A new risk factor for coronary artery disease can be detected by an ApoA1 mAb-based assay.

BACKGROUND: This study aimed to find coronary artery disease (CAD) related apolipoprotein A1 (ApoA1) monoclonal antibody (mAb) and to evaluate the diagnostic value of the assay based on it. METHODS: Patients with CAD diagnosed by coronary angiography (disease group, n = 180) and healthy subjects (control group, n = 199) were recruited. The correlation between methods and CAD were evaluated by Spearman's rank correlation coefficients. Receiver operating characteristic (ROC) curve analysis was used to evaluate the auxiliary diagnostic value of methods for CAD. Odds ratios (ORs) of the test results in CAD were estimated using logistic regression analysis. RESULTS: Measurements from an ApoA1 mAb were found significantly positively correlated with CAD (r = 0.243, P < 0.01), unlike the measurements from the ApoA1 pAb were negatively correlated with CAD (r = -0.341, P < 0.001). The areas under the ROC curve of the ApoA1 mAb and pAb measurements were 0.704 and 0.563, respectively, in patients with normal HDL-C levels. ApoA1 values from the mAb assay had a significant positive impact on CAD risk. CONCLUSION: An ApoA1 mAb-based assay can distinguish a high-density lipoprotein (HDL) subclass positively related to CAD, which can be used to improve and reappraise CAD risk assessment.

Report of a Novel Molecular Profile in Malignant Insulinoma.

Pancreatic neuroendocrine tumors, or pNETs, represent a rare and clinically heterogenous subset of pancreatic neoplasms. One such pNET, the insulinoma, is found to be malignant in just 4% of all insulinomas. Due to the exceedingly uncommon occurrence of these tumors, there is controversy regarding the optimal evidence-based management for these patients. We therefore report on a 70-year-old male patient admitted with 3 months of episodic confusion with concurrent hypoglycemia. The patient was found to have inappropriately elevated endogenous insulin levels during these episodes, and somatostatin-receptor subtype 2 selective imaging revealed a pancreatic mass metastatic to local lymph nodes, spleen, and the liver. Fine needle aspiration of pancreatic and liver lesions confirmed the diagnosis of a low grade pancreatic neuroendocrine tumor. Molecular analysis of tumor tissue revealed a novel mutational profile consistent with pNET. The patient was initiated on octreotide therapy. However, treatment with octreotide alone demonstrated limited efficacy in controlling the patient's symptoms, prompting consideration of other therapies.

Approach to Mediastinal Fine Needle Aspiration Cytology.

Mediastinal fine needle aspirations are routinely encountered in cytopathology practice. Mediastinal lesions may pose diagnostic challenges owing to their rarity and locations associated with the complexity of the mediastinal anatomic structures in the thoracic cavity. Diagnosing mediastinal lesions and guiding patient management usually require correlating with clinical and radiologic findings, being familiar with cytomorphologic features and appropriately triaging the diagnostic material for ancillary testing. This review proposes a practical approach to interpret mediastinal fine needle aspirations and emphasizes potential diagnostic pitfalls for mediastinal lesions including benign cysts, thymic neoplasms, lymphoproliferative disorders, germ cell tumors, mesenchymal tumors, and metastatic tumors.

Enhancement of the Thermoelectric Performance of Cu2GeSe3 via Isoelectronic (Ag, S)-co-substitution.

Recently, ternary Cu-based Cu-IV-Se (IV = Sb, Ge, and Sn) compounds have received extensive attention in the thermoelectric field. Compared with Cu-Sb-Se and Cu-Sn-Se, Cu-Ge-Se compounds have been less studied due to its poor Seebeck coefficient and high thermal conductivity. Here, the Cu2GeSe3 material with high electrical conductivity was first prepared, and then, its effective mass was increased by doping with S, which led to the Seebeck coefficient of the doped sample being 1.93 times higher than that of pristine Cu2GeSe3 at room temperature. Moreover, alloying Ag at the Cu site in the Cu2GeSe2.96S0.04 sample could further cause a 5.16 times increase in the Seebeck coefficient at room temperature, and the lattice thermal conductivity was remarkably decreased because of the introduction of the dislocations in the Cu2GeSe3 sample. Finally, benefitted from the high Seebeck coefficient and low thermal conductivity, a record high ZT = 0.9 at 723 K was obtained for the Cu1.85Ag0.15GeSe2.96S0.04 sample, which increased 345% in comparison with the pristine Cu2GeSe3, and it is among the highest reported values for Cu2GeSe3-based thermoelectric.

CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy.

Adoptive cell therapy with chimeric antigen receptor (CAR) immunotherapy has made tremendous progress with five CAR T therapies approved by the US Food and Drug Administration for hematological malignancies. However, CAR immunotherapy in solid tumors lags significantly behind. Some of the major hurdles for CAR immunotherapy in solid tumors include CAR T cell manufacturing, lack of tumor-specific antigens, inefficient CAR T cell trafficking and infiltration into tumor sites, immunosuppressive tumor microenvironment (TME), therapy-associated toxicity, and antigen escape. CAR Natural Killer (NK) cells have several advantages over CAR T cells as the NK cells can be manufactured from pre-existing cell lines or allogeneic NK cells with unmatched major histocompatibility complex (MHC); can kill cancer cells through both CAR-dependent and CAR-independent pathways; and have less toxicity, especially cytokine-release syndrome and neurotoxicity. At least one clinical trial showed the efficacy and tolerability of CAR NK cell therapy. Macrophages can efficiently infiltrate into tumors, are major immune regulators and abundantly present in TME. The immunosuppressive M2 macrophages are at least as efficient as the proinflammatory M1 macrophages in phagocytosis of target cells; and M2 macrophages can be induced to differentiate to the M1 phenotype. Consequently, there is significant interest in developing CAR macrophages for cancer immunotherapy to overcome some major hurdles associated with CAR T/NK therapy, especially in solid tumors. Nevertheless, both CAR NK and CAR macrophages have their own limitations. This comprehensive review article will discuss the current status and the major hurdles associated with CAR T and CAR NK therapy, followed by the structure and cutting-edge research of developing CAR macrophages as cancer-specific phagocytes, antigen presenters, immunostimulators, and TME modifiers.

The emergence and epidemic characteristics of the highly mutated SARS-CoV-2 Omicron variant.

Recently, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) was first identified in Botswana in November 2021. It was first reported to the World Health Organization (WHO) on November 24. On November 26, 2021, according to the advice of scientists who are part of the WHO's Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE), the WHO defined the strain as a variant of concern (VOC) and named it Omicron. Compared to the other four VOCs (Alpha, Beta, Gamma, and Delta), the Omicron variant was the most highly mutated strain, with 50 mutations accumulated throughout the genome. The Omicron variant contains at least 32 mutations in the spike protein, which was twice as many as the Delta variant. Studies have shown that carrying many mutations can increase infectivity and immune escape of the Omicron variant compared with the early wild-type strain and the other four VOCs. The Omicron variant is becoming the dominant strain in many countries worldwide and brings new challenges to preventing and controlling coronavirus disease 2019 (COVID-19). The current review article aims to analyze and summarize information data about the biological characteristics of amino acid mutations, the epidemic characteristics, immune escape, and vaccine reactivity of the Omicron variant, hoping to provide a scientific reference for monitoring, prevention, and vaccine development strategies for the Omicron variant.

Diagnostic Challenges in Fine-Needle Aspiration Cytology of Mediastinal Tumors and Lesions.

CONTEXT.­: Mediastinal tumors/lesions are frequently encountered in daily cytopathology practice. These lesions are accessible through endoscopic/endobronchial ultrasound-guided or computed tomography-guided fine-needle aspiration cytology and represent a wide range of primary and metastatic tumors. This often poses diagnostic challenges because of the complexity of the mediastinal anatomic structures. Tumors metastatic to mediastinal lymph nodes represent the most common mediastinal lesions and must be differentiated from primary lesions. OBJECTIVE.­: To provide an updated review on the fine-needle aspiration cytology of mediastinal tumors/lesions, with an emphasis on diagnostic challenges. This review encompasses thymic epithelial neoplasms, mediastinal lymphoproliferative disorders, germ cell tumors, neuroendocrine tumors, soft tissue tumors, and metastatic tumors. Differential diagnoses; useful ancillary studies, including targeted immunohistochemical panels; and diagnostic pitfalls are discussed. DATA SOURCES.­: Data were gathered from a PubMed search of peer-reviewed literature on mediastinal tumors. Data were also collected from the authors' own practices. CONCLUSIONS.­: Fine-needle aspiration cytology plays a vital role in evaluation of mediastinal lesions. Being familiar with the clinical and cytomorphologic features of these lesions, appropriately triaging the diagnostic material for ancillary testing, and correlating with radiologic findings are important in arriving at correct diagnoses and guiding management.

The Effect of Tramadol Versus Sufentanil on Controlling Postoperative Pain for Men Who Smoke and Do Not Smoke: A Randomized Clinical Trial.

BACKGROUND: Smoking behavior alters the analgesic threshold, which challenges postoperative pain management for patients who smoke. OBJECTIVES: We aimed to assess the analgesic efficacy of tramadol versus sufentanil in relieving postoperative pain for patients who do and do not smoke who underwent a partial hepatectomy. STUDY DESIGN: Double-blinded randomized controlled trial. SETTING: Eastern Hepatobiliary Surgery Hospital, Shanghai, China. METHODS: All patients in this study were men. A total of 66 patients who smoke were randomly assigned to receive tramadol or sufentanil (n = 33 each). In addition, a total of 66 patients who do not smoke were randomly assigned to receive tramadol or sufentanil (n = 33 each). The primary outcome was the consumption of additional analgesics within the first 48 hours to control postoperative pain. Secondary outcomes included the postoperative pain level, the frequency of postoperative nausea and vomiting, the sedation score, and the frequency of fever within 48 hours postsurgery. RESULTS: A significant interaction between "analgesic strategy" and "smoking history" was detected on the consumption of additional analgesics. In those who smoke, the requests for additional doses of analgesics were significantly less in those receiving tramadol than those receiving sufentanil; such a difference was not observed in those who do not smoke. The postoperative pain level was not significantly different between the tramadol group and the sufentanil group within patients who smoke within 48 hours postsurgery. The incidence of treatment-related adverse events was not significantly different between the tramadol group and the sufentanil group within both those who do and do not smoke. LIMITATIONS: Only men patients were included. Also, the superior analgesic effect and the incidence of adverse events of tramadol in patients who smoke were only assessed within the first 48 hours postsurgery. CONCLUSIONS: Our data suggest that tramadol has a better analgesic effect than sufentanil in relieving postoperative pain in patients who smoke.

Nicotine withdrawal induces hyperalgesia via downregulation of descending serotonergic pathway in the nucleus raphe magnus.

Patients deprived of cigarettes exhibit increased pain sensitivity during perioperative periods, yet the underlying neuroanatomical and molecular bases of this hypersensitivity are unclear. The present study showed that both the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were significantly decreased in a rat model of nicotine withdrawal. These rats showed less tryptophan hydroxylase 2 (TPH2) positive neurons and reduced TPH2 expression in the nucleus raphe magnus (NRM), and thus resulted in decreased 5-hydroxytryptamine (5-HT) levels in cerebrospinal fluid. Intrathecal injection of 5-HT or NRM microinjection of TPH-overexpression adeno-associated virus alleviated nicotine withdrawal-induced hyperalgesia, whereas 5-HT receptor pharmacological blockade by methysergide (a 5-HT receptor antagonist) exacerbated hypersensitivity and diminished the difference between the two groups. Together, these data indicate that hyperalgesia after nicotine withdrawal is mediated by declined descending serotonergic pathways in the NRM. This provides a new perspective to improve the postoperative pain management of patients, especially the smokers.

Radiofrequency Ablation (RFA) Combined with Transcatheter Arterial Chemoembolization (TACE) for Patients with Medium-to-Large Hepatocellular Carcinoma: A Retrospective Analysis of Long-Term Outcome.

BACKGROUND The aim of this study was to investigate the prognostic value of radiofrequency ablation (RFA) plus transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) patients with tumor size ranging from 3.0 to 10.0 cm. MATERIAL AND METHODS We retrospectively analyzed data on 201 patients with medium-to-large HCC. According to treatment procedure, the patients were divided into the TACE group (n=124) and the TACE+RFA group (n=77). We recorded data on patient safety, subcapsular hepatic hematoma, large amount of ascites, liver abscess, gallbladder injury, and local skin infection. The overall survival (OS) and progression-free survival (PFS) in the 2 groups were analyzed and compared between groups. RESULTS The median PFS was 4.00 months (3.00-5.00 months) in the TACE group and 9.13 months (6.64-11.62 months) in the TACE+RFA group (P<0.001). Median OS was 12.00 months (8.88-15.13 months) in the TACE group and 27.57 months (20.06-35.08 months) in the TACE+RFA group (P<0.001). In the TACE+RFA group, multivariate Cox regression analysis showed that tumor size ≤5 cm) (HR: 1.952, 95% CI: 1.213-3.143, P=0.006), hepatitis B (HR: 2.323, 95% CI: 1.096-4.923, P=0.028), TACE times (1 or >1) (HR: 1.867, 95% CI: 1.156-3.013, P=0.011), alpha-fetoprotein (AFP) level >200 ng/ml (HR: 2.426, 95% CI: 1.533-3.839, P<0.001), and AST level >40 U/L (HR: 1.946, 95% CI: 1.196-3.166, P=0.007) were independent prognostic factors for overall survival. CONCLUSIONS Combination therapy of TACE with RFA is a safe and effective treatment for patients with medium-to-large HCC, with the long-term beneficial effect of retarding tumor progression and improving PFS and OS.

MicroRNA-330 Directs Downregulation of the GABABR2 in the Pathogenesis of Pancreatic Cancer Pain.

Pancreatic cancer is one of the most aggressive and deadly malignancies with a very poor prognosis. Pancreatic cancer-induced visceral pain is very common and is generally presented among the initial symptoms in patients; such pain is strongly associated with poor quality of life, impaired functional activity, and decreased survival. However, the principal neurobiological mechanisms of pain caused by pancreatic cancer have not been fully elucidated. Accumulating studies have shown that miRNAs play a major role in chronic pain by suppressing key molecules involved in nociception. In the present study, we report that microRNA (miR)-330 is highly expressed in the spinal dorsal horn (SDH) of nude mice with pancreatic cancer pain. Mimicking pancreatic carcinoma-induced SDH miR-330 upregulation by microinjection of miR-330 mimic into the SDH significantly induced abdominal mechanical allodynia in normal nude mice. Additionally, we found that the expression of GABABR2 was significantly decreased in the SDH of nude mice with pancreatic cancer pain and was regulated directly by miR-330 both in vitro and in vivo. Furthermore, inhibition of miR-330 rescued the expression of GABABR2 and alleviated pancreatic carcinoma-induced abdominal pain hypersensitivity in nude mice with pancreatic carcinoma. These results show that miR-330 participates in the genesis of pancreatic carcinoma-induced pain hypersensitivity by inhibiting GABABR2 expression in the SDH and might be a potential therapeutic target for pancreatic cancer pain.

MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth.

Intrinsically disordered proteins (IDPs)/intrinsically unstructured proteins are characterized by the lack of fixed or stable tertiary structure, and are increasingly recognized as an important class of proteins with major roles in signal transduction and transcriptional regulation. In this study, we report the identification and functional characterization of a previously uncharacterized protein (UPF0258/KIAA1024), major intrinsically disordered Notch2-associated receptor 1 (MINAR1). While MINAR1 carries a single transmembrane domain and a short cytoplasmic domain, it has a large extracellular domain that shares no similarity with known protein sequences. Uncharacteristically, MINAR1 is a highly IDP with nearly 70% of its amino acids sequences unstructured. We demonstrate that MINAR1 physically interacts with Notch2 and its binding to Notch2 increases its stability and function. MINAR1 is widely expressed in various tissues including the epithelial cells of the breast and endothelial cells of blood vessels. MINAR1 plays a negative role in angiogenesis as it inhibits angiogenesis in cell culture and in mouse matrigel plug and zebrafish angiogenesis models. Furthermore, while MINAR1 is highly expressed in the normal human breast, its expression is significantly downregulated in advanced human breast cancer and its re-expression in breast cancer cells inhibited tumor growth. Our study demonstrates that MINAR1 is an IDP that negatively regulates angiogenesis and growth of breast cancer cells.

Comparison of programmed death-ligand 1 (PD-L1) immunostain for nonsmall cell lung carcinoma between paired cytological and surgical specimens.

BACKGROUND: programmed death-ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-L1), which are targeted by several anti-PD-1 and PD-L1 drugs for lung cancer treatment. In clinical practice, many lung cancer cases only have cytology samples available to test PD-L1. Our current study compared the PD-L1 immunohistochemistry (IHC) between paired cytological and surgical samples. MATERIALS AND METHODS: Formalin-fixed lung cancer tissue microarray and paired cell blocks and surgical specimens from the same patients with a confirmed diagnosis of lung squamous cell carcinoma (SCC, n = 29) and adenocarcinoma (AC, n = 23) were sectioned for PD-L1 IHC. RESULTS: PD-L1 was expressed on tumor cells in 16 of 29 (55%) SCC surgical specimens and 18 of 29 (62%) paired cytologic specimens with 83% matched immunostains. PD-L1 was expressed on tumor cells in 13 of 23 (57%) AC surgical specimens and in 17 of 23 (74%) paired cytologic specimens with 79% matched immunostains. The PD-L1 was expressed on inflammatory cells in 20 of 23 (87%) AC surgical specimens and in 15 of 23 (65%) paired cytologic specimens with 70% matched immunostains. The PD-L1 was expressed on inflammatory cells in 18 of 29 (62%) SCC surgical specimens and in 12 of 29 (41%) paired cytologic specimens with 79% matched immunostains. CONCLUSIONS: PD-L1 immunostain in cytology samples matched very well with paired surgical samples in both SCC and AC cases. The cytologic samples present slightly higher sensitivity for PD-L1 immunostain on tumor cells as compared to surgical biopsies.

Establishment of a murine pancreatic cancer pain model and microarray analysis of pain­associated genes in the spinal cord dorsal horn.

There is emerging evidence on the mechanisms of pancreatic cancer pain. Following the establishment of an orthotropic transplantation model of pancreatic cancer, microarray analysis was performed to identify changes in the expression levels of pain­associated genes in the spinal cord. A mouse model of pancreatic cancer­induced pain was established by implanting SW 1990 cells into the pancreases of female BALB/c­nu mice. The survival rate and body weight were measured following orthotropic transplantation. Gross anatomical techniques and hematoxylin and eosin staining were used to analyze the pancreatic tumor tissue. Multiple behavioral tests were also performed to assess pain­associated responses. Additionally, using samples from mice with or without observable pain, microarray analysis was performed to determine the gene expression profiles in the spinal cord dorsal horn. The survival rate of mice with pancreatic cancer was high during the initial 3 weeks post­surgery, although the body weight decreased progressively. Gross anatomical techniques demonstrated that the tumor size increased significantly following the surgery, and this result was confirmed by solid tumor masses in the pancreatic tissues of the mouse model. Observable pain behavioral responses were also examined in the pancreatic cancer model by measuring the mechanical threshold of the abdominal skin, hunching behavior and visceromotor responses. The profiles of 10 pain specific­associated genes in the spinal cord dorsal horn that accurately reflect the molecular pathological progression of disease were also identified. In conclusion, the present study has developed a novel animal model of pancreatic cancer pain in BALB/c­nu mice that resembles human pancreatic cancer pain, and the expression of pain­associated genes in the spinal cord dorsal horn has been profiled. The results of the present study may further the understanding of the molecular mechanisms that mediate pancreatic cancer pain.

Pathology: A Satisfying Medical Profession.

Medical students are often unsure about the viability of a career as a physician in pathology. In particular, they are concerned that pathologists may not have a gratifying lifestyle or be well compensated. These worries may cause angst among medical students considering pathology and among junior pathology residents wondering if they made the correct career choice. A 2016 survey of nearly 20 000 physicians including nearly 400 pathologists provides reassuring data about compensation and career choice. This survey showed that 52% of pathologists are satisfied with their career choice and 63% are satisfied with their compensation. Among the 26 specialties that were surveyed, pathologists ranked 2 in believing that they were fairly compensated. Moreover, 66% of pathologists find that making diagnostic decisions, a core aspect of our discipline, is the most rewarding aspect of their career. Pathologists also ranked among the highest groups of physicians in reporting happiness at work and among the lowest groups reporting burnout. Overall, these 2016 surveys show that the majority of pathologists find deep satisfaction in their careers as pathologists.

Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells.

Cyclin-dependent kinases 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry. Most human cancers contain overactive CDK4/6-cyclin D, and CDK4/6-specific inhibitors are promising anti-cancer therapeutics. Here, we investigate the critical functions of CDK4/6-cyclin D kinases, starting from an unbiased screen in the nematode Caenorhabditis elegans. We found that simultaneous mutation of lin-35, a retinoblastoma (Rb)-related gene, and fzr-1, an orthologue to the APC/C co-activator Cdh1, completely eliminates the essential requirement of CDK4/6-cyclin D (CDK-4/CYD-1) in C. elegans. CDK-4/CYD-1 phosphorylates specific residues in the LIN-35 Rb spacer domain and FZR-1 amino terminus, resembling inactivating phosphorylations of the human proteins. In human breast cancer cells, simultaneous knockdown of Rb and FZR1 synergistically bypasses cell division arrest induced by the CDK4/6-specific inhibitor PD-0332991. Our data identify FZR1 as a candidate CDK4/6-cyclin D substrate and point to an APC/C(FZR1) activity as an important determinant in response to CDK4/6-inhibitors.

Renal Inflammatory Myofibroblastic Tumor: A Case Report and Comprehensive Review of Literature.

Inflammatory myofibroblastic tumor (IMT) is a rare benign tumor found in various organs with a sparse number of cases reported in the kidney. We report a case of IMT in a 48-year-old male who underwent laparoscopic partial nephrectomy for a 2.4 cm renal mass suspicious for renal cell carcinoma. Pathologic findings revealed spindle shaped cells in a myxoid background with lymphoid aggregates consistent with inflammatory myofibroblastic tumor.

C. elegans MCM-4 is a general DNA replication and checkpoint component with an epidermis-specific requirement for growth and viability.

DNA replication and its connection to M phase restraint are studied extensively at the level of single cells but rarely in the context of a developing animal. C. elegans lin-6 mutants lack DNA synthesis in postembryonic somatic cell lineages, while entry into mitosis continues. These mutants grow slowly and either die during larval development or develop into sterile adults. We found that lin-6 corresponds to mcm-4 and encodes an evolutionarily conserved component of the MCM2-7 pre-RC and replicative helicase complex. The MCM-4 protein is expressed in all dividing cells during embryonic and postembryonic development and associates with chromatin in late anaphase. Induction of cell cycle entry and differentiation continues in developing mcm-4 larvae, even in cells that went through abortive division. In contrast to somatic cells in mcm-4 mutants, the gonad continues DNA replication and cell division until late larval development. Expression of MCM-4 in the epidermis (also known as hypodermis) is sufficient to rescue the growth retardation and lethality of mcm-4 mutants. While the somatic gonad and germline show substantial ability to cope with lack of zygotic mcm-4 function, mcm-4 is specifically required in the epidermis for growth and survival of the whole organism. Thus, C. elegans mcm-4 has conserved functions in DNA replication and replication checkpoint control but also shows unexpected tissue-specific requirements.