Viral mimicry and endocrine system: Divulging the importance in host-microbial crosstalk.

Host-pathogen interactions are complex associations which evolve over long co-evolutionary histories. Pathogens exhibit different mechanisms to gain advantage over their host. Mimicry of host factors is an influential tool in subverting host mechanisms to ensure pathogenesis. This chapter discusses such molecular mimicry exhibited during viral infections. Understanding the evolutionary relationships, shared identity and functional impact of the virus encoded mimics is critical. With a particular emphasis on viral mimics and their association with cancer and autoimmune diseases, this chapter highlights the importance of molecular mimicry in virus biology.

The substantial burden of iatrogenic vascular injury on the vascular surgery workforce at an academic medical center.

OBJECTIVE: Vascular surgeons are often called upon to provide emergent surgical assistance to other specialties for iatrogenic complications, both intraoperatively and in the inpatient setting. The management of iatrogenic vascular injury remains a critical role of the vascular surgeon, especially in the context of the increasing adoption of percutaneous procedures by other specialties. This study aims to characterize consultation timing, management, and outcomes for iatrogenic vascular injuries. METHODS: This study identified patients for whom vascular surgery was consulted for iatrogenic vascular complications from February 1, 2022, to May 12, 2023. Patient information, including demographic information, injury details, and details of any operative intervention, was retrospectively collected from February 1, 2022, to October 13, 2022, and prospectively collected for the remainder of the study period. Analyses were performed with R (version 2022.02.03). RESULTS: There were 87 patients with consultations related to iatrogenic vascular injury. Of these, 42 (46%) were female and the mean age was 59 years (±18 years). The most common consulting services were cardiology (32%), cardiothoracic surgery (26%), general surgery (8%), and neurointerventional radiology (10%). Reasons for consultation included hemorrhage (36%), limb ischemia (36%), and treatment of pseudoaneurysm (23%). A total of 24% of consults were intraoperative, 20% of consults related to extracorporeal membrane oxygenation cannulation, and 16% of consults related to ventricular assist devices including left ventricular assist device and intra-aortic balloon pump. The majority of these consult requests (60%) occurred during evening and night hours (5 PM to 7 AM). Emergent intervention was required in 62% of cases and consisted of primary open surgical repair of arterial injury (54%), endovascular intervention (21%), and open thromboembolectomy (15%). Overall, in-hospital mortality for the patient cohort was 20% and the reintervention rate was 23%, reflecting the underlying complexity of the illness and nature of the vascular injury in this patient group. CONCLUSIONS: Vascular surgeons play an essential role in managing emergent life-threatening hemorrhagic and ischemic iatrogenic vascular complications in the hospitalized setting. The complications require immediate bedside or intraoperative consult and often emergent open surgical or endovascular intervention. Furthermore, many of these require urgent management in the evening or overnight hours, and therefore the high frequency of these events represents a potential significant resource utilization and workforce issue to the vascular surgery workforce.

Human Tumor-Associated Macrophages and Neutrophils Regulate Antitumor Antibody Efficacy through Lethal and Sublethal Trogocytosis.

The clinical benefits of tumor-targeting antibodies (tAb) are modest in solid human tumors. The efficacy of many tAbs is dependent on Fc receptor (FcR)-expressing leukocytes that bind Fc fragments of tAb. Tumor-associated macrophages (TAM) and neutrophils (TAN) represent the majority of FcR+ effectors in solid tumors. A better understanding of the mechanisms by which TAMs and TANs regulate tAb response could help improve the efficacy of cancer treatments. Here, we found that myeloid effectors interacting with tAb-opsonized lung cancer cells used antibody-dependent trogocytosis (ADT) but not antibody-dependent phagocytosis. During this process, myeloid cells "nibbled off" tumor cell fragments containing tAb/targeted antigen (tAg) complexes. ADT was only tumoricidal when the tumor cells expressed high levels of tAg and the effectors were present at high effector-to-tumor ratios. If either of these conditions were not met, which is typical for solid tumors, ADT was sublethal. Sublethal ADT, mainly mediated by CD32hiCD64hi TAM, led to two outcomes: (i) removal of surface tAg/tAb complexes from the tumor that facilitated tumor cell escape from the tumoricidal effects of tAb; and (ii) acquisition of bystander tAgs by TAM with subsequent cross-presentation and stimulation of tumor-specific T-cell responses. CD89hiCD32loCD64lo peripheral blood neutrophils (PBN) and TAN stimulated tumor cell growth in the presence of the IgG1 anti-EGFR Ab cetuximab; however, IgA anti-EGFR Abs triggered the tumoricidal activity of PBN and negated the stimulatory effect of TAN. Overall, this study provides insights into the mechanisms by which myeloid effectors mediate tumor cell killing or resistance during tAb therapy. SIGNIFICANCE: The elucidation of the conditions and mechanisms by which human FcR+ myeloid effectors mediate cancer cell resistance and killing during antibody treatment could help develop improved strategies for treating solid tumors.

Application of functional proteomics in understanding RNA virus-mediated infection.

Together with the expansion of genome sequencing research, the number of protein sequences whose function is yet unknown is increasing dramatically. The primary goals of functional proteomics, a developing area of study in the realm of proteomic science, are the elucidation of the biological function of unidentified proteins and the molecular description of cellular systems at the molecular level. RNA viruses have emerged as the cause of several human infectious diseases with large morbidity and fatality rates. The introduction of high-throughput sequencing tools and genetic-based screening approaches over the last few decades has enabled researchers to find previously unknown and perplexing elements of RNA virus replication and pathogenesis on a scale never feasible before. Viruses, on the other hand, frequently disrupt cellular proteostasis, macromolecular complex architecture or stoichiometry, and post-translational changes to take over essential host activities. Because of these consequences, structural and global protein and proteoform monitoring is highly necessiated. Mass spectrometry (MS) has the potential to elucidate key details of virus-host interactions and speed up the identification of antiviral targets, giving precise data on the stoichiometry of cellular and viral protein complexes as well as mechanistic insights, has lately emerged as a key part of the RNA virus biology toolbox as a functional proteomics approach. Affinity-based techniques are primarily employed to identify interacting proteins in stable complexes in living organisms. A protein's biological role is strongly suggested by its relationship with other members of a certain protein complex that is involved in a particular process. With a particular emphasis on the most recent advancements in defining host responses and their translational implications to uncover novel tractable antiviral targets, this chapter provides insight on several functional proteomics techniques in RNA virus biology.

The natural history and long-term follow-up of splenic artery aneurysms.

OBJECTIVE: Although splenic artery aneurysms (SAAs) are the most common visceral aneurysm, there is a paucity of literature on the behavior of these entities. The objective of this study was to review the natural history of patients with SAA. METHODS: This single-institution, retrospective analysis studied patients with SAA diagnosed by computed tomography imaging between 2015 and 2019, identified by our institutional radiology database. Imaging, demographic, and clinical data were obtained via the electronic medical record. The growth rate was calculated for patients with radiologic follow-up. RESULTS: The cohort consisted of 853 patients with 890 SAAs, of whom 692 were female (81.2%). There were 37 women (5.3%) of childbearing age (15-50 years). The mean age at diagnosis was 70.9 years (range: 28-100 years). Frequently observed medical comorbidities included hypertension (70.2%), hypercholesterolemia (54.7%), and prior smoking (32.2%). Imaging indications included abdominal pain (37.3%), unrelated follow-up (28.0%), and follow-up of a previously noted visceral artery aneurysm (8.6%). The mean diameter at diagnosis was 13.3 ± 6.3 mm. Anatomic locations included the splenic hilum (36.0%), distal splenic artery (30.3%), midsplenic artery (23.9%), and proximal splenic artery (9.7%). Radiographically, the majority were saccular aneurysms (72.4%) with calcifications (88.5%). One patient (38-year-old woman) was initially diagnosed at the time of rupture of a 25 mm aneurysm; this patient underwent immediate endovascular intervention with no complications. The mean clinical follow-up among 812 patients was 4.1 ± 4.0 years, and the mean radiological follow-up among 514 patients was 3.8 ± 6.8 years. Of the latter, 122 patients (23.7%) experienced growth. Aneurysm growth rates for initial sizes <10 mm (n = 123), 10 to 19 mm (n = 353), 20 to 29 mm (n = 34), and >30 mm (n = 4) were 0.166 mm/y, 0.172 mm/y, 0.383 mm/y, and 0.246 mm/y, respectively. Of the entire cohort, 27 patients (3.2%) eventually underwent intervention (81.5% endovascular), with the most common indications including size/growth criteria (70.4%) and symptom development (18.5%). On multivariate analysis, only prior tobacco use was significantly associated with aneurysm growth (P = .028). CONCLUSIONS: The majority of SAAs in this cohort remained stable in size, with few patients requiring intervention over a mean follow-up of 4 years. Current guidelines recommending treatment of asymptomatic aneurysms >30 mm appear appropriate given their slow progression. Despite societal recommendations for intervention for all SAAs among women of childbearing age, only a minority underwent vascular surgical consultation and intervention in this series, indicating that these recommendations are likely not well known in the general medical community.

Retroviral b-Zip protein (HBZ) contributes to the release of soluble and exosomal immune checkpoint molecules in the context of neuroinflammation.

HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neuroinflammatory demyelinating condition of the spinal cord. We have previously shown that aberrant expression and activity of immune checkpoint (ICP) molecules such as PD-1 and PD-L1/PD-L2, negatively associates with the cytolytic potential of T cells in individuals with HAM/TSP. Interestingly, ICPs can exist in a soluble cell-free form and can be carried on extracellular vesicles (EVs) and exosomes (small EVs, <300nm) while maintaining their immunomodulatory activity. Therefore, we investigated the role of soluble and exosomal ICPs in HTLV-1 associated neuroinflammation. For the very first time, we demonstrate a unique elevated presence of several stimulatory (CD27, CD28, 4-1BB) and inhibitory (BTLA, CTLA-4, LAG-3, PD-1, PD-L2) ICP receptors in HAM/TSP sera, and in purified exosomes from a HAM/TSP-derived HTLV-1-producing (OSP2) cells. These ICPs were found to be co-localized with the endosomal sorting complex required for transport (ESCRT) pathway proteins and exhibited functional binding with their respective ligands. Viral proteins and cytokines (primarily IFNγ) were found to be present in purified exosomes. IFNγ exposure enhanced the release of ICP molecules while antiretroviral drugs (Azidothymidine and Lopinavir) significantly inhibited this process. HTLV-1 b-Zip protein (HBZ) has been linked to factors that enhance EV release and concurrent knockdown here led to the reduced expression of ESCRT associated genes (eg. Hrs, Vsp4, Alix, Tsg101) as well as abrogated the release of ICP molecules, suggesting HBZ involvement in this process. Moreso, exosomes from OSP2 cells adversely affected CD8 T-cell functions by dimishing levels of cytokines and cytotoxic factors. Collectively, these findings highlight exosome-mediated immunmodulation of T-cell functions with HBZ and ESCRT pathways as an underlying mechanism in the context of HTLV-1-induced neuroinflammation.

Mechanism of cell cycle regulation and cell proliferation during human viral infection.

Over the history of the coevolution of Host viral interaction, viruses have customized the host cellular machinery into their use for viral genome replication, causing effective infection and ultimately aiming for survival. They do so by inducing subversions to the host cellular pathways like cell cycle via dysregulation of important cell cycle checkpoints by viral encoded proteins, arresting the cell cycle machinery, blocking cytokinesis as well as targeting subnuclear bodies, thus ultimately disorienting the cell proliferation. Both DNA and RNA viruses have been active participants in such manipulation resulting in serious outcomes of cancer. They achieve this by employing different mechanisms-Protein-protein interaction, protein-phosphorylation, degradation, redistribution, viral homolog, and viral regulation of APC at different stages of cell cycle events. Several DNA viruses cause the quiescent staged cells to undergo cell cycle which increases nucleotide pools logistically significantly persuading viral replication whereas few other viruses arrest a particular stage of cell cycle. This allows the latter group to sustain the infection which allows them to escape host immune response and support viral multiplication. Mechanical study of signaling such viral mediated pathways could give insight into understanding the etiology of tumorigenesis and progression. Overall this chapter highlights the possible strategies employed by DNA/RNA viral families which impact the normal cell cycle but facilitate viral infected cell replication. Such information could contribute to comprehending viral infection-associated disorders to further depth.

Translational vaccinomics and structural filtration algorithm to device multiepitope vaccine for catastrophic monkeypox virus.

Recent outbreak of monkeypox disease commenced in April 2022, and on May 7, the first confirmed case was reported. The world health organization then designated monkeypox disease as a public health emergency of international outrage on July 23, after it spread to 70 non-endemic nations in less than 15 days. This catastrophic viral infection encourages the development of antiviral therapeutics due to the lack of specific treatments with negligible adverse effects. This analysis developed a highly immunogenic multiepitope subunit vaccine against the monkeypox virus using an in silico translational vaccinomics technique. Highly antigenic B cell and T cell (HTL and CTL) epitopes were predicted and conjugated with the help of unique linkers. An adjuvant (ß-defensin) and a pan-HLA DR sequence were attached at the vaccine construct's N-terminal to invoke a robust immunological response. Additionally, physiochemical, allergic, toxic, and antigenic properties were anticipated. Interactions between the vaccine candidate and the TLR3 demonstrated that the vaccine candidate triggers a robust immunological response. Finally, the stability is confirmed by the molecular dynamics study. In contrast, the modified vaccine candidate's ability to produce a protective immune response were verified by an immune dynamics simulation study conducted via C-ImmSim server. This study validates the generation of B cell, Th cell, and Tc cell populations as well as the production of IFN-γ.

Exploring the role of secretory proteins in the human infectious diseases diagnosis and therapeutics.

Secretory proteins are playing important role during the host-pathogen interaction to develop the infection or protection into the cell. Pathogens developing infectious disease to human being are taken up by host macrophages or number of immune cells, play an important role in physiological, developmental and immunological function. At the same time, infectious agents are also secreting various proteins to neutralize the resistance caused by host cells and also helping the pathogens to develop the infection. Secretory proteins (secretome) are only developed at the time of host-pathogen interaction, therefore they become very important to develop the targeted and potential therapeutic strategies. Pathogen specific secretory proteins released during interaction with host cell provide opportunity to develop point of care and rapid diagnostic kits. Proteins secreted by pathogens at the time of interaction with host cell have also been found as immunogenic in nature and numbers of vaccines have been developed to control the spread of human infectious diseases. This chapter highlights the importance of secretory proteins in the development of diagnostic and therapeutic strategies to fight against human infectious diseases.

Identification of multi-targeting natural antiviral peptides to impede SARS-CoV-2 infection.

SARS-CoV-2 and its variants cause serious health concerns throughout the world. The alarming increase in the daily number of cases has become a nightmare in many low-income countries; although some vaccines are available, their high cost and low vaccine production make them unreachable to ordinary people in developing countries. Other treatment strategies are required for novel therapeutic options. The peptide-based drug is one of the alternatives with low toxicity, more specificity, and ease of synthesis. Herein, we have applied structure-based virtual screening to identify potential peptides targeting the critical proteins of SARS-CoV-2. Non-toxic natural antiviral peptides were selected from the enormous number of peptides. Comparative modeling was applied to prepare a 3D structure of selected peptides. 3D models of the peptides were docked using the ClusPro docking server to determine their binding affinity and peptide-protein interaction. The high-scoring peptides were docked with other crucial proteins to analyze multiple targeting peptides. The two best peptides were subjected to MD simulations to validate the structure stability and evaluated RMSD, RMSF, Rg, SASA, and H-bonding from the trajectory analysis of 100 ns. The proposed lead peptides can be used as a broad-spectrum drug and potentially develop as a therapeutic to combat SARS-CoV-2, positively impacting the current pandemic. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02113-9.

Severity of neonatal influenza infection is driven by type I interferon and oxidative stress.

Neonates exhibit increased susceptibility to respiratory viral infections, attributed to inflammation at the developing pulmonary air-blood interface. IFN I are antiviral cytokines critical to control viral replication, but also promote inflammation. Previously, we established a neonatal murine influenza virus (IV) model, which demonstrates increased mortality. Here, we sought to determine the role of IFN I in this increased mortality. We found that three-day-old IFNAR-deficient mice are highly protected from IV-induced mortality. In addition, exposure to IFNß 24 h post IV infection accelerated death in WT neonatal animals but did not impact adult mortality. In contrast, IFN IIIs are protective to neonatal mice. IFNß induced an oxidative stress imbalance specifically in primary neonatal IV-infected pulmonary type II epithelial cells (TIIEC), not in adult TIIECs. Moreover, neonates did not have an infection-induced increase in antioxidants, including a key antioxidant, superoxide dismutase 3, as compared to adults. Importantly, antioxidant treatment rescued IV-infected neonatal mice, but had no impact on adult morbidity. We propose that IFN I exacerbate an oxidative stress imbalance in the neonate because of IFN I-induced pulmonary TIIEC ROS production coupled with developmentally regulated, defective antioxidant production in response to IV infection. This age-specific imbalance contributes to mortality after respiratory infections in this vulnerable population.

MiRNA-SARS-CoV-2 dialogue and prospective anti-COVID-19 therapies.

COVID-19 is a highly transmissible disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), affects 226 countries and continents, and has resulted in >6.2 million deaths worldwide. Despite the efforts of all scientific institutions worldwide to identify potential therapeutics, no specific drug has been approved by the FDA to treat the COVID-19 patient. SARS-CoV-2 variants of concerns make the potential of publicly known therapeutics to respond to and detect disease onset highly improbable. The quest for universal therapeutics pointed to the ability of RNA-based molecules to shield and detect the adverse effects of the COVID-19 illness. One such candidate, miRNA (microRNA), works on regulating the differential expression of the target gene post-transcriptionally. The prime focus of this review is to report the critical miRNA molecule and their regular expression in patients with COVID-19 infection and associated comorbidities. Viral and host miRNAs control the etiology of COVID-19 infection throughout the life cycle and host inflammatory response, where host miRNAs are identified as a double-edged showing as a proviral and antiviral response. The review also covered the role of viral miRNAs in mediating host cell signaling expression during disease pathology. Studying molecular interactions between the host and the SARS-CoV-2 virus during COVID-19 pathogenesis offers the chance to use miRNA-based therapeutics to reduce the severity of the illness. By utilizing an appropriate delivery vehicle, these small non-coding RNA could be envisioned as a promising biomarker in designing a practical RNAi-based treatment approach of clinical significance.

Metal-ligand Lability and Ligand Mobility Enables Framework Transformation via Ligand Release in a Family of Crystalline 2D Coordination Polymers.

A family of seven silver(I)-perfluorocarboxylate-quinoxaline coordination polymers, [Ag4 (O2 CRF )4 (quin)4 ] 1-5 (RF =(CF2 )n-1 CF3 )4 , n=1 to 5); [Ag4 (O2 C(CF2 )2 CO2 )2 (quin)4 ] 6; [Ag4 (O2 CC6 F5 )4 (quin)4 ] 7 (quin=quinoxaline), denoted by composition as 4 : 4 : 4 phases, was synthesised from reaction of the corresponding silver(I) perfluorocarboxylate with excess quinoxaline. Compounds 1-7 adopt a common 2D layered structure in which 1D silver-perfluorcarboxylate chains are crosslinked by ditopic quinoxaline ligands. Solid-state reaction upon heating, involving loss of one equivalent of quinoxaline, yielding new crystalline 4 : 4 : 3 phases [Ag4 (O2 C(CF2 )n-1 CF3 )4 (quin)3 ]n (8-10, n=1 to 3), was followed in situ by PXRD and TGA studies. Crystal structures were confirmed by direct syntheses and structure determination. The solid-state reaction converting 4 : 4 : 4 to 4 : 4 : 3 phase materials involves cleavage and formation of Ag-N and Ag-O bonds to enable the structural rearrangement. One of the 4 : 4 : 3 phase coordination polymers (10) shows the remarkably high dielectric constant in the low electric field frequency range.

The Association Between Preoperative Independent Ambulatory Status and Outcomes After Open Abdominal Aortic Aneurysm Repairs.

BACKGROUND: Preoperative functional status is appreciated as a key determinant of decision-making when evaluating patients for complex elective surgeries. We used the Vascular Quality Initiative to analyze the effect of being able to independently ambulate on outcomes after open abdominal aortic aneurysm (AAA) repairs. METHODS: We identified all patients who underwent elective or urgent open AAA repairs from January 2013 to August 2019 in the Vascular Quality Initiative registry. We recorded demographic variables, comorbidities, and operative factors such as approach, operative ischemia time, proximal clamp site, and presence of iliac aneurysms. Short-term and long-term outcomes included 30-day mortality, any perioperative complications, failure to rescue (defined as death after a complication), and 1-year all-cause mortality. We dichotomized patients based on their ability to independently ambulate (Ambulatory) or inability to ambulate independently (Non-Ambulatory) and used both multivariable logistic regressions and cox-proportional hazards models to evaluate outcomes. RESULTS: Of 5,371 patients, 328 (6.1%) could not ambulate independently and were more likely to be older (median age 69 vs. 72), female (25% vs. 38%), and have greater comorbidities. Overall outcomes were: 4.3% for 30-day mortality, 38.7% for complications, 10.2% for failure-to-rescue, and 6.9% for 1-year mortality. Univariate analysis showed higher rates of all adverse outcomes in non-ambulatory patients. On adjusted analysis, non-ambulatory patients had increased odds of complications by 46% (OR 1.46 [95%-CI 1.11-1.91]) and 1-year mortality by 46% (HR 1.46 [95%-CI 1.06-1.99]), but not failure to rescue (OR 1.05 [95%-CI 0.67-1.62]) or 30-day mortality (OR 1.22 [95%-CI 0.82-1.81]). Increased hospital volume, age, and increased operative renal ischemia time were independently associated with adverse outcomes. CONCLUSIONS: Non-ambulatory status was observed in a small percentage of patients undergoing open AAA repair but was associated with higher rates of post-operative complications and 1-year mortality. Ambulatory capacity is one of the key determinants of outcomes following open AAA repair. In patients with poor ambulatory function, a conservative approach is highly recommended over invasive open surgical intervention.

Leveraging Hierarchical Self-Assembly Pathways for Realizing Colloidal Photonic Crystals.

Colloidal open crystals are attractive materials, especially for their photonic applications. Self-assembly appeals as a bottom-up route for structure fabrication, but self-assembly of colloidal open crystals has proven to be elusive for their mechanical instability due to being low-coordinated. For such a bottom-up route to yield a desired colloidal open crystal, the target structure is required to be thermodynamically favored for designer building blocks and also kinetically accessible via self-assembly pathways in preference to metastable structures. Additionally, the selection of a particular polymorph poses a challenge for certain much sought-after colloidal open crystals for their applications as photonic crystals. Here, we devise hierarchical self-assembly pathways, which, starting from designer triblock patchy particles, yield in a cascade of well-separated associations first tetrahedral clusters and then tetrastack crystals. The designed pathways avoid trapping into an amorphous phase. Our analysis reveals how such a two-stage self-assembly pathway via tetrahedral clusters promotes crystallization by suppressing five- and seven-membered rings that hinder the emergence of the ordered structure. We also find that slow annealing promotes a bias toward the cubic polymorph relative to the hexagonal counterpart. Finally, we calculate the photonic band structures, showing that the cubic polymorph exhibits a complete photonic band gap for the dielectric filling fraction directly realizable from the designer triblock patchy particles. Unexpectedly, we find that the hexagonal polymorph also supports a complete photonic band gap, albeit only for an increased filling fraction, which can be realized via postassembly processing.

Liver Cancer-Specific Serine Protease Inhibitor Kazal Is a Potentially Novel Biomarker for the Early Detection of Hepatocellular Carcinoma.

INTRODUCTION: Liver cancer-secreted serine protease inhibitor Kazal (LC-SPIK) is a protein that is specifically elevated in cases of hepatocellular carcinoma (HCC). We assessed the performance of LC-SPIK in detecting HCC, including its early stages, in patients with cirrhosis, hepatitis B virus (HBV), and hepatitis C virus (HCV). METHODS: We enrolled 488 patients, including 164 HCC patients (81 early HCC) and 324 controls in a blinded, prospective, case-control study. Serum LC-SPIK levels were determined by an enzyme-linked immunosorbent assay-based assay. The performance of serum LC-SPIK and α-fetoprotein (AFP), including area under the curve (AUC), sensitivity, and specificity, are compared. The performance of LC-SPIK was evaluated in an independent validation cohort with 102 patients. RESULTS: In distinguishing all HCC patients from those with cirrhosis and chronic HBV/HCV, LC-SPIK had an AUC of 0.87, with 80% sensitivity and 90% specificity using a cutoff of 21.5 ng/mL. This is significantly higher than AFP, which had an AUC of 0.70 and 52% sensitivity and 86% specificity using a standard cutoff value of 20.0 ng/mL. For early-stage HCC (Barcelona Clinic Liver Cancer stage 0 and A), LC-SPIK had an AUC of 0.85, with 72% sensitivity and 90% specificity, compared with AFP, which had an AUC of 0.61, with 42% sensitivity and 86% specificity. In addition, LC-SPIK accurately detected the presence of HCC in more than 70% of HCC patients with false-negative AFP results. DISCUSSION: The study provided strong evidence that LC-SPIK detects HCC, including early-stage HCC, with high sensitivity and specificity, and might be useful for surveillance in cirrhotic and chronic HBV/HCV patients, who are at an elevated risk of developing HCC.

Phenotypic and functional analysis of malignant mesothelioma tumor-infiltrating lymphocytes.

Given the growing interest and promising preliminary results of immunotherapy in malignant pleural mesothelioma (MPM), it has become important to more fully understand the immune landscape in this tumor. This may be especially relevant in deciding who might benefit most from checkpoint blockade or agonist antibody therapy. Since the phenotype of tumor infiltrating lymphocytes (TILs) in MPM has not been fully described and their function has not been carefully assessed, we collected fresh tumor and blood from 22 patients undergoing surgical resection and analysed single cell suspensions by flow cytometry. The functionality of TILs was assessed by measurement of cytokine expression (IFN-γ) following overnight stimulation ex vivo. Results showed low numbers of CD8+ TILs whose function was either moderately or severely suppressed. The degree of TIL hypofunction did not correlate with the presence of co-existing macrophages or neutrophils, nor with expression of the inhibitory receptors PD-1, CD39 and CTLA-4. Hypofunction was associated with higher numbers of CD4 regulatory T cells (Tregs) and with expression of the inhibitory receptor TIGIT. On the other hand, presence of tissue-resident memory (Trm) cells and expression of TIM-3 on CD8+ cells were positively associated with cytokine production. However, Trm function was partially suppressed when the transcription factor Eomesodermin (Eomes) was co-expressed. Understanding the function of TILs in malignant mesothelioma may have clinical implications for immunotherapy, especially in choosing the best immunotherapy targets. Our data suggests that Treg cell blocking agents or TIGIT inhibitor antibodies might be especially valuable in these patients.

Human tumor-associated monocytes/macrophages and their regulation of T cell responses in early-stage lung cancer.

Data from mouse tumor models suggest that tumor-associated monocyte/macrophage lineage cells (MMLCs) dampen antitumor immune responses. However, given the fundamental differences between mice and humans in tumor evolution, genetic heterogeneity, and immunity, the function of MMLCs might be different in human tumors, especially during early stages of disease. Here, we studied MMLCs in early-stage human lung tumors and found that they consist of a mixture of classical tissue monocytes and tumor-associated macrophages (TAMs). The TAMs coexpressed M1/M2 markers, as well as T cell coinhibitory and costimulatory receptors. Functionally, TAMs did not primarily suppress tumor-specific effector T cell responses, whereas tumor monocytes tended to be more T cell inhibitory. TAMs expressing relevant MHC class I/tumor peptide complexes were able to activate cognate effector T cells. Mechanistically, programmed death-ligand 1 (PD-L1) expressed on bystander TAMs, as opposed to PD-L1 expressed on tumor cells, did not inhibit interactions between tumor-specific T cells and tumor targets. TAM-derived PD-L1 exerted a regulatory role only during the interaction of TAMs presenting relevant peptides with cognate effector T cells and thus may limit excessive activation of T cells and protect TAMs from killing by these T cells. These results suggest that the function of TAMs as primarily immunosuppressive cells might not fully apply to early-stage human lung cancer and might explain why some patients with strong PD-L1 positivity fail to respond to PD-L1 therapy.

Surveillance, Auditing, and Feedback Can Reduce Surgical Site Infection Dramatically: Toward Zero Surgical Site Infection.

BACKGROUND: We evaluated the Surveillance of Surgical Site Infection (SSI), Auditing, and Feedback (SAF) effect on the rate of compliance with an SSI care bundle and measured its effectiveness in reducing the SSI rate. METHOD: A prospective cohort study from January 2014 to December 2016 was classified into three phases: pre-SAF, early-SAF, and late-SAF. Pre-operative baseline characteristics of 24,677 patients who underwent orthopedic, cardiovascular thoracic surgery (CTVS) or urologic operations were recorded. Univariable analyses of the SSI rates in the pre-SAF and post-SAF phases were performed. Percentage compliance and non-compliance with each care component were calculated. Correlation between reduction in the SSI rate and increase in compliance with the pre-operative, peri-operative, and post-operative care-bundle components was performed using the Spearman test. RESULTS: There was a significant decrease in the SSI rate in orthopedic procedures that involved surgical implantation and in mitral valve/aortic valve (MVR/AVR) cardiac operations, with a relative risk (RR) ratio of 0.19 (95% confidence interval [CI] 0.12-0.31) and 0.08 (95% CI 0.03-0.22), respectively. The SSI rate was inversely correlated with the rate of compliance with pre-operative (r = -0.738; p = 0.037), peri-operative (r = - 0.802; p = 0.017), and post-operative (r = -0.762; p = 0.028) care bundles. CONCLUSION: Implementation of the Surveillance of SSI, Auditing, and Feedback bundle had a profound beneficial effect on the SSI rate, thereby reducing healthcare costs and improving patient quality of life.