Involvement of Lipophagy and Chaperone-Mediated Autophagy in the Pathogenesis of Non-Alcoholic Fatty Liver Disease by Regulation of Lipid Droplets.

Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of lipids in the form of lipid droplets in more than 5% of hepatocytes. It is regarded as a range of diverse pathologies, including simple steatosis and steatohepatitis. The structural characteristics of lipid droplets, along with their protein composition, mainly including perilipins, have been implicated in the etiology of the disease. These proteins have garnered increasing attention as a pivotal regulator since their levels and distinct expression appear to be associated with the progression from simple steatosis to steatohepatitis. Perilipins are target proteins of chaperone-mediated autophagy, and their degradation is a prerequisite for lipolysis and lipophagy to access the lipid core. Both lipophagy and chaperone-mediated autophagy have significant implications on the development of the disease, as evidenced by their upregulation during the initial phases of simple steatosis and their subsequent downregulation once steatosis is established. On the contrary, during steatohepatitis, the process of chaperone-mediated autophagy is enhanced, although lipophagy remains suppressed. Evidently, the reduced levels of autophagic pathways observed in simple steatosis serve as a defensive mechanism against lipotoxicity. Conversely, in steatohepatitis, chaperone-mediated autophagy fails to compensate for the continuous generation of small lipid droplets and thus cannot protect hepatocytes from lipotoxicity.

Investigation of Clinically Significant Molecular Aberrations in Patients with Prostate Cancer: Implications for Personalized Treatment, Prognosis and Genetic Testing.

The data on tumor molecular profiling of European patients with prostate cancer is limited. Our aim was to evaluate the prevalence and prognostic and predictive values of gene alterations in unselected patients with prostate cancer. The presence of gene alterations was assessed in patients with histologically confirmed prostate cancer using the ForeSENTIA® Prostate panel (Medicover Genetics), targeting 36 clinically relevant genes and microsatellite instability testing. The primary endpoint was the prevalence of gene alterations in homologous recombination repair (HRR) genes. Overall, 196 patients with prostate cancer were evaluated (median age 72.2 years, metastatic disease in 141 (71.9%) patients). Gene alterations were identified in 120 (61%) patients, while alteration in HRR genes were identified in 34 (17.3%) patients. The most commonly mutated HRR genes were ATM (17, 8.7%), BRCA2 (9, 4.6%) and BRCA1 (4, 2%). The presence of HRR gene alterations was not associated with advanced stage (p = 0.21), age at diagnosis (p = 0.28), Gleason score (p = 0.17) or overall survival (HR 0.72; 95% CI: 0.41-1.26; p = 0.251). We identified clinically relevant somatic gene alterations in European patients with prostate cancer. These molecular alterations have prognostic significance and therapeutic implications and/or may trigger genetic testing in selected patients. In the era of precision medicine, prospective research on the predictive role of these alterations for innovative treatments or their combinations is warranted.

Volumetric apparent diffusion coefficient histogram analysis of the testes in nonobstructive azoospermia: a noninvasive fingerprint of impaired spermatogenesis?

OBJECTIVES: To explore the association between testicular volumetric apparent diffusion coefficient (ADC) histogram analysis metrics and histologic categories in nonobstructive azoospermia (NOA). The role of ADC histogram analysis in predicting the presence of spermatozoa, prior to testicular sperm extraction (TESE), was also investigated. METHODS: Forty-one NOA men and 17 age-matched controls underwent scrotal MRI with diffusion-weighted imaging. Histogram analysis of ADC data of the whole testis was performed. Metrics including mean, standard deviation, median, mode, 25th percentile, 75th percentile, skewness, kurtosis, and entropy of volumetric ADC histograms were calculated. Nonparametric statistical tests were used to assess differences in ADC histogram parameters between NOA histologic categories (hypospermatogenesis, severe hypospermatogenesis, early maturation arrest, and Sertoli cell-only syndrome) and normal testes and, between NOA with positive and negative sperm retrieval. RESULTS: Normal testes had a lower mean, median, mode, 25th percentile (p < 0.001), and 75th percentile of ADC (p = 0.001), compared to NOA histologic phenotypes. NOA with hypospermatogenesis had a lower 25th percentile of ADC compared to NOA with severe hypospermatogenesis. Regression analysis revealed that the 25th percentile of ADC had a moderately negative correlation with NOA histologic phenotype. The median ADC proved the most significant metric (p = 0.007) to predict the presence of sperm. CONCLUSIONS: Testicular volumetric ADC histogram parameters may contribute in the identification of the subpopulation of NOA men with a specific type of spermatogenic arrest. KEY POINTS: • Volumetric ADC histogram analysis metrics may be used as noninvasive markers of impaired spermatogenesis in nonobstructive azoospermia. • The 25th percentile of ADC proved useful in discriminating between NOA testes with hypospermatogenesis and severe hypospermatogenesis. • The median ADC proved the most significant parameter to predict the presence of viable spermatozoa prior to TESE.

In vivo biochemical investigation of spermatogenic status: 1H-MR spectroscopy of testes with nonobstructive azoospermia.

OBJECTIVES: To evaluate the biochemical milieu in testes with nonobstructive azoospermia (NOA) by using proton MR spectroscopy (1H-MRS) in detecting differences in testicular metabolites between histological stages of NOA and in assessing the possible presence of spermatozoa before microdissection testicular sperm extraction (mTESE). METHODS: Forty-nine NOA men and fifty age-matched controls were included in this prospective study. A single-voxel point-resolved spectroscopy sequence with TR/TE (2000/25 ms) was used. NOA testes were classified using the higher Johnsen score (hJS) (group 1, hJS ≥ 8; and group 2, hJS < 8). Nonparametric statistical tests were used to assess differences in normalized metabolite concentrations, defined as ratios of the metabolite concentrations versus creatine concentration between (a) NOA and controls, (b) NOA groups, and (c) NOA with positive and negative sperm retrieval. RESULTS: Normalized concentrations of total choline (median 0.396 vs 1.09 mmol/kg, p = 0.002), myo-inositol (median 1.985 vs 3.19 mmol/kg, p = 0.002), and total lipids and macromolecules (TLM) resonating at 0.9 ppm (median 0.962 vs 2.43 mmol/kg, p = 0.024), 1.3 ppm (median 4.88 vs 10.7 mmol/kg, p = 0.043), and 2.0 ppm (median 2.33 vs 5.96 mmol/kg, p = 0.007) were reduced in NOA testes compared with controls. Decreased concentrations of TLM 2.0 (median 3.755 vs 0.436 mmol/kg, p = 0.043) were found in group 2 compared with group 1. Increased normalized concentrations of glutamate were observed in NOA testes with failed sperm retrieval (median 0.321 vs 0.000 mmol/kg, p = 0.028). CONCLUSIONS: 1H-MRS provides metabolic information about the testis in NOA patients and assesses spermatogenic status before mTESE. KEY POINTS: • NOA testes differed from age-matched controls, in terms of reduced normalized concentrations of tChol, mI, and lipids. • TLM 2.0 peaks were found useful in the identification of NOA testes with the presence of foci of advanced spermatogenesis up to the haploid gamete stage. • Glu proved a reliable metabolic signature of spermatogenesis in NOA population by assessing the possible presence of sperm after mTESE.

Successful treatment with rituximab of IgG4-related disease coexisting with adult-onset asthma and periocular xanthogranuloma.

Immunoglobulin G4-related disease (IgG4RD) is a systemic fibro-inflammatory disease of unknown aetiology, which is characterized by tumefactive lymphoplasmatocytic infiltrative lesions, with a predominance of IgG4 positive plasma cells, fibrosis and obliterative phlebitis. Adult-onset asthma and periocular xanthogranuloma (AAPOX) is a rare disease of unknown aetiology characterized by violaceous or yellow cutaneous papules and nodules usually accompanied with adult-onset asthma. We report a case of IgG4RD associated with AAPOX. We also conducted a literature search with keywords including IgG4RD and AAPOX. A 36-year-old woman presented with bilateral exophthalmos and periorbital oedema. Keratoconjunctivitis sicca, painless left parotid gland and submandibular left lymph node enlargement were also noted. Two and half years ago biopsy of yellow plaques of her right lower eyelid confirmed periorbital xanthogranuloma. She underwent parotid gland biopsy which showed IgG4RD. She was treated with steroids and two cycles of rituximab with complete remission. The literature review revealed 8 articles describing 14 cases with IgG4RD and AAPOX, 9 men and 5 women (ratio M:F = 1.8:1) were affected. The age at diagnosis was greater in men compared to women. In the majority of patients, ophthalmic presentation included bilateral upper and lower eyelid swelling while systemic features were asthma, lacrimal and parotid involvement, lymphadenopathy, sclerosing pancreatitis and sclerosing cholangitis. Prednisone and rituximab were effective treatments. It has to be clarified whether the association between IgG4RD and AAPOX represents shared pathophysiology, a common underlying cause or coincidence. Rituximab added to steroids resulted in complete remission of the two entities.

Antigen-presenting cells in ocular surface diseases.

PURPOSE: To review the role of antigen-presenting cells (APC) in the pathogenesis of ocular surface diseases (OSD). METHODS: A thorough literature search was performed in PubMed database. An additional search was made in Google Scholar to complete the collected items. RESULTS: APCs have the ability to initiate and direct immune responses and are found in most lymphoid and non-lymphoid tissues. APCs continuously sample their environment, present antigens to T cells and co-ordinate immune tolerance and responses. Many different types of APCs have been described and there is growing evidence that these cells are involved in the pathogenesis of OSD. OSD is a complex term for a myriad of disorders that are often characterized by ocular surface inflammation, tear film instability and impairment of vision. CONCLUSIONS: This review summarizes the current knowledge concerning the immunotopographical distribution of APCs in the normal ocular surface. APCs appear to play a critical role in the pathology of a number of conditions associated with OSD including infectious keratitis, ocular allergy, dry eye disease and pterygium.

Testicular Apparent Diffusion Coefficient and Magnetization Transfer Ratio: Can These MRI Parameters Be Used to Predict Successful Sperm Retrieval in Nonobstructive Azoospermia?

OBJECTIVE. The aim of our study was to assess if testicular apparent diffusion coefficient (ADC) and magnetization transfer ratio (MTR) can be used as MRI parameters to predict the presence of spermatozoa retrieved after microdissection testicular sperm extraction (mTESE) in men with nonobstructive azoospermia (NOA). MATERIALS AND METHODS. The study included 49 men with NOA and 45 age-matched control subjects. Participants underwent scrotal MRI between June 2013 and January 2017, 1 day before mTESE. Testicular volume (TV), ADC, and MTR were measured. NOA testes were classified as follows: group 1, testes with higher Johnsen score of ≥ 8; and group 2, testes with higher Johnsen score of < 8. Nonparametric statistical tests were used to assess differences in TV, ADC, and MTR between men with NOA and control subjects, the two NOA groups, and NOA testes with positive sperm retrieval and NOA testes with negative sperm retrieval. RESULTS. TV (p < 0.001) was reduced and both ADC (p < 0.001) and MTR (p = 0.013) were increased in NOA testes compared with normal testes. A positive correlation between higher Johnsen score and TV (p < 0.001) and a negative correlation between higher Johnsen score and both ADC (p = 0.015) and MTR (p = 0.003) were found. TV (p < 0.001) was reduced in NOA testes with failed sperm retrieval compared with NOA testes with positive sperm retrieval. On the contrary, ADC (p = 0.011) and MTR (p = 0.045) were significantly increased in NOA testes with negative sperm retrieval. CONCLUSION. On the basis of our preliminary data, TV, ADC, and MTR might represent useful MRI parameters in the workup of patients with NOA by helping to predict the presence of spermatozoa after mTESE.

Diffusion tensor imaging parameters in testes with nonobstructive azoospermia.

BACKGROUND: The development of noninvasive imaging parameters having the capacity to identify the population of men with nonobstructive azoospermia (NOA) where a successful sperm retrieval outcome is of great clinical significance. PURPOSE/HYPOTHESIS: To assess differences of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in NOA testes with impaired spermatogenesis and the possible association with the presence of spermatozoa after testicular sperm extraction (TESE). STUDY TYPE: Retrospective. POPULATION: Twenty NOA men (35 testes) and 21 age-matched controls (36 testes). FIELD STRENGTH/SEQUENCE: 1.5T, T1 WI-SE T2 WI-FSE FS SS-EP-DTI. ASSESSMENTS: The MRI data were analyzed by two radiologists in consensus. The average ADC and FA of testicular parenchyma was measured. NOA testes were classified as NOA with higher Johnsen score (JS) ≥8 (group 1) and JS <8 (group 2). STATISTICAL TESTS: Parametric and nonparametric statistical tests were used to compare ADC and FA between NOA groups and normal testes (group 3) and to evaluate a possible association with the presence of spermatozoa after TESE. RESULTS: Differences in ADC were found between groups 1 and 2 (P = 0.043) and groups 2 and 3 (P = 0.004), but not between groups 1 and 3 (P = 0.418). Higher values of FA were found both in NOA testes with JS ≥8 (P < 0.001) and JS <8 (P < 0.001) compared to controls. ADC (P = 0.096) and FA (P = 0.516) did not demonstrate differences in NOA testes with or without spermatozoa at TESE. DATA CONCLUSION: Both ADC and FA are increased in NOA testes compared to a normal population. ADC was proven to be a more useful diagnostic adjunct tool in the identification of the population of NOA men with foci of advanced spermatogenesis. However, DTI parameters were not predictive of sperm retrieval after TESE. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1318-1325.

Association of osteopontin with specific prognostic factors and survival in adjuvant breast cancer trials of the Hellenic Cooperative Oncology Group.

BACKGROUND: The shift towards an earlier diagnosis of breast cancer (BC) highlights the need for biomarkers that would identify patients at risk for relapse and metastatic spread and indicate the potential value of additional treatment strategies. Osteopontin (OPN) is a matricellular protein that has been suggested to be a potential biomarker in BC. In the present study, we used archived BC patient samples to assess the clinical utility of OPN. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples from 975 patients were collected from two large phase III randomized adjuvant chemotherapy trials (HE10/97 and HE10/00) that included patients with high risk BC. All tissue samples were assessed for ER, PgR, Ki67 and HER2 protein expression. OPN protein and mRNA expression was evaluated using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, respectively. RESULTS: OPN mRNA expression data were available for 814 patients, whereas OPN protein expression data were available for 546 patients. The majority of patients were ER/PgR-positive (78.3%), HER2-negative (76.5%) and Ki67-positive (55.2%) and had received adjuvant radiation therapy (76.8%) and hormonal therapy (81.1%). OPN mRNA expression was significantly associated with age (60.9% in high OPN tumors vs. 54.1% in low OPN tumors, p = 0.047), ER/PgR-negative status (25.7 vs. 17.2%, p = 0.004) and BC subtypes (p = 0.021). In addition, high OPN mRNA expression was significantly associated with reduced DFS (HR 1.26, 95% CI 1.00-1.59, Wald's p = 0.050) and OS (HR 1.37, 95% CI 1.05-1.78, p = 0.019), while it retained its prognostic significance for both DFS (HR 1.39, 95% CI 1.10-1.77, p = 0.007) and OS (HR 1.54, 95% CI 1.61-2.05, p = 0.003) in the multivariate analysis. CONCLUSIONS: We showed that high OPN mRNA expression is associated with decreased DFS and OS in a large cohort of BC patients treated with adjuvant chemotherapy in a clinical trial setting. Our results suggest that OPN may serve as a prognostic factor and a potential target for therapy. Trial registration Australian New Zealand Clinical Trials Registry; HE10/97 ACTRN12611000506998; HE10/00 ACTRN12609001036202.

The expression of corticotropin-releasing hormone family peptides in premalignant and malignant vulvar lesions.

OBJECTIVES: To examine the relation of corticotropin-releasing hormone (CRH) family peptides with inflammatory processes and oncogenesis, emphasizing in vulvar inflammatory, premalignant and malignant lesions, as well as to investigate the possibility of lesion cells immunoescaping, utilizing FAS/FAS-L complex. METHODS: Immunohistochemical expression of CRH, urocortin (UCN), FasL and their receptors CRHR1, CRHR2 and Fas was studied in vulvar tissue sections obtained from patients with histologically confirmed diagnosis of lichen, vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell carcinoma (VSCC). The patient cohort was selected from a tertiary teaching Hospital in Greece, between 2005 and 2015. For each of the disease categories, immunohistochemical staining was evaluated and the results were statistically compared. RESULTS: A progressive increase of the cytoplasmic immunohistochemical expression of CRH and UCN, from precancerous lesions to VSCC was observed. A similar increase was detected for Fas and FasL expression. Nuclear localization of UCN was demonstrated in both premalignant and VSCC lesions, with staining being significantly intensified in carcinomas, particularly in the less differentiated tumor areas or in the areas at invasive tumor front. CONCLUSIONS: Stress response system and CRH family peptides seem to have a role in inflammation maintenance and progression of vulvar premalignant lesions to malignancy. It seems that stress peptides may locally modulate the stroma through Fas/FasL upregulation, possibly contributing to vulvar cancer development.

Complex cystic liver lesions: classification, diagnosis, and management.

Cystic liver disease has been increasingly reported in the literature, with a prevalence as high as 15-18%. Hepatic cysts are usually discovered incidentally, while their characterization and classification rely on improved imaging modalities. Complex cystic liver lesions comprise a wide variety of novel, re-introduced, and re-classified clinical entities. This spectrum of disorders ranges from non-neoplastic conditions to benign and malignant tumors. Their clinicopathological features, prognostic factors, and oncogenic pathways are incompletely understood. Despite representing a heterogeneous group of disorders, they can have similar clinical and imaging characteristics. As a result, the diagnosis and management of complex liver cysts can become quite challenging. Furthermore, inappropriate diagnosis and management can lead to high morbidity and mortality. In this review, we aim to offer up-to-date insight into the diagnosis, classification, and management of the most common complex cystic liver lesions.

Ten-year clinical outcome, toxicity and compliance of dose-dense sequential adjuvant administration of cyclophosphamide & epirubicin followed by docetaxel in patients with early breast cancer: A hellenic cooperative oncology group observational study (HE 10/10) with concurrent investigation of significance of tumor infiltrating lymphocytes.

BACKGROUND: Dose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8+ lymphocytes were also evaluated in the same cohort. PATIENTS AND METHODS: Totally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8+ lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8+ lymphocytes in tumor stroma (sCD8) as well as the total number of CD8+ lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry. RESULTS: Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0-81.5) and 81.7% (95% CI 79.0-84.1), respectively. Interestingly, higher CD8+ T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome. CONCLUSIONS: In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8+ lymphocytes in BC patients with early-stage disease.

Novel microRNA-based assay demonstrates 92% agreement with diagnosis based on clinicopathologic and management data in a cohort of patients with carcinoma of unknown primary.

BACKGROUND: Cancer of unknown or uncertain primary is a major diagnostic and clinical challenge, since identifying the tissue-of-origin of metastases is crucial for selecting optimal treatment. MicroRNAs are a family of non-coding, regulatory RNA molecules that are tissue-specific, with a great potential to be excellent biomarkers. METHODS: In this study we tested the performance of a microRNA-based assay in formalin-fixed paraffin-embedded samples from 84 CUP patients. RESULTS: The microRNA based assay agreed with the clinical diagnosis at presentation in 70% of patients; it agreed with the clinical diagnosis obtained after patient management, taking into account response and outcome data, in 89% of patients; it agreed with the final clinical diagnosis reached with supplemental immunohistochemical stains in 92% of patients, indicating a 22% improvement in agreement from diagnosis at presentation to the final clinical diagnosis. In 18 patients the assay disagreed with the presentation diagnosis and was in agreement with the final clinical diagnosis, which may have resulted in the administration of more effective chemotherapy. In three out of four discordant cases in which supplemental IHC was performed, the IHC results validated the assay's molecular diagnosis. CONCLUSIONS: This novel microRNA-based assay shows high accuracy in identifying the final clinical diagnosis in a real life CUP patient cohort and could be a useful tool to facilitate administration of optimal therapy.

Perirenal fat invasion on renal cell carcinoma: evaluation with multidetector computed tomography-multivariate analysis.

OBJECTIVE: The objective of this study was to assess the accuracy of multidetector computed tomography (CT) in diagnosing perinephric (PN) and/or renal sinus (RS) fat invasion in patients with renal cell carcinoma (RCC), with reference to the CT findings predictive for the diagnosis of invasion. METHODS: This was a retrospective study of 48 RCCs. Examinations were performed on a 16-row CT scanner, including unenhanced and 3-phase contrast-enhanced CT scanning. Unenhanced transverse images and multiplanar reformations of each contrast-enhanced CT phase were evaluated. The predictive value of CT findings in diagnosing PN and/or RS fat invasion was determined using multivariate logistic regression analysis. RESULTS: The CT findings that were most predictive for the diagnosis of PN fat invasion were the presence of contrast-enhancing nodules in the PN fat and tumoral margins. Invasion of the pelvicaliceal system was the most significant predictor in the diagnosis of RS fat invasion. CONCLUSIONS: Multidetector CT provides satisfactory results in detecting PN and/or RS fat invasion in RCC.

Coexistence of Crohn's disease in a patient with systemic lupus erythematosus.

The concurrence of inflammatory bowel disease with systemic lupus erythematosus (SLE) is rare. The concomitant diagnosis of Crohn's disease and SLE is even more rare. The patient, a 40-year-old woman, was admitted to our hospital because of relapsing episodes of abdominal pain, diarrheas upper and lower extremities arthralgias, Raynaud's phenomenon with positive antinuclear antibodies, and fever for the last 2 years. The patient was diagnosed elsewhere with SLE and treated with hydroxychloroquine. Her medical history also included tonsillectomy and total hip replacement after a car accident. Family history was unremarkable. Physical examination was unremarkable except of very mild pain at lower left abdominal quadrant. Laboratory tests showed erythrocyte sedimentation rate at 32 mm/h, C-reactive protein at 36 mg/dl, positive rheumatoid factor, and increased C3, C4, positive antinuclear antibodies with the presence of anti-Sm and anti-RNP antibodies. Ileocolonoscopy revealed colonic inflammation with ulcers and pseudopolyps. Subsequent biopsies were diagnostic of Crohn's disease. Patient was diagnosed with Crohn's colitis concomitant to systemic lupus erythematosus and was started on therapy with azathioprine 2 mg/Kg, methylprednisolone 16 mg/d with slow tapering, mesalazine 1.5 g/day, and hydroxychloroquine. Patient is in excellent health status on the six-month follow-up.

The shape and the thickness of the anterior cruciate ligament along its length in relation to the posterior cruciate ligament: a cadaveric study.

PURPOSE: The purpose of this study was to evaluate the shape of the native anterior cruciate ligament (ACL) along its length in relation to the posterior cruciate ligament (PCL) and compare it with the size of the 3 commonly used autografts (bone-patellar tendon-bone [BPTB], single-bundle hamstring, and double-bundle hamstring). METHODS: With the knee in extension, we filled the intercondylar notch with paraffin, fixing the cruciate ligaments in their natural position, in 8 cadaveric specimens. The ACL-PCL tissue specimen, embedded in paraffin, was removed en bloc. Gross sections were prepared in the coronal plane and were evaluated histologically. The width, thickness, and cross-sectional area of both the ACL and PCL were determined. The dimensions of the semitendinosus tendon (ST), gracilis tendon (GT), and BPTB grafts were measured and compared with those of the native ACL. RESULTS: The PCL occupies the largest part of the intercondylar area, leaving only a small space for the ACL in knee extension. The ACL midsubstance has a width of 5 mm, resembling a band shape. Only before its tibial insertion does the ACL fan out and take the form of its tibial attachment. The BPTB graft has a thickness of 5.8 mm, whereas the ST and GT grafts have a thickness of 6.25 mm and 4.5 mm, respectively, and are comparable to the midsubstance of the ACL but undersized in the tibial insertion (P = .0016 for BPTB graft, P = .002 for ST graft, and P = .0003 for GT graft). A quadruple-looped ST-GT graft, with a diameter of 8 mm, is oversized in the midsubstance (P = .0002) but fits better in the tibial attachment. CONCLUSIONS: The ACL midsubstance has a width of 5 mm, resembling a band shape. Before its tibial insertion, the ACL fans out like a trumpet, taking the form of its wide tibial attachment. CLINICAL RELEVANCE: The dimensions of the native ACL have to be considered in graft selection for anatomic ACL reconstruction.

The Role of Oxidative Stress and Cellular Senescence in the Pathogenesis of Metabolic Associated Fatty Liver Disease and Related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) represents a worryingly increasing cause of malignancy-related mortality, while Metabolic Associated Fatty Liver Disease (MAFLD) is going to become its most common cause in the next decade. Understanding the complex underlying pathophysiology of MAFLD-related HCC can provide opportunities for successful targeted therapies. Of particular interest in this sequela of hepatopathology is cellular senescence, a complex process characterised by cellular cycle arrest initiated by a variety of endogenous and exogenous cell stressors. A key biological process in establishing and maintaining senescence is oxidative stress, which is present in multiple cellular compartments of steatotic hepatocytes. Oxidative stress-induced cellular senescence can change hepatocyte function and metabolism, and alter, in a paracrine manner, the hepatic microenvironment, enabling disease progression from simple steatosis to inflammation and fibrosis, as well as HCC. The duration of senescence and the cell types it affects can tilt the scale from a tumour-protective self-restricting phenotype to the creator of an oncogenic hepatic milieu. A deeper understanding of the mechanism of the disease can guide the selection of the most appropriate senotherapeutic agent, as well as the optimal timing and cell type targeting for effectively combating HCC.

Intraoperative Flow Cytometry for the Evaluation of Meningioma Grade.

Meningiomas are the most frequent central nervous system tumors in adults. The majority of these tumors are benign. Nevertheless, the intraoperative identification of meningioma grade is important for modifying surgical strategy in order to reduce postoperative complications. Here, we set out to investigate the role of intraoperative flow cytometry for the differentiation of low-grade (grade 1) from high-grade (grade 2-3) meningiomas. The study included 59 patients. Intraoperative flow cytometry analysis was performed using the 'Ioannina Protocol' which evaluates the G0/G1 phase, S-phase, mitosis and tumor index (S + mitosis phase fraction) of a tumor sample. The results are available within 5 min of sample receipt. There were 41 grade 1, 15 grade 2 and 3 grade 3 meningiomas. High-grade meningiomas had significantly higher S-phase fraction, mitosis fraction and tumor index compared to low-grade meningiomas. High-grade meningiomas had significantly lower G0/G1 phase fraction compared to low-grade meningiomas. Thirty-eight tumors were diploids and twenty-one were aneuploids. No significant difference was found between ploidy status and meningioma grade. ROC analysis indicated 11.4% of tumor index as the optimal cutoff value thresholding the discrimination between low- and high-grade meningiomas with 90.2% sensitivity and 72.2% specificity. In conclusion, intraoperative flow cytometry permits the detection of high-grade meningiomas within 5 min. Thus, surgeons may modify tumor removal strategy.