mutations.

Squamous carcinogenesis is incompletely understood, but more recent genetic studies support that the order of acquired mutations is important. This paper will review more recent genetic studies with an emphasis on the potential truncal mutations, mutations critical to the trunk of the cancer evolutionary tree, in actinic keratosis, squamous cell carcinoma in situ, cutaneous squamous cell carcinoma, keratoacanthoma, and keratoacanthoma-like squamous proliferation.

AMACR Expression is a Potential Diagnostic Marker in Apocrine Lesions of Breast, and is Associated with High Histologic Grade and Lymph Node Metastases in Some Invasive Apocrine Breast Cancers.

BACKGROUND: Carcinoma with apocrine differentiation (AC) is a subtype of breast carcinoma with apocrine features in >90% of the tumor. Molecular studies demonstrate AC has high expression of androgen receptor (AR) mRNA. Pure AC lack estrogen receptor (ER), progesterone receptor (PR), and express AR, with variable human epidermal growth factor 2 (HER2) status. Currently, in triple negative AC, no targetable therapies or specific diagnostic markers exist. MATERIALS AND METHODS: α-Methylacyl CoA racemase (AMACR) expression was investigated as a marker of apocrine differentiation using a single-plex immunoperoxidase stain, and a novel AMACR/p63 dual stain in a subset of cases, across 1) benign apocrine lesions (apocrine metaplasia, adenosis) 2) apocrine DCIS (ADCIS), 3) AC/ invasive ductal carcinoma (IDC) with apocrine features, 4) non-apocrine triple negative breast cancer (TNBC) and 5) IDC, no special type. A sub-set of cases were evaluated by tissue microarray. RESULTS: AMACR expression was increased in both AC and ADCIS, with minimal expression in benign breast tissue, TNBC and IDC, NST cases. In invasive cases, those with positive AMACR (>5% positivity) were significantly associated with higher histologic grade (P = .006), initial N stage (chi squared 0.044), and lack of ER or PR expression (both P < .001), with no correlation with overall survival. Analysis of TCGA breast cancer datasets revealed AMACR expression was significantly higher in molecularly defined apocrine carcinomas relative to basal and luminal subtypes. Moreover, high AMACR expression predicted worse relapse-free and distant-metastasis free survival, among both ER-/PR-/Her2- and ER-/PR-/Her2+ breast cancer cohorts (log-rank P = .081 and .00011, respectively). CONCLUSION: AMACR represents a promising diagnostic and prognostic marker in apocrine breast lesions. Further study is needed to determine the biologic and clinical significance of this protein in AC.

Claudin-4 Upregulation in Acantholytic and Autoimmune-Mediated Bullous Disorders.

Claudin-4 is a key component of tight junctions, which play an important role in the formation of the epidermal barrier by forming a circumferential network in the granular layer that serves as a gatekeeper of the paracellular pathway. The aim of this study is to illustrate claudin-4 immunohistochemical staining patterns of different blistering disorders. We collected 35 cases, including two Hailey-Hailey disease, one Darier disease, three Grover disease, one acantholytic acanthoma, two warty dyskeratoma, 11 pemphigus vulgaris (PV) including six mucosal PV, and two pemphigus foliaceus. For comparison, we included five cases of normal skin, five eczema, and three bullous pemphigoid cases. Claudin-4 demonstrated weak-to-moderate expression in keratinocytes located in the stratum granulosum, keratinocytes surrounding hair follicles, and adnexal glands. Further, claudin-4 exhibited moderate-to-strong membranous staining in disrupted keratinocytes surrounding and within the acantholytic and bullous areas in 16/22 of the acantholytic cases (not seen in the six cases of mucosal PV) and all three bullous pemphigoids. This finding suggests that claudin-4 is upregulated in these conditions, which may be a compensatory response to the disrupted barrier function. This finding could shed light on the molecular mechanisms underlying disrupted barrier function in blistering disorders, independent of the specific underlying disease mechanism.

Ki-67 index assessment on FNA specimens of gastrointestinal stromal tumor: Correlation with mitotic rate and potential predictive value for risk stratification.

BACKGROUND: Risk assessment of gastrointestinal stromal tumor (GIST) is challenging on cytology specimens. This study aims to determine whether Ki-67 index evaluated on fine-needle aspiration (FNA) specimens can correlate with the mitotic rate of GIST in surgical specimens and provide further risk assessment. METHODS: Cases with cell blocks containing adequate tumor cells and surgical resections were included. Ki-67 immunostain was retrospectively performed on cell block sections, and Ki-67 index was calculated on the "hot spot" areas. RESULTS: This study included 50 GIST cases from stomach (n = 45; 90%), duodenum (n = 4; 8%), and distal esophagus (n = 1; 2%). The tumor size ranged from 1.5 cm to 21 cm (mean, 5.4 cm). Based on the mitotic count, 37 GISTs (74%) had low mitotic rate (LMR) and 13 GISTs (26%) had high mitotic rate (HMR). The spindle cell, epithelioid, and mixed types accounted for 60%, 14%, and 26% of GIST, respectively. Ki-67 index counted on cell block sections correlated well with mitotic count evaluated in surgical specimens (r = 0.8031). Mean Ki-67 index was higher in HMR than LMR groups (3.5% vs. 1%, p < .001). The receiver operating characteristic curve using Ki-67 index to predict mitotic rate was further analyzed, and area under the curve was 0.839. Using a cutoff of 2.5% yielded a sensitivity of 70% at 92% specificity. CONCLUSIONS: This study demonstrates good correlations between Ki-67 index and mitotic count or risk stratification, suggesting that Ki-67 index evaluated on cytology specimens may offer a promising approach to preoperatively predict the mitotic rate and risk of GIST.

Human herpesvirus 8-negative effusion-based large B-cell lymphoma: a distinct entity with unique clinicopathologic characteristics.

Rare cases of human herpesvirus 8 (HHV8)-negative effusion-based large B-cell lymphoma (EB-LBCL) occur in body cavities without antecedent or concurrent solid mass formation. In contrast to HHV8 + primary effusion lymphoma (PEL), EB-LBCL has no known association with HIV or HHV8 infection. However, the small sample sizes of case reports and series worldwide, especially from non-Japanese regions, have precluded diagnostic uniformity. Therefore, we conducted a retrospective, multi-institutional study of 55 cases of EB-LBCL and performed a comprehensive review of an additional 147 cases from the literature to identify distinct clinicopathologic characteristics. In our study, EB-LBCL primarily affected elderly (median age 80 years), immunocompetent patients and manifested as lymphomatous effusion without a solid component. The lymphomatous effusions mostly occurred in the pleural cavity (40/55, 73%), followed by the pericardial cavity (17/55, 31%). EB-LBCL expressed CD20 (53/54, 98%) and PAX5 (23/23, 100%). Most cases (30/36, 83%) were of non-germinal center B-cell subtype per the Hans algorithm. HHV8 infection was absent (0/55, 0%), while Epstein-Barr virus was detected in 6% (3/47). Clinically, some patients were managed with drainage alone (15/34, 44%), while others received rituximab alone (4/34, 12%) or chemotherapy (15/34, 44%). Eventually, 56% (22/39) died with a median overall survival (OS) of 14.9 months. Our findings were similar to those from the literature; however, compared to the non-Japanese cases, the Japanese cases had a significantly higher incidence of pericardial involvement, a higher rate of chemotherapy administration, and longer median OS. Particularly, we have found that Japanese residence, presence of pericardial effusion, and absence of MYC rearrangement are all favorable prognostic factors. Our data suggest that EB-LBCL portends a worse prognosis than previously reported, although select patients may be managed conservatively. Overall, EB-LBCL has distinct clinicopathologic characteristics, necessitating the establishment of separate diagnostic criteria and consensus nomenclature.

Cholesterol Metabolic Markers for Differential Evaluation of Patients with Hyperlipidemia and Familial Hypercholesterolemia.

The cholesterol metabolism in humans can be indirectly reflected by measuring cholesterol metabolism marker levels. We aimed to investigate the association of cholesterol homeostasis markers on standard lipid profiling components in familial hypercholesteremia and hyperlipidemia patients. A total of 69 hyperlipidemia patients, 25 familial hypercholesteremia (FHC) patients, and 64 healthy controls were enrolled in this study. We performed routine testing of blood lipid water. Gas chromatography was used to determine the changes in the concentration of cholesterol synthesis (squalene, desmosterol, and lathosterol) and absorption markers (campesterol, sitosterol, and stigmasterol) in the blood. Baseline hyperlipidemia patients displayed significantly higher total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels in comparison to the control group, which was reflected in the increased levels of squalene, desmosterol, campesterol, and sitosterol observed (P < 0.05) in the hyperlipidemia patients. The desmosterol, lathosterol, campesterol, stigmasterol, and sitosterol were statistically different in the FHC group than the hyperlipidemic group (P < 0.05). The proportions of squalene/cholesterol, lathosterol/cholesterol, stigmasterol/cholesterol, and sitosterol/cholesterol in the FHC group were lower than those in the hyperlipidemic group; only desmosterol/cholesterol was higher than that in the hyperlipidemic group. Correlation studies between lipid metabolic factors showed that the proportion of moderate and strong correlations was much higher in the FHC group than in the other two groups (76.92% vs. 32.50% and 31.25%). Logistic regression analysis showed that the concentrations of glucose, LDL-C, lactosterol, and sitosterol were all independent risk factors for developing hyperlipidemia. This result was further confirmed by the ROC curve. These results indicated that the study of cholesterol synthesis and decomposition markers can serve as a reference index for related diseases caused by changes in its concentration.

Improving Generalization of Deep Learning Models for Diagnostic Pathology by Increasing Variability in Training Data: Experiments on Osteosarcoma Subtypes.

BACKGROUND: Artificial intelligence has an emerging progress in diagnostic pathology. A large number of studies of applying deep learning models to histopathological images have been published in recent years. While many studies claim high accuracies, they may fall into the pitfalls of overfitting and lack of generalization due to the high variability of the histopathological images. AIMS AND OBJECTS: Use the model training of osteosarcoma as an example to illustrate the pitfalls of overfitting and how the addition of model input variability can help improve model performance. MATERIALS AND METHODS: We use the publicly available osteosarcoma dataset to retrain a previously published classification model for osteosarcoma. We partition the same set of images into the training and testing datasets differently than the original study: the test dataset consists of images from one patient while the training dataset consists images of all other patients. We also show the influence of training data variability on model performance by collecting a minimal dataset of 10 osteosarcoma subtypes as well as benign tissues and benign bone tumors of differentiation. RESULTS: The performance of the re-trained model on the test set using the new partition schema declines dramatically, indicating a lack of model generalization and overfitting. We show the additions of more and moresubtypes into the training data step by step under the same model schema yield a series of coherent models with increasing performances. CONCLUSIONS: In conclusion, we bring forward data preprocessing and collection tactics for histopathological images of high variability to avoid the pitfalls of overfitting and build deep learning models of higher generalization abilities.

Effects of long-term fertilizer management on soil labile organic carbon fractions and hydrolytic enzyme activity under a double-cropping rice system of southern China.

Fertilization is an effective way to improve soil quality, increase soil fertility and soil microbial diversity in paddy soil. To explore the changes of soil labile organic carbon (C) fractions and hydrolytic enzyme activity after 34 years fertilization treatments in a field experiment in double-cropping rice system of southern China. There were four treatments, including chemical fertilizer alone (MF), rice residue and chemical fertilizer (RF), 30% organic matter and 70% chemical fertilizer (OM), and the control without fertilizer input (CK). We measured soil organic carbon (SOC) content, soil labile organic C fractions, SOC related hydrolytic enzyme activity, correlation coefficients of soil enzyme activity with SOC content and its labile organic C fractions. The results showed that MF, RF and OM increased SOC content by 4.5%, 22.4% and 53.5%, respectively. Compared with MF and CK, RF and OM increased soil labile organic C fractions [cumulative C mineralization (Cmin), permanganate oxidizable C (KMnO4-C), particulate organic C (POC), dissolved organic C (DOC), light fraction organic C (LFOC), microbial biomass C (MBC)] and the proportion of each labile organic C fractions to total organic C. The contents of Cmin, KMnO4-C, POC, DOC, LFOC and MBC under OM treatment were 3.5, 3.1, 3.7, 1.9, 1.2 and 1.9 times higher than CK treatment, respectively. The proportion of labile organic C fractions to total organic C of RF and OM treatments was significantly higher than that in CK. The order of soil hydrolytic enzyme activity [α-glucosidase (αG), ß-glucosidase (ßG), ß-xylosidase (ßX), cellobiohydrolase (GBH), and N-acetyl-ß-glucosaminidase (NAG)] was OM>RF>MF>CK. The soil hydrolytic enzyme activity under OM treatment increased by 111.8%, 14.1%, 127.3%, 285.6% and 91.4% compared with CK, respectively. Furthermore, RF and OM treatments were beneficial to soil peroxidase (POD) activity. MF treatment was beneficial to soil polyphenol oxidase (PPO) activity. There was a significant positive correlation between soil hydrolytic enzyme activity and SOC content and its labile organic C fractions. In conclusion, the combined application of organic manure, rice straw returning and chemical fertilizer is an effective method to improve soil labile organic C fractions and hydrolytic enzyme activity in a double-cropping rice paddy field of southern China.

Respiratory Rates Derived From Arterial Blood Pressure Waveforms in Telemetered Dogs.

The objective of this study was to extract low frequency respiratory "artifacts" from a standard arterial blood pressure (ABP) waveform to simultaneously derive reliable breathing rates (BR). Arterial blood pressure derived BR values were characterized against respiratory rates simultaneously obtained from the Respiratory Inductive Plethysmography (RIP) system (EMKA). Reference compounds were introduced to evaluate responsiveness of the derived measures to respiratory depressants and stimulants. Male beagle dogs (n = 3) were instrumented with minimally invasive telemetry devices for measurements of ABP and heart rate. The RIP system was utilized simultaneously to collect respiratory rate, tidal volume, and minute volume of each animal following pharmacological challenges. Early results revealed the derived BR's from ABP waveforms did not correlate well with those measured from the RIP system. Post study X-ray visualization revealed suboptimal catheter positioning, causing poor concordance of BR tallied from the ABP waveforms. Follow-up evaluations were conducted using additional animals instrumented with the ABP catheter tip placement advanced proximal to the thoracic diaphragm. Preliminary data from this subset of animals significantly improved the correlation of BR derived from ABP and respiratory rates recorded by the RIP. This proof of concept investigation was intended to evaluate an algorithm designed to extract additional data from routine cardiac waveforms. We clearly demonstrated that with optimal blood pressure catheter placement and acquisition algorithm, a reliable breathing rate can also be extracted from safety studies without the need for additional studies/animals to capture those respiratory end points.

Effects of long-term fertilization practices on heavy metal cadmium accumulation in the surface soil and rice plants of double-cropping rice system in Southern China.

Fertilizer regime is playing an important role in heavy metal cadmium (Cd) accumulation in paddy soils and crop plant. It is necessary to assess the Cd accumulation in soils and rice (Oryza sativa L.) plants under long-term fertilization managements, and the results which help to assess the environmental and food risk in Southern China. However, the effects of different organic manure and chemical fertilizers on Cd accumulation in soils and rice plant remain unclear under intensively cultivated rice conditions. Therefore, the objective was to explore Cd accumulation in paddy soils and rice plant at mature stage under different long-term fertilization managements in the double-cropping rice system. Cd accumulation in the surface soils (0-20 cm) and rice plant with chemical fertilizer alone (MF), rice straw residue and chemical fertilizer (RF), 30% organic matter and 70% chemical fertilizer (LOM), 60% organic matter and 40% chemical fertilizer (HOM), and without fertilizer input (CK) basis on 32 years long-term fertilization experiment were analyzed. The results showed that the soil total Cd content was increased by 0.296 and 0.351 mg kg-1 and 0.261 and 0.340 mg kg-1 under LOM and HOM treatments at early and late rice mature stages, respectively, compared with the CK treatment. And the soil available Cd content was increased by 0.073 and 0.137 mg kg-1 and 0.102 and 0.160 mg kg-1 under LOM and HOM treatments at early and late rice mature stages, respectively, compared with the CK treatment. The bioconcentration factor of Cd across different parts of rice plant was the highest in root, followed by stem and grain, and the lowest in leaves. At early and late rice mature stages, the root Cd concentration of rice plant was increased by 0.689 and 0.608 mg kg-1 with HOM treatment, the stem Cd concentration of rice plant was increased by 0.666 and 0.758 mg kg-1 with RF treatment, and the leaf and grain Cd concentration of rice plant was increased 0.094 and 0.082 mg kg-1 and 0.086 and 0.083 mg kg-1 with LOM treatment, respectively, compared with the CK treatment. The soil Cd single-factor contaminant index (PCd) under different fertilization treatments was as the following HOM > LOM > RF > MF > CK. Meanwhile, the PCd with LOM and HOM treatments was higher than that of the MF, RF, and CK treatments, but there is no significant difference between that of MF and RF treatments. Therefore, long-term application of rice straw residue and chemical fertilizer had no obvious effect on the accumulation of Cd in paddy soils and grain, and soil Cd accumulation was increased as application of organic fertilizer.