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Background The main focus of several studies concerned with cancer progression and metastasis is to analyze the mechanisms that allow cancer cells to interact and quickly adapt with their environment. Integrins, a family of transmembrane glycoproteins, play a major role in invasive and metastatic processes. Integrins are involved in cell adhesion in both cell-extracellular matrix and cell-cell interactions, and particularly, β1 integrin is involved in proliferation and differentiation of cells in the development of epithelial tissues. This work aimed to investigate the putative role of β1 integrin expression on survival and metastasis in patients with breast invasive ductal carcinoma (IDC). In addition, we compared the expression of β1 integrin in patients with ductal carcinoma in situ (DCIS). Methods Through tissue microarray (TMA) slides containing 225 samples of IDC and 67 samples of DCIS, β1 integrin expression was related with several immunohistochemical markers and clinicopathologic features of prognostic significance. Results β1 integrin was overexpressed in 32.8% of IDC. In IDC, β1 integrin was related with HER-2 (p = 0.019) and VEGF (p = 0.011) expression and it had a significant relationship with metastasis and death (p = 0.001 and p = 0.05, respectively). Kaplan-Meier survival analysis showed that the overexpression of this protein is very significant (p = 0.002) in specific survival (number of months between diagnosis and death caused by the disease). There were no correlation between IDC and DCIS (p = 0.559) regarding β1 integrin expression. Conclusions Considering that the expression of β1 integrin in breast cancer remains controversial, specially its relation with survival of patients, our findings provide further evidence that β1 integrin can be a marker of poor prognosis in breast cancer. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6652215267393871

Head and neck squamous cell carcinoma remains challenging to treat with no improvement in survival rates over the past 50 years. Thus, there is an urgent need to discover more reliable therapeutic targets and biomarkers for HNSCC. Matriptase, a type-II transmembrane serine protease, induces malignant transformation in epithelial stem cells through proteolytic activation of pro-HGF and PAR-2, triggering PI3K-AKT-mTOR and NFKB signaling. The serine protease inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI) inhibits the matriptase-driven proteolytic pathway, directly blocking kallikreins in epithelial differentiation. Hence, we hypothesized LEKTI could inhibit matriptase-dependent squamous cell carcinogenesis, thus implicating kallikreins in this process. Double-transgenic mice with simultaneous expression of matriptase and LEKTI under the keratin-5 promoter showed a prominent rescue of K5-Matriptase+/0 premalignant phenotype. Notably, in DMBA-induced SCC, heterotopic co-expression of LEKTI and matriptase delayed matriptase-driven tumor incidence and progression. Co-expression of LEKTI reverted altered Kallikrein-5 expression observed in the skin of K5-Matriptase+/0 mice, indicating that matriptase-dependent proteolytic pathway inhibition by LEKTI occurs through kallikreins. Moreover, we showed that Kallikrein-5 is necessary for PAR-2-mediated IL-8 release, YAP1-TAZ/TEAD activation, and matriptase-mediated oral squamous cell carcinoma migration. Collectively, our data identify a third signaling pathway for matriptase-dependent carcinogenesis in vivo. These findings are critical for the identification of more reliable biomarkers and effective therapeutic targets in Head and Neck cancer.

BMP6 is a central cytokine in the induction of Sjögren's syndrome-associated (SS-associated) secretory hypofunction. However, the upstream initiation leading to the production of this cytokine in SS is unknown. In this study, RNA ISH on salivary gland sections taken from patients with SS indicated monocytic lineage cells as a cellular source of BMP6. RNA-Seq data on human salivary glands suggested that TLR4 signaling was an upstream regulator of BMP6, which was confirmed by in vitro cell assays and single-cell transcriptomics of human PBMCs. Further investigation showed that HSP70 was an endogenous natural TLR4 ligand that stimulated BMP6 expression in SS. Release of HSP70 from epithelial cells could be triggered by overexpression of lysosome-associated membrane protein 3 (LAMP3), a protein also associated with SS in several transcriptome studies. In vitro studies supported the idea that HSP70 was released as a result of lysosomal exocytosis initiated by LAMP3 expression, and reverse transcription PCR on RNA from minor salivary glands of patients with SS confirmed a positive correlation between BMP6 and LAMP3 expression. BMP6 expression could be experimentally induced in mice by overexpression of LAMP3, which developed an SS-like phenotype. The newly identified LAMP3/HSP70/BMP6 axis provided an etiological model for SS gland dysfunction and autoimmunity.

Primary Sjögren’s syndrome (pSS) is a complex autoimmune disease characterized by dysfunction of secretory epithelia with only palliative therapy. Patients present with a constellation of symptoms, and the diversity of symptomatic presentation has made it difficult to understand the underlying disease mechanisms. In this study, aggregation of unbiased transcriptome profiling data sets of minor salivary gland biopsies from controls and Sjögren’s syndrome patients identified increased expression of lysosome-associated membrane protein 3 (LAMP3/CD208/DC-LAMP) in a subset of Sjögren’s syndrome cases. Stratification of patients based on their clinical characteristics suggested an association between increased LAMP3 expression and the presence of serum autoantibodies including anti-Ro/SSA, anti-La/SSB, anti-nuclear antibodies. In vitro studies demonstrated that LAMP3 expression induces epithelial cell dysfunction leading to apoptosis. Interestingly, LAMP3 expression resulted in the accumulation and release of intracellular TRIM21 (one component of SSA), La (SSB), and α-fodrin protein, common autoantigens in Sjögren’s syndrome, via extracellular vesicles in an apoptosis-independent mechanism. This study defines a clear role for LAMP3 in the initiation of apoptosis and an independent pathway for the extracellular release of known autoantigens leading to the formation of autoantibodies associated with this disease. ClinicalTrials.gov Identifier: NCT00001196, NCT00001390, NCT02327884.

Activation of the mechanistic/mammalian target of rapamycin (mTOR) kinase in models of acute and chronic pain is strongly implicated in mediating enhanced translation and hyperalgesia. However, the molecular mechanisms by which mTOR regulates nociception remain unclear. Here we show that deletion of the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a major mTOR downstream effector, which represses eIF4E activity and cap-dependent translation, leads to mechanical, but not thermal pain hypersensitivity. Mice lacking 4E-BP1 exhibit enhanced spinal cord expression of neuroligin 1, a cell-adhesion postsynaptic protein regulating excitatory synapse function, and show increased excitatory synaptic input into spinal neurons, and a lowered threshold for induction of synaptic potentiation. Pharmacological inhibition of eIF4E or genetic reduction of neuroligin 1 levels normalizes the increased excitatory synaptic activity and reverses mechanical hypersensitivity. Thus, translational control by 4E-BP1 downstream of mTOR effects the expression of neuroligin 1 and excitatory synaptic transmission in the spinal cord, and thereby contributes to enhanced mechanical nociception. Despite the unpleasant feeling it causes, pain is necessary for survival as it helps individuals to avoid objects, environments and situations that cause damage to their body. However, millions of people experience long-lasting “chronic” pain, or are hypersensitive to pain. There are few treatments available for these conditions, but these treatments do not work well for the majority of patients, and can have serious side effects. To develop new treatments, researchers must first better understand how chronic pain develops. Pain is transmitted to the brain in the form of electrical signals “fired” along nerve fibers. Different nerves transmit information about different types of pain: for example, pain caused by a sharp object pressed against the skin activates a different set of neurons to those activated when touching something dangerously hot. Studies in mice have suggested that a protein called mTOR that is found inside neurons is important for them to fire pain signals. However, it is not clear exactly how mTOR contributes to pain signaling, although it is known to affect the activities of several other proteins in neurons. One protein that mTOR affects the activity of is called 4E-BP1. Now, Khoutorsky, Bonin, Sorge et al. show that mice that lack 4E-BP1 behave in ways that suggest they are hypersensitive to poking or pinching sensations. However, the mice did not show hypersensitivity when they touched a hot surface. Further investigation revealed that the neurons in the spinal cord of mice that lack 4E-BP1 produce abnormally high amounts of a molecule called neuroligin 1, which makes the neurons more likely to fire and thus signal pain. Khoutorsky, Bonin, Sorge et al. found that treating mice that lack 4E-BP1 with a compound that reduces neuroligin 1 production causes their neurons to fire more normally. This also reduces the animals’ apparent signs of hypersensitivity to pressure on their skin. It will be important in future studies to identify additional targets of 4E-BP1 in the spinal cord that could contribute to increased mechanical sensation, and also to study the role of 4E-BP1 in peripheral nerves.

Background: Cutaneous peripheral neuropathies have been associated with changes of the sensory fiber innervation in the dermis and epidermis. These changes are mediated in part by the increase in local expression of trophic factors. Increase in target tissue nerve growth factor has been implicated in the promotion of peptidergic afferent and sympathetic efferent sprouting following nerve injury. The primary source of nerve growth factor is cells found in the target tissue, namely the skin. Recent evidence regarding the release and extracellular maturation of nerve growth factor indicate that it is produced in its precursor form and matured in the extracellular space. It is our hypothesis that the precursor form of nerve growth factor should be detectable in those cell types producing it. To date, limitations in available immunohistochemical tools have restricted efforts in obtaining an accurate distribution of nerve growth factor in the skin of naïve animals and those with neuropathic pain lesions. It is the objective of this study to delineate the distribution of the precursor form of nerve growth factor to those cell types expressing it, as well as to describe its distribution with respect to those nerve fibers responsive to it. Results: We observed a decrease in peptidergic fiber innervation at 1 week after the application of a chronic constriction injury (CCI) to the sciatic nerve, followed by a recovery, correlating with TrkA protein levels. ProNGF expression in CCI animals was significantly higher than in sham-operated controls from 1–4 weeks post-CCI. ProNGF immunoreactivity was increased in mast cells at 1 week post-CCI and, at later time points, in keratinocytes. P75 expression within the dermis and epidermis was significantly higher in CCI-operated animals than in controls and these changes were localized to neuronal and non-neuronal cell populations using specific markers for each. Conclusions: We describe proNGF expression by non-neuronal cells over time after nerve injury as well as the association of NGF-responsive fibers to proNGF-expressing target tissues. ProNGF expression increases following nerve injury in those cell types previously suggested to express it.

Objective: This study assesses the associations between dendritic cells, HPV 6 and 11, and Recurrent Respiratory Papillomatosis (RRP) aggressiveness. Methods: The Derkay score was calculated using information obtained from the medical records. Biopsies from 36 patients with juvenile RRP (JRRP) and 43 adult RRP (ARRP) patients were analyzed under light microscopy, and their clinical data were collected. Immunohistochemical analysis using antibodies against CD83, CD1a, Factor XIIIa, and S100 was performed, and inflammatory cells were quantified. Data obtained were analyzed using the chi-squared test, in addition to the Mann–Whitney and Z tests for two proportions, considering a confidence interval of 95% and p < 0.05 as statistically significant. Results: A higher quantity of S100 was identified in the epithelium (p < 0.001) and in the conjunctive tissue (p = 0.027) among the ARRP cases, while CD83 (p = 0.025) and Factor XIIIa (p = 0.018), both in the epithelium, were identified among the JRRP cases. We observed significant association between a higher quantity of CD83 in the epithelium in the juvenile group with a low Derkay index (p = 0.034) and with HPV 6 (p = 0.039). Conclusions: An increased quantity of dendritic cells is present in individuals diagnosed with RRP, regardless of age, and this may be related to the lower Derkay index, regardless of the HPV type detected.

Vulvar carcinoma is the fourth most frequently encountered malignancy of the female reproductive tract. Among vulvar neoplasms, 0.1% to 5% are of Bartholin gland origin. Primary adenoid cystic carcinoma of the Bartholin gland is very rare. To date, only about 60 cases have been reported in the world literature. Microscopic examination reveals a neoplasm of cribriform pattern composed of nests and columns of cells of bland appearance arranged concentrically around glandlike spaces filled with eosinophilic periodic acid-Schiff–positive diastase-resistant material. Immunohistochemically, the tumor cells express low-molecular-weight keratins, carcinoembryonic antigen, lysozyme, α1-antichymotrypsin, S100, and type IV collagen. Adenoid cystic carcinoma of the Bartholin gland is a slow-growing but locally very aggressive neoplasm with high capacity for recurrence. Perineural and lymphatic invasion is characteristic of this tumor and may explain its propensity for causing pain and recurrence. The treatment may range from simple local excision to radical vulvectomy, with or without partial to complete regional lymphadenectomy.

Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that peripheral nerve injury induces the generation of a male-specific inflammatory microglia subtype, and demonstrate increased proliferation of microglia in male as compared to female mice. We also show time- and sex-specific transcriptional changes in different microglial subpopulations following peripheral nerve injury. Apolipoprotein E ( Apoe ) is the top upregulated gene in spinal cord microglia at chronic time points after peripheral nerve injury in mice. Furthermore, polymorphisms in the APOE gene in humans are associated with chronic pain. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia, and identify a link between ApoE and chronic pain in humans. Microglia subpopulations may differentially contribute to pain. Here, the authors show that peripheral nerve injury induces time- and sex-specific transcriptional changes in mouse spinal cord microglia subpopulations and that ApoE is linked to neuropathic pain hypersensitivity in mice and humans.

Neuropathic pain (NP) is an ineffectively treated, debilitating chronic pain disorder that is associated with maladaptive changes in the central nervous system, particularly in the spinal cord. Murine models of NP looking at the mechanisms underlying these changes suggest an important role of microglia, the resident immune cells of the central nervous system, in various stages of disease progression. However, given the number of different NP models and the resource limitations that come with tracking longitudinal changes in NP animals, many studies fail to truly recapitulate the patterns that exist between pain conditions and temporal microglial changes. This review integrates how NP studies are being carried out in murine models and how microglia changes over time can affect pain behavior in order to inform better study design and highlight knowledge gaps in the field. 258 peer-reviewed, primary source articles looking at spinal microglia in murine models of NP were selected using Covidence. Trends in the type of mice, statistical tests, pain models, interventions, microglial markers and temporal pain behavior and microglia changes were recorded and analyzed. Studies were primarily conducted in inbred, young adult, male mice having peripheral nerve injury which highlights the lack of generalizability in the data currently being collected. Changes in microglia and pain behavior, which were both increased, were tested most commonly up to 2 weeks after pain initiation despite aberrant microglia activity also being recorded at later time points in NP conditions. Studies using treatments that decrease microglia show decreased pain behavior primarily at the 1- and 2-week time point with many studies not recording pain behavior despite the involvement of spinal microglia dysfunction in their development. These results show the need for not only studying spinal microglia dynamics in a variety of NP conditions at longer time points but also for better clinically relevant study design considerations.