The anteromedial retinaculum in ACL-injured knees: An overlooked injury?

PURPOSE: The purpose of this study was to retrospectively analyse the pattern of injury to the medial knee structures in anterior cruciate ligament (ACL) injured patients. It was hypothesised that anteromedial injuries would be more common than posteromedial lesions. METHODS: One hundred and twenty subjects aged 18-25 years with a primary ACL injury were included. Patients were excluded if the time between injury and magnetic resonance imaging (MRI) was more than 28 days or if a knee dislocation or fracture was present. The MRIs were analysed with particular emphasis on injuries to the medial knee structures, menisci and bone bruise patterns. Injuries to the ligaments and anteromedial retinaculum (AMR) were graded according to severity, ranging from periligamentous oedema (grade I), partial fibre disruption of less or more than 50% (grade IIa or IIb) to complete tears (grade III). RESULTS: AMR injury was seen in 87 subjects (72.5%) on the coronal plane and in 88 (73.3%) on the axial plane, with grade III lesions observed in 27 (22.5%) and 29 knees (24.2%). Injuries to the superficial medial collateral ligament (sMCL), deep MCL (dMCL) and posterior oblique ligament (POL) were detected in 60 patients (50%), 93 patients (77.5%) and 38 patients (31.6%). However, grade III injuries to the POL were observed in only seven knees (5.8%). Medial meniscus injuries were associated with lesions of the sMCL and AMR (p < 0.05), while lateral meniscus injuries were significantly more common in patients with dMCL rupture (p < 0.05). CONCLUSION: Data from this study suggest that injuries to the AMR are much more common than posteromedial lesions in subjects with ACL injuries. LEVEL OF EVIDENCE: Level IV.

SEI growth on Lithium metal anodes in solid-state batteries quantified with coulometric titration time analysis.

Lithium-metal batteries with a solid electrolyte separator are promising for advanced battery applications, however, most electrolytes show parasitic side reactions at the low potential of lithium metal. Therefore, it is essential to understand how much (and how fast) charge is consumed in these parasitic reactions. In this study, a new electrochemical method is presented for the characterization of electrolyte side reactions occurring on active metal electrode surfaces. The viability of this new method is demonstrated in a so-called anode-free stainless steel ∣ Li6PS5Cl ∣ Li cell. The method also holds promise for investigating dendritic lithium growth (and dead lithium formation), as well as for analyzing various electrolytes and current collectors. The experimental setup allows easy electrode removal for post-mortem analysis, and the SEI's heterogeneous/layered microstructure is revealed through complementary analytical techniques. We expect this method to become a valuable tool in the future for solid-state lithium metal batteries and potentially other cell chemistries.

Associations between an international COVID-19 job exposure matrix and SARS-CoV-2 infection among 2 million workers in Denmark.

OBJECTIVES: This study investigates the associations between the Danish version of a job exposure matrix for COVID-19 (COVID-19-JEM) and Danish register-based SARS-CoV-2 infection information across three waves of the pandemic. The COVID-19-JEM consists of four dimensions on transmission: two on mitigation measures, and two on precarious work characteristics. METHODS: The study comprised 2 021 309 persons from the Danish working population between 26 February 2020 and 15 December 2021. Logistic regression models were applied to assess the associations between the JEM dimensions and overall score and SARS-CoV-2 infection across three infection waves, with peaks in March-April 2020, December-January 2021, and February-March 2022. Sex, age, household income, country of birth, wave, residential region and during wave 3 vaccination status were accounted for. RESULTS: Higher risk scores within the transmission and mitigation dimensions and the overall JEM score resulted in higher odds ratios (OR) of a SARS-CoV-2 infection. OR attenuated across the three waves with ranges of 1.08-5.09 in wave 1, 1.06-1.60 in wave 2, and 1.05-1.45 in those not (fully) vaccinated in wave 3. In wave 3, no associations were found for those fully vaccinated. In all waves, the two precarious work dimensions showed weaker or inversed associations. CONCLUSIONS: The COVID-19-JEM is a promising tool for assessing occupational exposure to SARS-CoV-2 and other airborne infectious agents that mainly spread between people who are in close contact with each other. However, its usefulness depends on applied restrictions and the vaccination status in the population of interest.

Novel approach of desensitization in allergic reaction to Olaparib.

INTRODUCTION: PARP (Poly ADP Ribose Polymerase) inhibitors are an effective maintenance therapy for various entities, such as BRCA (breast cancer gene) mutated or HRD (homologous recombination deficiency) positive primary platin-sensitive advanced ovarian cancer after platin induction therapy and in relapse after responding to carboplatin reinduction. Other entities are metastatic BRCA mutated pancreas, prostate and Her2-negative breast cancer. Therefore, patients with allergic reactions to PARP inhibitors should undergo a desensitization procedure to be able to receive this efficient therapy. CASE REPORT: We conducted a two-day desensitization on a 45-year-s old patient with advanced ovarian cancer who displayed symptoms of an allergic reaction to Olaparib. MANAGEMENT AND OUTCOME: Using an Olaparib tablet suspension, we orally administered increasing Olaparib doses, starting with 12.5 mg and reaching a cumulative dose of 387.5 mg on the first day and starting with 100 mg and reaching a cumulative dose of 600 mg on the second day, without concomitant antiallergic medication.Except for mild erythema on day one receding within the hour, no further allergic reactions appeared during desensitization. The patient has since received 300 mg of Olaparib twice a day without further complications or interruptions. CONCLUSION: Desensitization in a two-day suspension protocol is a safe method that ensures effective maintenance therapy for patients with allergic reactions to PARP inhibitors.

Cultural evolution is not independent of linguistic evolution and social aspects of language use.

The bifocal stance theory (BST) focuses on cultural evolution without alluding to associated processes in linguistic evolution and language use. The authors briefly comment on language acquisition but leave underexplored the applicability of BST to linguistic evolution, to changes of language representations, and to possible consequences for constructing social identity, based on, for example, collective resilience processes within language communities.

Mapping densely packed αIIbß3 receptors in murine blood platelets with expansion microscopy.

Interrogating platelets and their densely packed, highly abundant receptor landscape is key to understand platelet clotting, a process that can save lives when stopping blood loss after an injury, but also kill when causing heart attack, stroke, or pulmonary embolism. The underlying key receptor distributions and interactions, in particular the relevance of integrin clustering, are not fully understood is because of highly abundant and densely distributed αIIbß3 receptors. This makes receptor distributions difficult to assess even by super-resolution fluorescence microscopy. Here, we combine dual-color expansion and confocal microscopy with colocalization analysis to assess platelet receptor organization without the need of a super-resolution microscope. We show that 4x expansion is highly straight-forward for super-resolution microscopy of platelets, while 10x expansion provides higher precision at the price of increased efforts in sample preparation and imaging. Quantifying various receptor colocalization scenarios we demonstrate that expansion microscopy can pinpoint receptor distributions and interactions in resting and activated platelets being superior to conventional methods that fail in such dense 3D scenarios with highly abundant receptors. We reveal the presence of αIIbß3 clusters in resting platelets, as well as in activated platelets, indicating that they contribute to the rapid platelet response during platelet clotting.

Were we stressed or was it just me - and does it even matter? Efforts to disentangle individual and collective resilience within real and imagined stressors.

Although resilience is a multi-level process, research largely focuses on the individual and little is known about how resilience may distinctly present at the group level. Even less is known about subjective conceptualizations of resilience at either level. Therefore, two studies sought to better understand how individuals conceptualize resilience both as an individual and as a group. Study 1 (N = 123) experimentally manipulated whether participants reported on either individual or group-based responses to real stressors and analysed their qualitative responses. For individual responses, subjective resilience featured active coping most prominently, whereas social support was the focus for group-based responses. As these differences might be attributable to the different stressors people remembered in either condition, Study 2 (N = 171) held a hypothetical stressor (i.e., natural disaster) constant. As expected, resilience at the group level emphasized maintaining group cohesion. Surprisingly, the group condition also reported increased likelihood to engage in blame, denial, and behavioural disengagement. Contrary to expectations, participants in the individual condition reported stronger desire to seek out new groups. The combined findings are discussed within the framework of resilience and social identity and highlight the necessity of accounting for multiple levels and subjective conceptualizations of resilience.

Lithium-Metal Anode Instability of the Superionic Halide Solid Electrolytes and the Implications for Solid-State Batteries.

Owing to high ionic conductivity and good oxidation stability, halide-based solid electrolytes regain interest for application in solid-state batteries. While stability at the cathode interface seems to be given, the stability against the lithium metal anode has not been explored yet. Herein, the formation of a reaction layer between Li3 InCl6 (Li3 YCl6 ) and lithium is studied by sputter deposition of lithium metal and subsequent in situ X-ray photoelectron spectroscopy as well as by impedance spectroscopy. The interface is thermodynamically unstable and results in a continuously growing interphase resistance. Additionally, the interface between Li3 InCl6 and Li6 PS5 Cl is characterized by impedance spectroscopy to discern whether a combined use as cathode electrolyte and separator electrolyte, respectively, might enable long-term stable and low impedance operation. In fact, oxidation stable halide-based lithium superionic conductors cannot be used against Li, but may be promising candidates as cathode electrolytes.

A positive diagnostic strategy is safe and saves endoscopies in patients with irritable bowel syndrome: A five-year follow-up of a randomized controlled trial.

BACKGROUND: Previously, the diagnosis of irritable bowel syndrome (IBS) required exclusion of organic causes by extensive diagnostic testing. Newer guidelines recommend IBS as a positive diagnosis based on symptoms with limited testing. We investigated the long-term safety and impact on use of health resources of a positive diagnostic strategy compared to a strategy of exclusion in patients with symptoms compatible with IBS. METHODS: In 2008-2010, primary care patients aged 18-50 years fulfilling the Rome III criteria for IBS without alarm signals were randomized to a positive diagnostic strategy (limited blood tests, n = 150) or a strategy of exclusion (extensive blood tests, fecal samples for intestinal parasites, and sigmoidoscopy with biopsies, n = 152). At five years, hospital-registered diagnoses and use of health resources including lower endoscopies were retrieved from national registries. Participants provided 5-year data on Rome III criteria for IBS, severity of symptoms, and quality of life. KEY RESULTS: Baseline mean age was 31.4 (SD 9.1) years; 79% were female. No cases of celiac disease, and gastrointestinal or gynecological cancers were diagnosed within five years. Negligible and comparable numbers were diagnosed with inflammatory bowel disease, benign gynecological conditions, and upper GI conditions in the two groups. The positive diagnosis strategy carried a higher number of lower endoscopies from year 1 to 5 (23 patients versus 13 patients in the exclusion group), but overall saved endoscopies. CONCLUSIONS & INFERENCES: A positive diagnosis of IBS was as safe as a diagnosis of exclusion in a five-year perspective and saved lower endoscopies; the study was registered at ClinicalTrials.gov numbers: NCT00659763/NCT01153295.

[Night work and pregnancy-related complications].

Night work has been associated with sleep disorders as well as cardiovascular, endocrinologic, metabolic and immunological disturbances as shown in this review. Several night shifts in a row and more than one night shift per week is associated with increased risk of pregnancy-related complications. A dose-response pattern has been shown between the number of night shifts during pregnancy and the risk of miscarriage, hypertensive disorders and sick leave. Individual risk assessment of pregnant night workers should focus on their general health, the intensity of night shifts and other adverse working conditions.

Detection of Methicillin Resistance in Staphylococcus aureus From Agar Cultures and Directly From Positive Blood Cultures Using MALDI-TOF Mass Spectrometry-Based Direct-on-Target Microdroplet Growth Assay.

Matrix-assisted laser desorption/ionization time-of-flight-mass spectrometry (MALDI-TOF MS)-based direct-on-target microdroplet growth assay (DOT-MGA) was recently described as a novel method of phenotypic antimicrobial susceptibility testing (AST). Here, we developed the application of MALDI-TOF MS-based DOT-MGA for Gram-positive bacteria including AST from agar cultures and directly from positive blood cultures (BCs) using the detection of methicillin resistance as example. Consecutively collected, a total of 14 methicillin-resistant Staphylococcus aureus (MRSA) and 14 methicillin-susceptible S. aureus (MSSA) clinical isolates were included. Furthermore, a collection of MRSA challenge strains comprising different SCCmec types, mec genes, and spa types was tested. Blood samples were spiked with MRSA and MSSA and positive BC broth processed by three different methods: serial dilution of BC broth, lysis/centrifugation, and differential centrifugation. Processed BC broth was directly used for rapid AST using DOT-MGA. Droplets of 6 µl with and without cefoxitin at the EUCAST breakpoint concentration were spotted in triplicates onto the surface of a MALDI target. Targets were incubated in a humidity chamber, followed by medium removal and on-target protein extraction with formic acid before adding matrix with an internal standard as a quality control (QC). Spectra were acquired and evaluated using MALDI Biotyper software. First, tests were considered as valid, if the growth control achieved an identification score of ≥1.7. For valid tests, same score criterion was used for resistant isolates when incubated with cefoxitin. An identification score <1.7 after incubation with cefoxitin defined susceptible isolates. On-target protein extraction using formic acid considerably improved detection of methicillin resistance in S. aureus and DOT-MGA showed feasible results for AST from agar cultures after 4 h incubation time. Comparing the different processing methods of positive BC broth, lysis/centrifugation method with a final dilution step 10-1 of the 0.5 McFarland suspension resulted in best test performance after 4 h incubation time. Overall, 96.4% test validity, 100% sensitivity, and 100% specificity were achieved for detection of methicillin resistance in clinical isolates. All strains of the MRSA challenge collection were successfully tested as methicillin-resistant. This first study on Gram-positive organisms showed feasibility and accuracy of MALDI-TOF MS-based DOT-MGA for rapid AST of S. aureus from agar cultures and directly from positive BCs.

Desert breath-How fog promotes a novel type of soil biocenosis, forming the coastal Atacama Desert's living skin.

The Atacama Desert is the driest non-polar desert on Earth, presenting precarious conditions for biological activity. In the arid coastal belt, life is restricted to areas with fog events that cause almost daily wet-dry cycles. In such an area, we discovered a hitherto unknown and unique ground covering biocenosis dominated by lichens, fungi, and algae attached to grit-sized (~6 mm) quartz and granitoid stones. Comparable biocenosis forming a kind of a layer on top of soil and rock surfaces in general is summarized as cryptogamic ground covers (CGC) in literature. In contrast to known CGC from arid environments to which frequent cyclic wetting events are lethal, in the Atacama Desert every fog event is answered by photosynthetic activity of the soil community and thus considered as the desert's breath. Photosynthesis of the new CGC type is activated by the lowest amount of water known for such a community worldwide thus enabling the unique biocenosis to fulfill a variety of ecosystem services. In a considerable portion of the coastal Atacama Desert, it protects the soil from sporadically occurring splash erosion and contributes to the accumulation of soil carbon and nitrogen as well as soil formation through bio-weathering. The structure and function of the new CGC type are discussed, and we suggest the name grit-crust. We conclude that this type of CGC can be expected in all non-polar fog deserts of the world and may resemble the cryptogam communities that shaped ancient Earth. It may thus represent a relevant player in current and ancient biogeochemical cycling.

Night work during pregnancy and preterm birth-A large register-based cohort study.

BACKGROUND: Melatonin stimulates the production of progesterone, which is essential for the maintenance of pregnancy. Since melatonin in blood is reduced due to work under illuminated conditions during night work, it has been hypothesized that night work may increase the risk of preterm birth. Previous meta-analyses have not revealed increased risk of preterm birth in women working night shifts during pregnancy. Still, these studies might have been limited by inaccurate self-reports of timing, intensity and duration of night work most likely causing bias towards the null. The aim of this is study was to investigate if the frequency and duration of night work during the first (week 1-12) and second (week 13-22) trimester of pregnancy were associated with risk of preterm birth when objective and prospective data on night work are used. METHOD: In a register-based prospective cohort study, we obtained individual day-to-day information on working hours from The Danish Working Hour Database (DWHD, a payroll database including all public service employees in administrative Danish Regions from 2007-2013) and information on preterm birth from the Danish Medical Birth Registry. Night-shift was defined as at least three working hours between 23:00 and 06:00. Preterm birth was defined as giving birth during gestational weeks 23-37. Odds of preterm birth according to working night shifts were analysed by logistic regression. RESULTS: We identified 16,501 pregnant women eligible for the study, of which 10,202 women (61.8%) had at least one night-shift during the first 22 gestational weeks. The risk of preterm birth was not elevated among women working night shifts compared to women working only day shifts during either the first or second trimester. Within night-shift workers, the risk was not related to the number of night shifts, the duration of night shifts, consecutive night shifts or quick returns defined as short intervals between shifts. Odds of preterm birth was not related to change of working schedule from the first to second trimester, although women changing from night shifts in the first trimester to day work only in the second trimester displayed a weak increased odds of preterm birth (OR 1.21, 95%CI 0.98-1.49) compared to women working night shifts in both trimesters. CONCLUSION: Our results, which are without bias from self-report of either exposure or outcome, are in line with the results of previous meta-analyses. Due to the detailed information on hours worked during pregnancy, we were able to investigate several dimensions of night work not previously investigated, of which none were associated with elevated risk of preterm birth.

Rapid Direct Susceptibility Testing from Positive Blood Cultures by the Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry-Based Direct-on-Target Microdroplet Growth Assay.

The recently developed direct-on-target microdroplet growth assay (DOT-MGA) allows rapid universal antimicrobial susceptibility testing (AST) using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Here, we investigated a direct application of this method on positive blood cultures (BCs) for the acceleration of sepsis diagnostics. Blood samples spiked with meropenem-nonsusceptible and meropenem-susceptible Enterobacterales isolates were inoculated into Bactec Plus Aerobic/F bottles and incubated in the Bactec automated system. Positive-BC broth was processed using four different methods, filtration/dilution, dilution, lysis/centrifugation, and differential centrifugation. For both dilution-based methods, AST was performed from 1:100, 1:1,000, and 1:10,000 dilutions of positive-BC broth in cation-adjusted Mueller-Hinton broth (CA-MHB). For both centrifugation-based methods, a 0.5 McFarland standard turbidity suspension was prepared from a bacterial pellet and adjusted to a final inoculum of 5 × 105 CFU/ml in CA-MHB. Six-microliter microdroplets with or without meropenem at the breakpoint concentration were spotted in triplicate onto a MALDI-TOF MS target, followed by incubation in a humidity chamber for 3 or 4 h and subsequent broth removal. Spectra were evaluated by MALDI Biotyper software. The test was considered valid if the growth control without antibiotic achieved an identification score of ≥1.7. For samples with meropenem, successful identification (score, ≥1.7) was interpreted as a nonsusceptible result, whereas failed identification (score, <1.7) defined susceptibility. The best test performance was achieved with the lysis/centrifugation method after a 4-h incubation. At this time point, 96.3% validity, 91.7% sensitivity, and 100% specificity were reached. This study demonstrated the feasibility and accuracy of a rapid DOT-MGA from positive BCs. Parallel to susceptibility determination, this method provides simultaneous species identification.

Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease characterized by a tumor microenvironment (TME) that overexpresses vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which can lead to neovascularization, tumor growth and metastasis. Therapeutic strategies inhibiting these signaling pathways might lead to innovative HNSCC treatments. Five HNSCC cell lines were characterized based on VEGFR1-3 and FGFR1-4 expression by sqRT-PCR and treated with three different tyrosine kinase inhibitors (TKIs) (nintedanib, dovitinib and pazopanib), all of which are effective against VEGFR and FGFR family members. Crystal violet assays were performed to analyze the effect of the treatments on cell growth (viability). Additionally, VEGFR1-3 and FGFR1-4 expression data were retrieved from The Cancer Genome Atlas (TCGA), and statistical analyses were performed to investigate the receptor expression level in the different cell lines and the efficacy of the single-agent treatments. A correlation analysis was performed to quantify the degree of relationship between receptor expression and drug efficacy. With the exception of VEGFR2, the targeted receptors were expressed at different levels in all of the cell lines. The cell lines exhibited concentration-dependent responses with cell line-specific differences toward two of the three TKIs (nintedanib and dovitinib). Notably, all of the cell lines were resistant to pazopanib. TKIs have potential as therapeutic agents for HNSCC. Cell line-specific differences were observed in our in vitro experiments. The observed pazopanib resistance could be explained by receptor expression. Further investigation is required to determine TKI efficacy in HNSCC.

Strategies for discontinuation of proton pump inhibitors: a systematic review.

PURPOSE: Proton pump inhibitors (PPIs) are considered to be overprescribed. Consensus on how to attempt discontinuation is, however, lacking. We therefore conducted a systematic review of clinical studies on discontinuation of PPIs. METHODS: Systematic review based on clinical studies investigating discontinuation strategies and discontinuation rates for users of antisecretory medication judged eligible for withdrawal. The databases Medline, Embase and Cochrane Library were searched to December 2013 using the terms antisecretory, anti-ulcer, PPI, acid suppressant, discontinuation, step-down, step down, cessation, tapering, withdrawal and withhold. Search terms were used either singularly or in combination. Papers written in English or Scandinavian were included. Concurrent hand searching was undertaken to pursue references of references. The website ClinicalTrials.gov was searched for unpublished results and ongoing studies. A total of 371 abstracts were scrutinized to determine relevancy. RESULTS: The thorough search resulted in six clinical studies on strategies for discontinuation of PPIs. All discontinuation regimens used in the studies differed, and several interventions have been tested in order to decrease use of PPIs. Discontinuations were reported across all studies ranging from 14% to 64% without deteriorating symptom control. Tapering seems to be a more effective discontinuation strategy than abrupt discontinuation. CONCLUSION: Discontinuation of PPIs is feasible in a clinical setting, and a substantial number of the patients treated without a clear indication can safely reduce or discontinue treatment. Tapering seems to be the most effective way of doing this.

A positive diagnostic strategy is noninferior to a strategy of exclusion for patients with irritable bowel syndrome.

BACKGROUND & AIMS: Guidelines recommend a positive strategy based on symptom criteria to diagnose patients with irritable bowel syndrome (IBS). We conducted a randomized noninferiority trial to determine whether a positive diagnostic strategy is noninferior to a strategy of exclusion, with regard to patients' health-related quality of life (HRQOL). METHODS: We studied 302 patients (18-50 years old) from primary care who were suspected of having IBS and referred by general practitioners. Patients who fulfilled the Rome III criteria for IBS with no alarm signals were randomly assigned to groups assessed by a strategy of exclusion (analyses of blood, stool samples for intestinal parasites, and sigmoidoscopies with biopsies) or a positive strategy (analyses of blood cell count and C-reactive protein). Patients were followed for 1 year. The primary end point was difference in change of HRQOL from baseline to 1 year between groups (on the basis of the Short Form 36 health survey, physical component summary, and noninferiority margin of 3 points). Secondary outcomes were change in gastrointestinal symptoms, satisfaction with management, and use of resources. Findings of diagnostic misclassification were registered. RESULTS: A positive strategy was noninferior to a strategy of exclusion (difference, 0.64; 95% confidence interval, -2.74 to 1.45). The positive diagnostic strategy had lower direct costs. Each approach had similar effects on symptoms, satisfaction, and subsequent use of health resources. No cases of inflammatory bowel disease, colorectal cancer, or celiac disease were found. CONCLUSIONS: In diagnosing IBS in primary care, use of a positive diagnostic strategy is noninferior to using a strategy of exclusion with regard to the patients' HRQOL. Our findings support the current guideline recommendations.

NF-κB signalling is attenuated by the E7 protein from cutaneous human papillomaviruses.

The high-risk Alpha-types of human papillomavirus (HPV) are the causative agent of cervical cancer, which is the second major cause of death among women worldwide. Recent investigations have shown that E7 from the Alpha-papillomavirus HPV-16 interacts with IKKα and IKKß of the IKK complex in the NF-κB pathway leading to an attenuation of the activity. There is a possible link between development of non-melanoma skin cancer and cutaneous Beta-papillomavirus but if these HPV types attenuate the NF-κB pathway is unclear. Seven different E7 proteins, representing four out of the five different species of the Beta genus (HPV-20, -37, -38, -92, -93 and -96) and one from the Gamma genus (HPV-4) were investigated for potential modulation of the NF-κB pathway in U2OS cells. Our results demonstrate that E7 from all the cutaneous HPV types were capable of inhibiting the NF-κB activity as well as E7 from HPV-16. In addition, E7 proteins from the cutaneous HPV types demonstrated interaction with IKKα but not with IKKß. The deregulation of the NF-κB pathway by cutaneous HPVs might contribute to the pathogenesis of non-melanoma skin cancers and its precursors.

Prognostic impact of hemoglobin levels before and during carboplatin/taxane-based chemotherapy in patients with primary invasive epithelial ovarian cancer.

BACKGROUND: Carboplatin/taxane-based chemotherapy is the standard treatment for advanced primary ovarian cancer. Anemia is a frequent side effect of platinum-containing chemotherapy regimens. Furthermore, ovarian cancer is often associated with tumor anemia. The aim of this study was to evaluate the prognostic relevance of the mean hemoglobin level before and during carboplatin/taxane-based chemotherapy. MATERIAL/METHODS: We studied retrospectively 92 patients with primary invasive epithelial ovarian cancer (EOC) receiving carboplatin/taxane-based chemotherapy. Hemoglobin levels were determined before each cycle of therapy. Study objectives were progression-free survival time (PFS) and overall survival time (OS). Univariate analyses and Cox-regression studies were undertaken to evaluate the prognostic impact of hemoglobin levels before and throughout chemotherapy. In addition, sensitivity/specificity analyses and Kaplan-Meier-studies were performed to determine the cut-off level of prognostically relevant hemoglobin levels. RESULTS: In univariate analysis hemoglobin levels throughout chemotherapy showed prognostic relevance in terms of PFS (p<0.05). Sensitivity/specificity and Kaplan-Meier analyses found a hemoglobin level of 11.2 g/dL to be a prognostically relevant cut-off level in terms of PFS (p<0.05). There was a borderline significance for pretherapeutic hemoglobin levels to influence PFS (p=0.07), with a prognostically relevant cut-off level of 11.6 g/dL (p=0.06). CONCLUSIONS: Hemoglobin levels before and particularly throughout therapy seem to have prognostic relevance for patients with primary EOC undergoing carboplatin/taxane-based chemotherapy. Further trials are required to confirm these data in a prospective attempt and to evaluate the role of correcting anemia as standard supportive therapy in the treatment of patients with primary EOC.

Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas.

Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes.