Expression profiles of MMP-9 and EMMPRIN in chronic rhinosinusitis with nasal polyps.

Objective: Metalloproteinases (MMPs) are implicated in tissue remodeling in chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to evaluate the expression profiles of MMP-9 and the extracellular matrix metalloproteinase inducer (EMMPRIN) in nasal polyps compared to healthy mucosa. Methods: Tissue samples from 37 CRSwNP patients undergoing functional endoscopic sinus surgery and mucosal specimens from 12 healthy controls were obtained intra-operatively. MMP-9 and EMMPRIN mRNA levels were assessed by reverse transcription-polymerase chain reaction and their protein expression by Western blot analysis. Results: MMP-9 mRNA expression levels were significantly elevated in CRSwNP compared to controls (p < 0.05). MMP-9 protein levels presented an increasing trend but with no statistical significance (p > 0.05). No statistically significant difference in EMMPRIN mRNA and protein levels was identified. Conclusions: Upregulation of MMP-9 in nasal polyps is evident and highlights its role in the pathogenesis of CRSwNP. The lack of concordance between MMP-9 mRNA and protein levels may be attributed to post-translational gene expression regulation. Although EMMPRIN expression was not significantly different between the two groups, its role remains to be elucidated. MMP-9 may be a valuable biomarker and treatment target in CRSwNP.

Noncoding RNA circuitry in melanoma onset, plasticity, and therapeutic response.

Melanoma, the cancer of the melanocyte, is the deadliest form of skin cancer with an aggressive nature, propensity to metastasize and tendency to resist therapeutic intervention. Studies have identified that the re-emergence of developmental pathways in melanoma contributes to melanoma onset, plasticity, and therapeutic response. Notably, it is well known that noncoding RNAs play a critical role in the development and stress response of tissues. In this review, we focus on the noncoding RNAs, including microRNAs, long non-coding RNAs, circular RNAs, and other small RNAs, for their functions in developmental mechanisms and plasticity, which drive onset, progression, therapeutic response and resistance in melanoma. Going forward, elucidation of noncoding RNA-mediated mechanisms may provide insights that accelerate development of novel melanoma therapies.

miRNAs as potential diagnostic biomarkers and pharmacogenomic indicators in psychiatric disorders.

The heterogeneity of psychiatric disorders and the lack of reliable biomarkers for prediction and treatments follow-up pose difficulties towards recognition and understanding of the molecular basis of psychiatric diseases. However, several studies based on NGS approaches have shown that miRNAs could regulate gene expression during onset and disease progression and could serve as potential diagnostic and pharmacogenomics biomarkers during treatment. We provide herein a detailed overview of circulating miRNAs and their expression profiles as biomarkers in schizophrenia, bipolar disorder and major depressive disorder and their role in response to specific treatments. Bioinformatics analysis of miR-34a, miR-106, miR-134 and miR-132, which are common among SZ, BD and MDD patients, showed brain enrichment and involvement in the modulation of critical signaling pathways, which are often deregulated in psychiatric disorders. We propose that specific miRNAs support accurate diagnosis and effective precision treatment of psychiatric disorders.

Revisiting miRNA Association with Melanoma Recurrence and Metastasis from a Machine Learning Point of View.

The diagnostic and prognostic value of miRNAs in cutaneous melanoma (CM) has been broadly studied and supported by advanced bioinformatics tools. From early studies using miRNA arrays with several limitations, to the recent NGS-derived miRNA expression profiles, an accurate diagnostic panel of a comprehensive pre-specified set of miRNAs that could aid timely identification of specific cancer stages is still elusive, mainly because of the heterogeneity of the approaches and the samples. Herein, we summarize the existing studies that report several miRNAs as important diagnostic and prognostic biomarkers in CM. Using publicly available NGS data, we analyzed the correlation of specific miRNA expression profiles with the expression signatures of known gene targets. Combining network analytics with machine learning, we developed specific non-linear classification models that could successfully predict CM recurrence and metastasis, based on two newly identified miRNA signatures. Subsequent unbiased analyses and independent test sets (i.e., a dataset not used for training, as a validation cohort) using our prediction models resulted in 73.85% and 82.09% accuracy in predicting CM recurrence and metastasis, respectively. Overall, our approach combines detailed analysis of miRNA profiles with heuristic optimization and machine learning, which facilitates dimensionality reduction and optimization of the prediction models. Our approach provides an improved prediction strategy that could serve as an auxiliary tool towards precision treatment.

Pharmacoepigenomics circuits induced by a novel retinoid-polyamine conjugate in human immortalized keratinocytes.

Retinoids are widely used in diseases spanning from dermatological lesions to cancer, but exhibit severe adverse effects. A novel all-trans-Retinoic Acid (atRA)-spermine conjugate (termed RASP) has shown previously optimal in vitro and in vivo anti-inflammatory and anticancer efficacy, with undetectable teratogenic and toxic side-effects. To get insights, we treated HaCaT cells which resemble human epidermis with IC50 concentration of RASP and analyzed their miRNA expression profile. Gene ontology analysis of their predicted targets indicated dynamic networks involved in cell proliferation, signal transduction and apoptosis. Furthermore, DNA microarrays analysis verified that RASP affects the expression of the same categories of genes. A protein-protein interaction map produced using the most significant common genes, revealed hub genes of nodal functions. We conclude that RASP is a synthetic retinoid derivative with improved properties, which possess the beneficial effects of retinoids without exhibiting side-effects and with potential beneficial effects against skin diseases including skin cancer.

KRASG12C Can Either Promote or Impair Cap-Dependent Translation in Two Different Lung Adenocarcinoma Cell Lines.

KRASG12C is among the most common oncogenic mutations in lung adenocarcinoma and a promising target for treatment by small-molecule inhibitors. KRAS oncogenic signaling is responsible for modulation of tumor microenvironment, with translation factors being among the most prominent deregulated targets. In the present study, we used TALENs to edit EGFRWT CL1-5 and A549 cells for integration of a Tet-inducible KRASG12C expression system. Subsequent analysis of both cell lines showed that cap-dependent translation was impaired in CL1-5 cells via involvement of mTORC2 and NF-κB. In contrast, in A549 cells, which additionally harbor the KRASG12S mutation, cap-dependent translation was favored via recruitment of mTORC1, c-MYC and the positive regulation of eIF4F complex. Downregulation of eIF1, eIF5 and eIF5B in the same cell line suggested a stringency loss of start codon selection during scanning of mRNAs. Puromycin staining and polysome profile analysis validated the enhanced translation rates in A549 cells and the impaired cap-dependent translation in CL1-5 cells. Interestingly, elevated translation rates were restored in CL1-5 cells after prolonged induction of KRASG12C through an mTORC1/p70S6K-independent way. Collectively, our results suggest that KRASG12C signaling differentially affects the regulation of the translational machinery. These differences could provide additional insights and facilitate current efforts to effectively target KRAS.

Gluteus maximus tendon transfer for chronic abductor insufficiency: the Geneva technique.

INTRODUCTION: The treatment options of chronic abductor insufficiency in the setting of muscle degeneration, are limited and technically demanding. We present the outcomes of a salvage technique for unreconstructable, chronic abductor tears performed by a single surgeon. METHODS: We retrospectively evaluated 38 patients who were surgically managed for chronic abductor insufficiency. Patients without hip implants and patients following primary or revision total hip arthroplasty (THA) were involved. All patients had a Trendelenburg gait, impaired muscle strength of abduction (⩽M4) and fatty degeneration of muscles (Goutallier ⩾3). They underwent transfer of a flap of the anterior third of gluteus maximus to the greater trochanter that was sutured under the slightly mobilised vastus lateralis. The level of pain, functional scores, muscle strength and Trendelenburg gait were re-evaluated at 12 postoperative months. RESULTS: The mean age of patients was 70.2 years. 10 patients received the tendon transfer on a native hip, 6 following primary THA and 22 after revision THA. The mean pain level (3.2 vs. 7, p < 0.001) and Harris Hip Score (80.2 vs. 41.6, p < 0.001) and the median abductor strength (4 vs. 3, p < 0.001) was significantly improved compared to the preoperative scores. 26 patients demonstrated negative and 12 positive Trendelenburg sign at 12 postoperative months. No serious complications were reported. CONCLUSIONS: This salvage technique improved the strength of abduction and functional results and reduced the level of pain in 80% of patients with chronic abductor tears. The short-term outcomes of the procedure were favourable; however, further evaluation is needed.

Anterior Cruciate Ligament Reconstruction With the All-Inside Technique: Equivalent Outcomes and Failure Rate at Three-Year Follow-Up Compared to a Doubled Semitendinosus-Gracilis Graft.

PURPOSE: To compare in terms of failure rates, clinical and functional outcomes the all-inside anterior cruciate ligament (ACL) reconstruction with double suspensory fixation and quadrupled semitendinosus autograft with anteromedial portal doubled semitendinosus-gracilis autograft with suspensory femoral and tibial interference screw fixation. METHODS: Forty-four patients were sequentially allocated into two groups and followed up prospectively for a 3-year period. The first group was the all-inside group and the second was the "classic" AM portal with S-G graft. Each group comprised 22 patients. All patients underwent KT-1000 testing preoperatively and at a minimum of six months postoperatively. Visual pain analog was recorded preoperatively and during both the immediate postoperative period and throughout the follow-up. The Lysholm knee score was used comparing the preoperative and 24-month timepoints. RESULTS: The visual analog scale (VAS) pain scores showed a significant difference at two weeks (2.4 vs 1.8, p < 0.01 ) in favor of the all-inside group, but that difference disappeared in the later follow-up visits. Similarly, there was no significant difference with Lysholm knee scores at two years and the side-to-side anterior translation measured with the KT-1000. At the three-year mark, there were no failures in either of the groups. CONCLUSION: The all-inside technique appears to be equivalent in terms of outcomes to the classic S-G technique, and given the less-invasive nature and versatility in graft choices is a safe and effective technique for primary ACL reconstruction.

Contribution of miRNAs, tRNAs and tRFs to Aberrant Signaling and Translation Deregulation in Lung Cancer.

Transcriptomics profiles of miRNAs, tRNAs or tRFs are used as biomarkers, after separate examination of several cancer cell lines, blood samples or biopsies. However, the possible contribution of all three profiles on oncogenic signaling and translation as a net regulatory effect, is under investigation. The present analysis of miRNAs and tRFs from lung cancer biopsies indicated putative targets, which belong to gene networks involved in cell proliferation, transcription and translation regulation. In addition, we observed differential expression of specific tRNAs along with several tRNA-related genes with possible involvement in carcinogenesis. Transfection of lung adenocarcinoma cells with two identified tRFs and subsequent NGS analysis indicated gene targets that mediate signaling and translation regulation. Broader analysis of all major signaling and translation factors in several biopsy specimens revealed a crosstalk between the PI3K/AKT and MAPK pathways and downstream activation of eIF4E and eEF2. Subsequent polysome profile analysis and 48S pre-initiation reconstitution experiments showed increased global translation rates and indicated that aberrant expression patterns of translation initiation factors could contribute to elevated protein synthesis. Overall, our results outline the modulatory effects that possibly correlate the expression of important regulatory non-coding RNAs with aberrant signaling and translation deregulation in lung cancer.

Lesions of the abductors in the hip.

Abductor tendon lesions and insertional tendinopathy are the most common causes of lateral thigh pain. Gluteal tendon pathology is more prevalent in women and frequency increases with age.Chronic atraumatic tears result in altered lower limb biomechanics. The chief complaint is lateral thigh pain. Clinical examination should include evaluation of muscle strength, lumbar spine, hip and fascia lata pathology. The hip lag sign and 30-second single leg stance tests are useful in diagnosing abductor insufficiency.Magnetic resonance imaging (MRI) is the gold-standard investigation to identify abductor tendon tears and evaluate the extent of muscle fatty infiltration that has predictive value on the outcome of abductor repair.Abductor tendinosis treatment is mainly conservative, including non-steroidal anti-inflammatory medications, activity modification, local corticosteroid injections, plasma-rich protein, physical and radial shockwave therapy. The limited number of available high-quality studies on treatment outcomes and limited evidence between tendinosis and partial ruptures make it difficult to provide definite conclusions regarding the best management of gluteal tendinopathy.Surgical management is indicated in complete and partial gluteal tendon tears that are unresponsive to conservative treatment.There are various open and arthroscopic surgical procedures for direct repair of abductor tendon tears. There is limited evidence concerning surgical management outcomes. Prerequisites for effective tendon suturing are neurologic integrity and limited muscle fatty infiltration. Chronic irreparable tears with limited muscle atrophy and limited fatty infiltration can be augmented with grafts. Gluteus maximus or/vastus lateralis muscle transfers are salvage reconstruction procedures for the management of chronic end-stage abductor tears with significant tendon insufficiency or gluteal atrophy. Cite this article: EFORT Open Rev 2020;5:464-476. DOI: 10.1302/2058-5241.5.190094.

Neoplastic metastases to the endocrine glands.

Endocrine organs are metastatic targets for several primary cancers, either through direct extension from nearby tumour cells or dissemination via the venous, arterial and lymphatic routes. Although any endocrine tissue can be affected, most clinically relevant metastases involve the pituitary and adrenal glands with the commonest manifestations being diabetes insipidus and adrenal insufficiency respectively. The most common primary tumours metastasing to the adrenals include melanomas, breast and lung carcinomas, which may lead to adrenal insufficiency in the presence of bilateral adrenal involvement. Breast and lung cancers are the most common primaries metastasing to the pituitary, leading to pituitary dysfunction in approximately 30% of cases. The thyroid gland can be affected by renal, colorectal, lung and breast carcinomas, and melanomas, but has rarely been associated with thyroid dysfunction. Pancreatic metastasis can lead to exo-/endocrine insufficiency with renal carcinoma being the most common primary. Most parathyroid metastases originate from breast and lung carcinomas and melanoma. Breast and colorectal cancers are the most frequent ovarian metastases; prostate cancer commonly affects the testes. In the presence of endocrine deficiencies, glucocorticoid replacement for adrenal and pituitary involvement can be life saving. As most metastases to endocrine organs develop in the context of disseminated disease, surgical resection or other local therapies should only be considered to ameliorate symptoms and reduce tumour volume. Although few consensus statements can be made regarding the management of metastases to endocrine tissues because of the heterogeneity of the variable therapies, it is important that clinicians are aware of their presence in diagnosis.

Pulmonary nocardiosis associated with Cushing's disease: a case report.

Nocardia spp. is a genus of Gram-positive bacteria which can cause cutaneous, pleuropulmonary, or disseminated disease. The latter two forms are encountered in immunocompromised patients, with prolonged usage of corticosteroids being a well-recognized risk factor. However, endogenous Cushing's syndrome is less frequently associated with nocardiosis. We report on a 40-year-old woman who presented for further workup of abnormal findings in the chest computed tomography (three lung nodules, one of which being cavitary). She underwent trans-thoracic fine-needle lung aspiration of the cavitary nodule, which led to the diagnosis of lung nocardiosis. Moreover, the identification of cushingoid features from the history and clinical examination initiated further investigation with hormonal laboratory assessment and bilateral inferior petrosal sinus sampling which established the diagnosis of pituitary adrenocorticotropic hormone (ACTH) hypersecretion (Cushing's disease).  We conclude that pulmonary nocardiosis can be an opportunistic infection as well as a presenting manifestation of Cushing's disease.

Translation regulation in skin cancer from a tRNA point of view.

Protein synthesis is a central and dynamic process, frequently deregulated in cancer through aberrant activation or expression of translation initiation factors and tRNAs. The discovery of tRNA-derived fragments, a new class of abundant and, in some cases stress-induced, small Noncoding RNAs has perplexed the epigenomics landscape and highlights the emerging regulatory role of tRNAs in translation and beyond. Skin is the biggest organ in human body, which maintains homeostasis of its multilayers through regulatory networks that induce translational reprogramming, and modulate tRNA transcription, modification and fragmentation, in response to various stress signals, like UV irradiation. In this review, we summarize recent knowledge on the role of translation regulation and tRNA biology in the alarming prevalence of skin cancer.

Hallux Osteoid Osteoma: A Case Report and Literature Review.

Osteoid osteoma is a benign bone tumour that mostly affects males in the second and third decade of their life. The lesion mainly occurs in long bones, usually in the femur and tibia, causing severe localized pain that is worse at night and responds to nonsteroidal anti-inflammatory drugs (NSAIDs). Diagnosis is usually made on the basis of history and radiographic findings. However, in more unusual locations as the hand and foot, diagnostic issues can arise. Treatment often includes complete removal of the tumor. We present a 22 year old male with osteoid osteoma involving the distal phalanx of the hallux. To our knowledge very few cases of great toe osteoid osteoma have been reported in the literature.

New Treatment Strategy for a Delayed Skin Necrosis Related to a Calcaneal Fracture.

In calcaneal avulsion fractures, skin necrosis as a result of pressure from the underlying fragment is a fairly common and serious complication. In spite of proper treatment, skin healing complication may occur. We report a calcaneal fracture case complicated by skin necrosis and managed with a novel treatment strategy including application of Platelet Rich Plasma (PRP) and Vacuum Assisted Closure (VAC). This is the first application of combined PRP and VAC treatment in a calcaneal fracture complicated by skin necrosis and was accompanied with very favorable outcomes while avoiding other more complex treatment modalities.

Intravascular Lymphoma as an Uncommon Cause of Anasarca.

OBJECTIVES: To report a case of intravascular lymphoma (IVL) in a Caucasian patient who presented with anasarca as his sole clinical sign. MATERIAL AND METHODS: A man presented with anasarca-type oedema and fatigue. After excluding heart failure, hepatic cirrhosis, nephrotic syndrome, hypothyroidism, AL-amyloidosis and adverse drug reaction which can all cause oedema, we turned our attention to capillary permeability disorders. RESULTS: Closer review of the bone marrow aspirate demonstrated haemophagocytic histiocytosis, while core, renal and duodenal biopsies showed a B-cell IVL. CONCLUSION: The differential diagnosis of anasarca, a relatively common clinical sign, should include IVL although the diagnosis may still be challenging. LEARNING POINTS: Anasarca-type oedema is an unusual initial presentation of intravascular lymphoma (IVL) and is normally attributed to capillary permeability disorders.Two clinical forms of IVL have been recognized: a Western form and an Asian variant which is characterized by haemophagocytosis.Patients of Caucasian origin who have the clinical features of the Asian variant of IVL make the diagnosis of this condition even more challenging.

HCV-RNA qualitative assay based on transcription mediated amplification improves the detection of hepatitis C virus infection in patients on hemodialysis: results from five hemodialysis units in central Greece.

BACKGROUND: End-stage renal disease patients (ESRD) on maintenance hemodialysis (HD) are at increased risk of acquiring hepatitis C virus (HCV) infection. An early and accurate diagnosis of HCV infection is important for the prevention of viral transmission and the management of ESRD patients on HD but conventional ELISA and PCR have often failed to reveal active HCV infection. OBJECTIVES: This study evaluated the prevalence of HCV infection in ESRD patients from all HD units in central Greece using a sensitive HCV-RNA transcription mediated amplification (TMA) assay and compared its sensitivity with that of anti-HCV ELISA. STUDY DESIGN: Anti-HCV antibody (third generation ELISA), HCV-RNA (TMA) and HCV genotypes (HCV TMA-LiPA) were determined in 366 ESRD Greek patients. RESULTS: In total, 132 (36%) ESRD patients were HCV positive by ELISA or TMA; 44 by TMA alone, 16 by ELISA alone and 72 positive by both assays. More than half of the viraemic patients had genotype 3a. CONCLUSIONS: HCV-RNA (TMA) assay appears to increase the accuracy in the diagnosis of HCV infection in HD patients compared to the anti-HCV ELISA and could serve as an additional screening tool in these patients.