Cathelicidin is a "fire alarm", generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa.

Pulmonary infections are a major global cause of morbidity, exacerbated by an increasing threat from antibiotic-resistant pathogens. In this context, therapeutic interventions aimed at protectively modulating host responses, to enhance defence against infection, take on ever greater significance. Pseudomonas aeruginosa is an important multidrug-resistant, opportunistic respiratory pathogen, the clearance of which can be enhanced in vivo by the innate immune modulatory properties of antimicrobial host defence peptides from the cathelicidin family, including human LL-37. Initially described primarily as bactericidal agents, cathelicidins are now recognised as multifunctional antimicrobial immunomodulators, modifying host responses to pathogens, but the key mechanisms involved in these protective functions are not yet defined. We demonstrate that P. aeruginosa infection of airway epithelial cells promotes extensive infected cell internalisation of LL-37, in a manner that is dependent upon epithelial cell interaction with live bacteria, but does not require bacterial Type 3 Secretion System (T3SS). Internalised LL-37 acts as a second signal to induce inflammasome activation in airway epithelial cells, which, in contrast to myeloid cells, are relatively unresponsive to P. aeruginosa. We demonstrate that this is mechanistically dependent upon cathepsin B release, and NLRP3-dependent activation of caspase 1. These result in LL-37-mediated release of IL-1ß and IL-18 in a manner that is synergistic with P. aeruginosa infection, and can induce caspase 1-dependent death of infected epithelial cells, and promote neutrophil chemotaxis. We propose that cathelicidin can therefore act as a second signal, required by P. aeruginosa infected epithelial cells to promote an inflammasome-mediated altruistic cell death of infection-compromised epithelial cells and act as a "fire alarm" to enhance rapid escalation of protective inflammatory responses to an uncontrolled infection. Understanding this novel modulatory role for cathelicidins, has the potential to inform development of novel therapeutic strategies to antibiotic-resistant pathogens, harnessing innate immunity as a complementation or alternative to current interventions.

Antimicrobial Effects and Mechanisms of Ethanol Extracts of Psoralea corylifolia Seeds Against Listeria monocytogenes and Methicillin-Resistant Staphylococcus aureus.

Psoralea corylifolia seeds contain many bioactive compounds commonly used in traditional Chinese medicine. In this study, the antibacterial activity and possible mechanism of P. corylifolia seed ethanol extract (PCEE) against foodborne pathogens were investigated. Both methicillin-resistant Staphylococcus aureus (MRSA) and Listeria monocytogenes had similar minimum inhibitory concentrations and minimum bactericidal concentrations of PCEE at 50 and 100 µg/mL, respectively. Furthermore, elevated OD260, protein concentration, and electric conductivity indicated irreversible damage to the cytoplasmic membranes of PCEE-treated cells. Indeed, the treated cells displayed disrupted membranes, incomplete and deformed shapes, and rupture as visualized by scanning electron microscopy. Multidrug-resistance efflux pump gene expression was also analyzed by quantitative reverse transcription PCR. Although the mdrL, mdrT, and lde genes of L. monocytogenes and the mepA gene of MRSA were upregulated, there was no significant difference that indicated an attempt by the efflux pumps to discharge PCEE. MRSA norA expression and abcA expression were significantly downregulated (p < 0.05). A possible mechanism for PCEE may be to cause an energy depletion, either by inhibiting adenosine triphosphate binding or by disturbing the proton gradient, resulting in membrane damage.

Improved Progression-Free Survival Associated with Tumor-Infiltrating Lymphocytes in High-Grade Endometrial Cancer.

Tumor-infiltrating lymphocytes (TILs) have emerged as a prognostic marker in endometrial cancer (EC). However, the role of TILs in EC with distinct histology grades and molecular types (such as mismatch repair [MMR] deficiency) has not yet been made clear. We retrospectively included 237 patients with primary EC who underwent a standard staging operation of laparoscopic or laparotomy total hysterectomy and bilateral salpingo-oophorectomy for analyses. An independent pathologist who was blind to the study patients' information reviewed the pathologic slides to assess TILs according to the method introduced by the International Immuno-Oncology Biomarkers Working Group in 2017. The outcomes of interest included both progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method was used to determine the curves of PFS and OS according to TILs, and also in the relevant subgroups (low-grade vs. high-grade, MMR-proficient vs. MMR-deficient). After a median follow-up duration of 1.82 years, 18 patients had experienced either disease progression or death. Overall, TILs (+) were not associated with PFS or OS. We did observe, however, that TILs (+) were associated with a better PFS (p = 0.045) in patients with high-grade EC, but not in those with low-grade tumors (p = 0.733). The effect of TILs on PFS was not observed in patients with MMR-proficient (p = 0.347) or MMR-deficient (p = 0.168) EC. TILs were associated with a better PFS in patients with high-grade EC. Our results suggest that TILs may be a potential prognostic marker in these patients.

Undifferentiated Carcinoma with Osteoclast-Like Giant Cells of the Common Bile Duct: A Case Report of a Rare Entity at an Unusual Location.

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) is a rare variant of carcinoma with unique radiological and pathological features. This unusual carcinoma has been reported in a variety of organs and pancreas is the most frequently involved anatomical site. UCOGC of pancreas attains a relatively indolent clinical behavior and should be distinguished from ordinary pancreatobiliary adenocarcinoma. This paper presents the first case of UCOGC involving the entire segment of common bile duct (CBD) and common hepatic duct (CHD) without extending to the pancreatic tissue. Getting familiar with its clinical, radiological and pathological characters can help establish accurate diagnosis despite the occurrence of an unusual location.

Colloid Carcinoma of the Pancreas with a Series of Radiological and Pathological Studies for Diagnosis: A Case Report.

Pancreatic colloid carcinoma is an uncommon and unique malignancy possessing a significantly more favorable prognosis than that of ordinary pancreatic ductal adenocarcinoma. Accurate diagnosis of this rare entity is thus important for leading the ensuing optimal treatment. Herein we report a case of colloid carcinoma of the pancreas with a series of imaging findings and pathologic assessments. Being familiar with these radio-pathological features makes early diagnosis possible prior to operation.

Hyaline Vascular Type of Unicentric Castleman Disease in a Kidney with End-Stage Renal Disease: A Case Report of a Rare Entity at an Unusual Location and a Special Clinical Setting.

Castleman disease (CD) is an unusual heterogeneous lymphoproliferative disorder that has been classified based on either clinical presentation and disease course or histologic features. Clinically, CD is divided into a unicentric CD (UCD) type and multicentric CD (MCD) type according to the extent of lymph node region involvement and the absence or presence of systemic symptoms. Histologically, it can be categorized into hyaline vascular (HV) type, plasma cell (PC) type and mixed type. The majority of HV-type CD involves a solitary lymph node, and excision surgery is often curative. On the contrary, MCD is a progressive and often fatal disease with lymphadenopathy in multiple nodes, and systemic therapy is needed. Herein we report a unique case of HV-type CD presenting as a single renal mass in a patient with end-stage renal disease (ESRD). Despite the rarity, CD should be included in the differential diagnosis of solitary renal mass lesions. An accurate diagnosis is important to avoid unnecessarily risky or extensive operations.

Distinctive patterns of marrow involvement by classic Hodgkin lymphoma are clues for diagnosis and subtyping.

Classic Hodgkin lymphoma (CHL) is a lymphoid neoplasm deriving from B cells in a rich inflammatory background. There are four histological subtypes with different epidemiological features. Bone marrow involvement by CHL is infrequent, and subtyping CHL from the bone marrow is not suggested as there might be discordant histopathology between the primary tumors and bone marrow specimens. In this study, we aimed to identify the histopathological features of bone marrow involved by CHL and tried to correlate these features with their subtypes. Among the 23 recruited cases, the frequencies of mixed cellularity (MC; 48%, 11/23) and nodular sclerosis (NS; 44%, 10/23) were similar. There were two patterns of marrow involvement: pattern A (fibrous), space-occupying lesions with alternating hypo- and hypercellular areas against a fibrotic background with dilated sinusoids and pattern B (histiocyte-rich), ill-defined granuloma-like lesions in which histiocytes merged with normal hematopoietic and inflammatory cells. Pattern A was more frequent in patients with CHL-NS than CHL-MC (100% vs. 18.2%; p < 0.001). Diagnostic Hodgkin cells and Reed-Sternberg (HRS) cells were identified in all cases, while HRS variant lacunar cells were occasionally discovered, particularly in the CHL-NS subtype (NS 100% vs. MC 9%; p < 0.001). The frequency of EBV association was higher in MC (64%) than that in NS (36%) subtype, but not statistically significant. Of the two patterns of marrow involvement, pattern A was more commonly associated with the NS subtype and less frequently associated with EBV. Recognizing the patterns of marrow involvement is important for diagnosis and may contribute to the subtyping of CHL.

Coexisting ossification of the posterior longitudinal ligament, intramedullary hemangioblastoma, and syringomyelia of the cervical spine: illustrative case.

BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) is a rare but potentially devastating cause of severe spinal cord compression and degenerative cervical myelopathy. Because OPLL is rarely accompanied by prominent syringomyelia, when both are observed, other causes of syringomyelia should be considered. Simultaneous presentation of OPLL and hemangioblastoma of the cervical spine is a rare encounter and has never been reported in the English-language literature. OBSERVATIONS: The authors present a case of a 64-year-old man with muscle weakness of the right upper limb and worsening dysesthesia of the right thumb and index finger. Noncontrast magnetic resonance imaging (MRI) of the cervical spine from another institution revealed OPLL from the C2 to C6 levels with severe spinal cord compression and prominent syringomyelia. Repeated MRI with contrast showed an intramedullary tumor, about 11 mm in diameter, at the right posterior aspect of the C4 level. The authors performed laminectomies from C1 to C6 with posterolateral fusion and removed the C4 tumor. Pathohistological examination of the tumor demonstrated hemangioblastoma. LESSONS: Careful evaluation of the preoperative imaging study is extremely important in surgical decision making. Although rare, concomitant cervical hemangioblastoma should be listed in the differential diagnosis when OPLL is accompanied with prominent syringomyelia.

Human beta-defensin 3 has immunosuppressive activity in vitro and in vivo.

Beta-defensins are antimicrobial peptides with an essential role in the innate immune response. In addition beta-defensins can also chemoattract cells involved in adaptive immunity. Until now, based on evidence from dendritic cell stimulation, human beta defensin-3 (hBD3) was considered pro-inflammatory. We present evidence here that hBD3 lacks pro-inflammatory activity in human and mouse primary Mphi. In addition, in the presence of LPS, hBD3 and the murine orthologue Defb14 (but not hBD2), effectively inhibit TNF-alpha and IL-6 accumulation implying an anti-inflammatory function. hBD3 also inhibits CD40/IFN-gamma stimulation of Mphi and in vivo, hBD3 significantly reduces the LPS-induced TNF-alpha level in serum. Recent work has revealed that hBD3 binds melanocortin receptors but we provide evidence that these are not involved in hBD3 immunomodulatory activity. This implies a dual role for hBD3 in antimicrobial activity and resolution of inflammation.

3-D printing model used to streamline surgical procedures for an intricate condition of airway compression caused by devastating mediastinal chondrosarcoma: a case report.

BACKGROUND: The condition of mediastinal chondrosarcoma causing severe airway compression has never been reported before, and its complexity makes its surgical management challenging. We implemented two new techniques to overcome this problem. Creative mockup analogy of a distorted trachea and tumor lesion using a 3-D printing module, with reprogramming by computed tomography, streamlined the panorama with intricate correlation. CASE PRESENTATION: Our patient was a previously healthy 52-year-old slender yellow man who had no obvious medical history. In the last 3 years, upper respiratory tract infection and productive cough were noted frequently, and the patient's symptoms were aggravated with shortness of breath when his head was positioned below 90 degrees during squatting and hunching of the body. The patient manifested prone sleep with ashen complexion, and he had lost 3-4 kg of body weight over the 3 weeks before admission to our hospital. Virtual bronchoscopy with computed tomography revealed an 8.3 × 7.5 × 4-cm lobulated right upper mediastinal mass with amorphous calcification and severe, intricate airway compression. A creative mockup analogy module of the distorted trachea and tumor was generated by 3-D printing and reprogrammed by computed tomography to streamline the sophisticated correlation. The patient underwent a two-stage operation comprising stabilization of the airway for innovative T-tube insertion preceded by thoracoscopy-assisted radical removal of the tumor. Postoperative adjuvant radiotherapy was administered. The patient recovered uneventfully and stayed healthy for 2 solid years in follow-up. CONCLUSIONS: An advanced 3-D printing model provides affirmative information related to treatment strategy and is also a prospective tool for better doctor-patient communication regarding the disease.

Density and size of lymphoid follicles are useful clues in differentiating primary intestinal follicular lymphoma from intestinal reactive lymphoid hyperplasia.

BACKGROUND: Primary intestinal follicular lymphoma (PI-FL) is a rare and indolent lymphoma and is challenging for diagnosis with endoscopic biopsy specimens. Whole slide imaging (WSI) has been increasingly used for assisting pathologic diagnosis, but not for lymphoma yet, probably because there are usually too many immunostained sections in a single case. In this study we attempted to identify morphological clues of PI-FL in the endoscopic biopsy specimens by measuring various parameters using WSI. METHODS: We retrospectively investigated 21 PI-FL cases, and scanned the HE sections from 17 of these cases with endoscopic biopsy specimens. Sections from 17 intestinal biopsies showing reactive lymphoid hyperplasia were scanned for comparison. The density and diameter of lymphoid follicles and the shortest distance of these follicles to the surface epithelia were measured on WSI. Comparisons of the aforementioned parameters were made between the neoplastic and reactive follicles. RESULTS: The density of follicles was significantly higher in PI-FL than that of reactive hyperplasia (median 0.5 vs. 0.2/mm2; p < 0.01). Furthermore, the neoplastic follicles were significantly larger (median diameter 756.9 vs. 479.7 µm; p < 0.01). The shortest distance of follicles to the surface epithelia tended to be closer in PI-FL (104.7 vs. 177.8 µm, p = 0.056), but not statistically significant. CONCLUSIONS: In this study we found that in PI-FL the density and diameter of lymphoid follicles as measured from WSI were significantly different from that of intestinal reactive lymphoid hyperplasia. When facing the diagnostic challenge between these two entities in routine practice, pathologists might be alerted by these morphological clues and request for immunohistochemistry for differential diagnosis.

The host defense peptide LL-37 selectively permeabilizes apoptotic leukocytes.

LL-37 is a cationic host defense peptide that is highly expressed during acute inflammation and that kills bacteria by poorly defined mechanisms, resulting in permeabilization of microbial membranes. High concentrations of LL-37 have also been reported to have cytotoxic effects against eukaryotic cells, but the peptide is clearly capable of differentiating between membranes with different compositions (eukaryotic versus bacterial membranes). Eukaryotic cells such as leukocytes change their membrane composition during apoptotic cell death, when they are turned into nonfunctional but structurally intact entities. We tested whether LL-37 exerted specific activity on apoptotic cells and found that the peptide selectively permeabilized the membranes of apoptotic human leukocytes, leaving viable cells unaffected. This activity was seemingly analogous to the direct microbicidal effect of LL-37, in that it was rapid, independent of known surface receptors and/or active cell signaling, and inhibitable by serum components such as high-density lipoprotein. A similar selective permeabilization of apoptotic cells was recorded for both NK cells and neutrophils. In the latter cell type, LL-37 permeabilized both the plasma and granule membranes, resulting in the release of both lactate dehydrogenase and myeloperoxidase. Apoptosis is a way for inflammatory cells to die silently and minimize collateral tissue damage by retaining tissue-damaging and proinflammatory substances within intact membranes. Permeabilization of apoptotic leukocytes by LL-37, accompanied by the leakage of cytoplasmic as well as intragranular molecules, may thus shift the balance between pro- and anti-inflammatory signals and in this way be of importance for the termination of acute inflammation.

Ultrasound-Guided Core Needle Biopsies of Breast Invasive Carcinoma: When One Core is Sufficient for Pathologic Diagnosis and Assessment of Hormone Receptor and HER2 Status.

Ultrasound (US)-guided core needle biopsy is considered the gold standard procedure with regard to preoperative diagnosis of breast carcinomas. However, there is no clear standard for the number of cores considered to be sufficient for pathologic evaluation, including the expression of surface hormone markers and HER2 status. Images and pathologic slides demonstrating breast invasive carcinoma from a single institution were thus retrospectively reviewed over a 12 month period. The results indicated that one core is sufficient for the diagnosis of invasive carcinomas, along with a reliable assessment of hormone receptor and HER2 status in many cases. The option of applying additional cores is recommended for some cases.

Secondary necrosis of apoptotic neutrophils induced by the human cathelicidin LL-37 is not proinflammatory to phagocytosing macrophages.

Cathelicidins are CHDP with essential roles in innate host defense but also more recently associated with the pathogenesis of certain chronic diseases. These peptides have microbicidal potential and the capacity to modulate innate immunity and inflammatory processes. PMN are key innate immune effector cells with pivotal roles in defense against infection. The appropriate regulation of PMN function, death, and clearance is critical to innate immunity, and dysregulation is implicated in disease pathogenesis. The efferocytosis of apoptotic PMN, in contrast to necrotic cells, is proposed to promote the resolution of inflammation. We demonstrate that the human cathelicidin LL-37 induced rapid secondary necrosis of apoptotic human PMN and identify an essential minimal region of LL-37 required for this activity. Using these LL-37-induced secondary necrotic PMN, we characterize the consequence for macrophage inflammatory responses. LL-37-induced secondary necrosis did not inhibit PMN ingestion by monocyte-derived macrophages and in contrast to expectation, was not proinflammatory. Furthermore, the anti-inflammatory effects of apoptotic PMN on activated macrophages were retained and even potentiated after LL-37-induced secondary necrosis. However, this process of secondary necrosis did induce the release of potentially harmful PMN granule contents. Thus, we suggest that LL-37 can be a potent inducer of PMN secondary necrosis during inflammation without promoting macrophage inflammation but may mediate host damage through PMN granule content release under chronic or dysregulated conditions.