Direct Observation of Polaritonic Chemistry by Nuclear Magnetic Resonance Spectroscopy.

Polaritonic chemistry is emerging as a powerful approach to modifying the properties and reactivity of molecules and materials. However, probing how the electronics and dynamics of molecular systems change under strong coupling has been challenging due to the narrow range of spectroscopic techniques that can be applied in situ. Here we develop microfluidic optical cavities for vibrational strong coupling (VSC) that are compatible with nuclear magnetic resonance (NMR) spectroscopy using standard liquid NMR tubes. VSC is shown to influence the equilibrium between two conformations of a molecular balance sensitive to London dispersion forces, revealing an apparent change in the equilibrium constant under VSC. In all compounds studied, VSC does not induce detectable changes in chemical shifts, J-couplings, or spin-lattice relaxation times. This unexpected finding indicates that VSC does not substantially affect molecular electron density distributions, and in turn has profound implications for the possible mechanisms at play in polaritonic chemistry under VSC and suggests that the emergence of collective behavior is critical.

The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction.

RATIONALE: The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime show cardiotoxicity. Moreover, UPS and autophagic-lysosomal pathway defects are implicated in cardiac pathogenesis. Hence, a better understanding of the cross-talk between the 2 catabolic pathways will help advance cardiac pathophysiology and medicine. OBJECTIVE: Systemic proteasome inhibition (PSMI) was shown to increase p62/SQSTM1 expression and induce myocardial macroautophagy. Here we investigate how proteasome malfunction activates cardiac autophagic-lysosomal pathway. METHODS AND RESULTS: Myocardial macroautophagy, TFEB (transcription factor EB) expression and activity, and p62 expression were markedly increased in mice with either cardiomyocyte-restricted ablation of Psmc1 (an essential proteasome subunit gene) or pharmacological PSMI. In cultured cardiomyocytes, PSMI-induced increases in TFEB activation and p62 expression were blunted by pharmacological and genetic calcineurin inhibition and by siRNA-mediated Molcn1 silencing. PSMI induced remarkable increases in myocardial autophagic flux in wild type mice but not p62 null (p62-KO) mice. Bortezomib-induced left ventricular wall thickening and diastolic malfunction was exacerbated by p62 deficiency. In cultured cardiomyocytes from wild type mice but not p62-KO mice, PSMI induced increases in LC3-II flux and the lysosomal removal of ubiquitinated proteins. Myocardial TFEB activation by PSMI as reflected by TFEB nuclear localization and target gene expression was strikingly less in p62-KO mice compared with wild type mice. CONCLUSIONS: (1) The activation of cardiac macroautophagy by proteasomal malfunction is mediated by the Mocln1-calcineurin-TFEB-p62 pathway; (2) p62 unexpectedly exerts a feed-forward effect on TFEB activation by proteasome malfunction; and (3) targeting the Mcoln1 (mucolipin1)-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac autophagic-lysosomal pathway activation during proteasome malfunction.

Evaluation of Undiagnosed HIV Estimates Computed from the CD4 Depletion Model in a Rural, Medium-low HIV Prevalence State.

The CD4 depletion model estimates diagnosis delays by approximating infection date from CD4 T-cell count at diagnosis, and back-calculation can compute the proportion of undiagnosed PLWHA. The model assumes the immigration of PLWHA to the U.S. is negligible and counts as a transmission event, which may be impractical outside high prevalence states. Duration of U.S. residency among foreign-born PLWHA and diagnosis delays were compared. The impact on estimates of undiagnosed PLWHA was tested through simulation with different proportions of foreign-born people assumed to have acquired HIV abroad. In 67% of foreign-born people, the mean (SD) years of delay (9.9 (6.3)) exceeded the duration of U.S. residency (2.0 (1.9)). Additionally, inaccuracies in the estimates for proportions of undiagnosed PLWHA were pronounced when foreign-born people who acquired HIV abroad comprised 30% of diagnoses. The CD4 model inadvertently misclassified some diagnoses as in-state transmission events. Consequently, simulated results demonstrated inaccuracies and unstable calculations.

Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

BACKGROUND: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER: JapicCTI-090880 (J003).

Impairment-driven cancer rehabilitation: an essential component of quality care and survivorship.

Adult cancer survivors suffer an extremely diverse and complex set of impairments, affecting virtually every organ system. Both physical and psychological impairments may contribute to a decreased health-related quality of life and should be identified throughout the care continuum. Recent evidence suggests that more cancer survivors have a reduced health-related quality of life as a result of physical impairments than due to psychological ones. Research has also demonstrated that the majority of cancer survivors will have significant impairments and that these often go undetected and/or untreated, and consequently may result in disability. Furthermore, physical disability is a leading cause of distress in this population. The scientific literature has shown that rehabilitation improves pain, function, and quality of life in cancer survivors. In fact, rehabilitation efforts can ameliorate physical (including cognitive) impairments at every stage along the course of treatment. This includes prehabilitation before cancer treatment commences and multimodal interdisciplinary rehabilitation during and after acute cancer treatment. Rehabilitation appears to be cost-effective and may reduce both direct and indirect health care costs, thereby reducing the enormous financial burden of cancer. Therefore, it is critical that survivors are screened for both psychological and physical impairments and then referred appropriately to trained rehabilitation health care professionals. This review suggests an impairment-driven cancer rehabilitation model that includes screening and treating impairments all along the care continuum in order to minimize disability and maximize quality of life.

[Tracheal resection after prolonged stenting in surgery for cicatricial stenosis]. / Rezektsiia trakhei posle dlitel'nogo stentirovaniia v khirurgii rubtsovogo stenoza.

OBJECTIVE: To analyze early and delayed results of various variants of circular tracheal resection (CTR) with anastomosis, to determine the safest approach, dates and conditions of correction, features of postoperative period in patients after previous tracheal surgery. MATERIAL AND METHODS: There were 831 patients with cicatricial tracheal stenosis. CTR was made in 330 (39.7%) patients. Most patients had previous prolonged ICU-stay. The patients were divided into 4 groups. Group 1 consisted of 61 (18.5%) patients after previous prolonged tracheal stenting. Group 2 included 45 (13.6%) patients who underwent circular tracheal resection with a functioning tracheostomy. Tracheostomy tube served as a stent in these patients. Group 3 enrolled 32 (9.7%) patients with previous staged reconstructive plastic surgeries on cranial segment of the respiratory tract. Tracheostomy or stent were absent in 192 (58.2%) patients who underwent circular tracheal resection at the first hospitalization. These patients were enrolled into the fourth (control) group. Favorable outcomes (without complications and mortality) were achieved in 85.5% (n=282) of patients. Postoperative complications occurred in 48 (14.5%) patients. Mortality rate was 0.6% (n=2). The greatest number of complications including anastomositis and restenosis was noted in patients after CTR and previous tracheoplasty with T-tube (n=8, 25%). The most common complication in patients after tracheal resection and previous stenting was anastomositis (14.7%). Long-term results depended on postoperative complications and methods of their correction. Recurrent stenosis occurred in 5 (1.5%) patients within the period of 3 months - 8 years. CTR after previous tracheoplasty with T-tube was carried out in 4 of these patients. CONCLUSION: Tracheal resection after preliminary stenting or tracheostomy is quite safe and technically feasible. Stenting allows postponing radical surgery for correction of concomitant diseases and closure of tracheostomy as a focus of infection within the surgical approach and further tracheal anastomosis. Tracheal resection with simultaneous closure of tracheostomy results a higher rate of postoperative complications compared with preliminary stenting.

HIV and viral hepatitis coinfection analysis using surveillance data from 15 US states and two cities.

Coinfection with human immunodeficiency virus (HIV) and viral hepatitis is associated with high morbidity and mortality in the absence of clinical management, making identification of these cases crucial. We examined characteristics of HIV and viral hepatitis coinfections by using surveillance data from 15 US states and two cities. Each jurisdiction used an automated deterministic matching method to link surveillance data for persons with reported acute and chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, to persons reported with HIV infection. Of the 504 398 persons living with diagnosed HIV infection at the end of 2014, 2.0% were coinfected with HBV and 6.7% were coinfected with HCV. Of the 269 884 persons ever reported with HBV, 5.2% were reported with HIV. Of the 1 093 050 persons ever reported with HCV, 4.3% were reported with HIV. A greater proportion of persons coinfected with HIV and HBV were males and blacks/African Americans, compared with those with HIV monoinfection. Persons who inject drugs represented a greater proportion of those coinfected with HIV and HCV, compared with those with HIV monoinfection. Matching HIV and viral hepatitis surveillance data highlights epidemiological characteristics of persons coinfected and can be used to routinely monitor health status and guide state and national public health interventions.

Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 (Alliance).

BACKGROUND: Observational studies suggest that higher levels of 25-hydroxyvitamin D3 (25(OH)D) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients. However, the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown. PATIENTS AND METHODS: We prospectively examined the influence of post-diagnosis predicted plasma 25(OH)D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial (CALGB 89803). Predicted 25(OH)D scores were computed using validated regression models. We examined the influence of predicted 25(OH)D scores on cancer recurrence and mortality (disease-free survival; DFS) using Cox proportional hazards. RESULTS: Patients in the highest quintile of predicted 25(OH)D score had an adjusted hazard ratio (HR) for colon cancer recurrence or mortality (DFS) of 0.62 (95% confidence interval [CI], 0.44-0.86), compared with those in the lowest quintile (Ptrend = 0.005). Higher predicted 25(OH)D score was also associated with a significant improvement in recurrence-free survival and overall survival (Ptrend = 0.01 and 0.0004, respectively). The benefit associated with higher predicted 25(OH)D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics, including microsatellite instability and KRAS, BRAF, PIK3CA, and TP53 mutation status. CONCLUSION: Higher predicted 25(OH)D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival. Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT00003835.

Morphokinetics of vitrified and warmed blastocysts predicts implantation potential.

PURPOSE: It was studied whether morphokinetics of blastocoele re-expansion and hatching in vitrified-warmed blastocysts is predictive of implantation, clinical pregnancy, and live birth. METHODS: In 144 patients aiming for single warmed blastocyst transfer, blastocysts were cultured in a new time-lapse system (Miri® TL) immediately after warming. Video sequences with an image interval of 5 min were annotated and the corresponding morphokinetic variables were correlated with pregnancy outcome. In detail, tRE (start of re-expansion), tCRE (completion of re-expansion), tAH (hatching from the manipulated zona pellucida), and presence of collapses were recorded. RESULTS: In the pregnant group, tRE and tCRE were significantly lower (0.69 ± 0.45 h and 2.16 ± 0.94 h) as compared to the non-pregnant group (1.23 ± 1.08 h and 2.70 ± 1.20 h). Both variables and the duration of re-expansion (tCRE-tRE) allowed for distinction between "non-pregnant," "loss of pregnancy," and live birth/ongoing pregnancy. Presence and number of collapses showed no correlation with outcome. CONCLUSIONS: Time-lapse imaging of vitrified-warmed blastocysts offers additional selection criteria allowing for prediction of implantation potential. As a consequence, cumulative pregnancy rate could be increased and time-to-pregnancy reduced.

[Legend, art and medicine]. / Légende, art et medicine.

The study of the heredity of mandibular proganthism has curiously been initiated by a legend and by the examination of a Brussels tapestry. The hereditary condition of mandibular prognathism was recognized by the study of numerous iconographic documents concerning the Habsburger family. Charles V was the most representative of this anomaly of the lower jaw. Numerous members of the Spanish House and of the Austrian House were afflicted with mandibular prognathism. Family intermarriages promoted the multiplication of mandibular anomaly in those important families.

L'étude de l'hérédité de la prognathie mandibulaire a curieusement été initiée par une légende et par l'examen d'une tapisserie de Bruxelles. L'étude de documents iconographiques de la famille des Habsbourg a permis de démontrer le caractère héréditaire de cette malformation. Charles Quint fut le représentant le plus caractéristique. De nombreux membres des Maisons d'Espagne et d'Autriche étaient prognathes. Les mariages consanguins ont permis la multiplication de cette hypertrophie de la mâchoire inférieure dans ces familles importantes.

Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway.

The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. These pathways are interdependent, and dysfunction in either pathway causes accumulation of ubiquitin-positive aggregates, a hallmark of human pathological conditions. To elucidate in vivo compensatory action(s) against proteasomal dysfunction, we developed mice with reduced proteasome activity in their livers. The mutant mice exhibited severe liver damage, accompanied by formation of aggregates positive for ubiquitin and p62/Sqstm1, an adaptor protein for both selective autophagy and the anti-oxidative Keap1-Nrf2 pathway. These aggregates were selectively entrapped by autophagosomes, and pathological features of livers with impaired proteasome activity were exacerbated by simultaneous suppression of autophagy. In contrast, concomitant loss of p62/Sqstm1 had no apparent effect on the liver pathology though p62/Sqstm1 was indispensable for the aggregates formation. Furthermore, defective proteasome function led to transcriptional activation of the Nrf2, which served as a physiological adaptation. Our in vivo data suggest that cells contain networks of cellular defense mechanisms against defective proteostasis.

Automated Sampling Procedures Supported by High Persistence of Bacterial Fecal Indicators and Bacteroidetes Genetic Microbial Source Tracking Markers in Municipal Wastewater during Short-Term Storage at 5°C.

Because of high diurnal water quality fluctuations in raw municipal wastewater, the use of proportional autosampling over a period of 24 h at municipal wastewater treatment plants (WWTPs) to evaluate carbon, nitrogen, and phosphorus removal has become a standard in many countries. Microbial removal or load estimation at municipal WWTPs, however, is still based on manually recovered grab samples. The goal of this study was to establish basic knowledge regarding the persistence of standard bacterial fecal indicators and Bacteroidetes genetic microbial source tracking markers in municipal wastewater in order to evaluate their suitability for automated sampling, as the potential lack of persistence is the main argument against such procedures. Raw and secondary treated wastewater of municipal origin from representative and well-characterized biological WWTPs without disinfection (organic carbon and nutrient removal) was investigated in microcosm experiments at 5 and 21°C with a total storage time of 32 h (including a 24-h autosampling component and an 8-h postsampling phase). Vegetative Escherichia coli and enterococci, as well as Clostridium perfringens spores, were selected as indicators for cultivation-based standard enumeration. Molecular analysis focused on total (AllBac) and human-associated genetic Bacteroidetes (BacHum-UCD, HF183 TaqMan) markers by using quantitative PCR, as well as 16S rRNA gene-based next-generation sequencing. The microbial parameters showed high persistence in both raw and treated wastewater at 5°C under the storage conditions used. Surprisingly, and in contrast to results obtained with treated wastewater, persistence of the microbial markers in raw wastewater was also high at 21°C. On the basis of our results, 24-h autosampling procedures with 5°C storage conditions can be recommended for the investigation of fecal indicators or Bacteroidetes genetic markers at municipal WWTPs. Such autosampling procedures will contribute to better understanding and monitoring of municipal WWTPs as sources of fecal pollution in water resources.

Treatment with Ca2+ ionophore improves embryo development and outcome in cases with previous developmental problems: a prospective multicenter study.

STUDY QUESTION: Does calcium ionophore treatment (A23187, calcimycin) improve embryo development and outcome in patients with a history of developmental problems/arrest? SUMMARY ANSWER: Application of A23187 leads to increased rates of cleavage to 2-cell stage, blastocyst formation and clinical pregnancy/live birth. WHAT IS KNOWN ALREADY: Studies on lower animals indicate that changes in intracellular free calcium trigger and regulate the events of cell division. In humans, calcium fluctuations were detected with a peak shortly before cell division. Interestingly, these calcium oscillations disappeared in arrested embryos. Mitotic division blocked with a Ca(2+) chelator could be restored by means of ionophores in an animal model. STUDY DESIGN, SIZE, DURATION: This prospective, multicenter (five Austrian centers), uncontrolled intervention study (duration 1 year) includes 57 patients who provided informed consent. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were complete embryo developmental arrest in a previous cycle (no transfer), complete developmental delay (no morula/blastocyst on Day 5), or reduced blastocyst formation on Day 5 (≤15%). Severe male factor patients and patients with <30% fertilization rate after ICSI were excluded because these would be routine indications for ionophore usage. The total of the 57 immediately preceding cycles in the same patients constituted the control cycles/control group. In the treatment cycles, all metaphase II-oocytes were exposed to a commercially available ready-to-use ionophore for 15 min immediately after ICSI. After a three-step washing procedure, in vitro culture was performed as in the control cycles, up to blastocyst stage when achievable. MAIN RESULTS AND THE ROLE OF CHANCE: Fertilization rate did not differ (75.4 versus 73.2%); however, further cleavage to 2-cell stage was significantly higher (P < 0.001) in the ionophore group (98.5%) when compared with the control cycles (91.9%). In addition, significantly more (P < 0.05) blastocysts formed on Day 5 in the study compared with the control group (47.6 versus 5.5%, respectively) and this was associated with a significant increase (P < 0.01) in the rates of implantation (44.4 versus 12.5%), clinical pregnancy (45.1 versus 12.8%) and live birth (45.1 versus 12.8%). All babies born at the time of writing (22/28) were healthy. LIMITATIONS, REASONS FOR CAUTION: The frequency of patients showing embryo developmental problems was expected to be low; therefore, a multicenter approach was chosen in order to increase sample size. In one-third of the cycles, the clinician or patient requested a change of stimulation protocol; however, this did not influence the developmental rate of embryos. WIDER IMPLICATIONS OF THE FINDINGS: This is the first evidence that developmental incompetence of embryos is an additional indication for ionophore treatment. The present approach is exclusively for overcoming cleavage arrest. STUDY FUNDING/COMPETING INTERESTS: No funding received. T.E. reports fees from Gynemed, outside the submitted work. All co-authors have no interest to declare.

Influence of intracervical and intravaginal seminal plasma on the endometrium in assisted reproduction: a double-blind, placebo-controlled, randomized study.

OBJECTIVE: To investigate the effect of intracervical and intravaginal application of seminal plasma on the endometrium, as assessed by endometrial/subendometrial vascularization and endometrial volume between the day of oocyte retrieval and the day of embryo transfer in an in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle. METHODS: This was a double-blind, placebo-controlled, randomized study including patients undergoing a first or second IVF/ICSI cycle. Homologous seminal plasma or placebo (sodium chloride) was injected into the cervix and posterior vaginal fornix just after follicle aspiration. Three-dimensional power Doppler examination was performed 30 min before oocyte retrieval and 30 min before embryo transfer. Main outcome measures were changes in vascularization flow index (VFI), flow index (FI) and vascularization index (VI) of the endometrium/subendometrium using VOCAL™ (Virtual Organ Computer-aided AnaLysis) and endometrial volume. RESULTS: One hundred patients agreed to participate in the study. Twenty-three patients were excluded, mainly as a result of canceled embryo transfer. Data were analyzed from 40 patients receiving seminal plasma and 37 receiving placebo. No significant differences between the two groups were seen in VFI, FI or VI of the endometrium or subendometrium or in endometrial volume on the day of oocyte pick-up and on the day of embryo transfer. CONCLUSION: Neither endometrial/subendometrial vascularization parameters nor endometrial volume seem to be affected by the application of seminal plasma in patients undergoing their first or second IVF/ICSI cycle.

Detection of seed DNA in regurgitates of granivorous carabid beetles.

Granivory can play a pivotal role in influencing regeneration, colonization as well as abundance and distribution of plants. Due to their high abundance, nutrient content and longevity, seeds are an important food source for many animals. Among insects, carabid beetles consume substantial numbers of seeds and are thought to be responsible for a significant amount of seed loss. However, the processes that govern which seeds are eaten and are therefore prevented from entering the seedbank are poorly understood. Here, we assess if DNA-based diet analysis allows tracking the consumption of seeds by carabids. Adult individuals of Harpalus rufipes were fed with seeds of Taraxacum officinale and Lolium perenne allowing them to digest for up to 3 days. Regurgitates were tested for the DNA of ingested seeds at eight different time points post-feeding using general and species-specific plant primers. The detection of seed DNA decreased with digestion time for both seed species, albeit in a species-specific manner. Significant differences in overall DNA detection rates were found with the general plant primers but not with the species-specific primers. This can have implications for the interpretation of trophic data derived from next-generation sequencing, which is based on the application of general primers. Our findings demonstrate that seed predation by carabids can be tracked, molecularly, on a species-specific level, providing a new way to unravel the mechanisms underlying in-field diet choice in granivores.

Healthy twin live-birth after ionophore treatment in a case of theophylline-resistant Kartagener syndrome.

PURPOSE: To evaluate whether it is a feasible option to target the oocyte (with Ca(2+)-ionophore) in case that sperm motility cannot be restored in Kartagener syndrome. METHODS: A case of a male Kartagener syndrome with exclusively immotile spermatozoa that did not react to the dimethylxanthine theophylline. Thus, half of the associated oocytes were treated for 15 min with the ready-to-use- ionophore CultActive immediately after ICSI whereas the other 50 % were injected with routine ICSI without artificial oocyte activation. Rates of fertilization, blastulation, pregnancy and live birth were evaluated. RESULTS: Fertilization check revealed that none of the conventionally injected but 4/6 (66.7 %) of the artificially activated oocytes showed two pronuclei. Three embryos were of good and one of fair quality. Corresponding blastocyst formation rate was 3 out of 4 (75 %). A double embryo transfer led to a healthy twin birth in the 34th week of gestation (two boys with a birth weight of 1724 g and 2199 g). CONCLUSIONS: This case indicates that Ca(2+)-ionophore treatment in cycles from theophylline-resistant Kartagener syndrome patients is a feasible option. The future will show if routine application of A23187 in Kartagener or primary cilia dyskinesis patients will be of benefit.

[Carabin]. / Les Carabins.

The French word Carabin, meaning today a medicine student, has has various origins in course of time: a valueless person, a mute and assistant-surgeon, a carbine armed horseman and finaly a military medicine student but it is since the long stay in Strasbourg of those students that carabin became synonymous with medicine student.

Implications for oxidative stress and astrocytes following 26S proteasomal depletion in mouse forebrain neurones.

Neurodegenerative diseases are characterized by progressive degeneration of selective neurones in the nervous system, but the underlying mechanisms involved in neuroprotection and neurodegeneration remain unclear. Dysfunction of the ubiquitin proteasome system is one of the proposed hypotheses for the cause and progression of neuronal loss. We have performed quantitative two-dimensional fluorescence difference in-gel electrophoresis combined with peptide mass fingerprinting to reveal proteome changes associated with neurodegeneration following 26S proteasomal depletion in mouse forebrain neurones. Differentially expressed proteins were validated by Western blotting, biochemical assays and immunohistochemistry. Of significance was increased expression of the antioxidant enzyme peroxiredoxin 6 (PRDX6) in astrocytes, associated with oxidative stress. Interestingly, PRDX6 is a bifunctional enzyme with antioxidant peroxidase and phospholipase A2 (PLA2) activities. The PLA2 activity of PRDX6 was also increased following 26S proteasomal depletion and may be involved in neuroprotective or neurodegenerative mechanisms. This is the first in vivo report of oxidative stress caused directly by neuronal proteasome dysfunction in the mammalian brain. The results contribute to understanding neuronal-glial interactions in disease pathogenesis, provide an in vivo link between prominent disease hypotheses and importantly, are of relevance to a heterogeneous spectrum of neurodegenerative diseases.

[Being a freshman in the year 1945]. / Etre "bleu" en 1945.

In 1945, the freshman was the witness of historical events such as the reception at the University of General de Gaulle, Sir W. Churchill and Sir A. Fleming. Other important events occured in that year: the end of the war in Europe, the revelation to the world of the nazi horours and the atomic bombing of Hiroshima. An extension of the principle of free thinking of facts and ideas appeared as a consequence of nazi occupation. The time was hard for the freshman concerning his studies and subsistance but the year 1945 was fascinating and came to an end with the revival, after seven years, of the grand student's feast of Saint-Verhaegen.

Impact of KRASG12 mutations on survival with trifluridine/tipiracil plus bevacizumab in patients with refractory metastatic colorectal cancer: post hoc analysis of the phase III SUNLIGHT trial.

BACKGROUND: In metastatic colorectal cancer (mCRC), KRAS mutations are often associated with poorer survival; however, the prognostic impact of specific point mutations is unclear. In the phase III SUNLIGHT trial, trifluridine/tipiracil (FTD/TPI) plus bevacizumab significantly improved overall survival (OS) versus FTD/TPI alone. We assessed the impact of KRASG12 mutational status on OS in SUNLIGHT. PATIENTS AND METHODS: In the global, open-label, randomized, phase III SUNLIGHT trial, adults with mCRC who had received no more than two prior chemotherapy regimens were randomized 1 : 1 to receive FTD/TPI alone or FTD/TPI plus bevacizumab. In this post hoc analysis, OS was assessed according to the presence or absence of a KRASG12 mutation in the overall population and in patients with RAS-mutated tumors. RESULTS: Overall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRASG12 mutation and 88 with a non-KRASG12RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRASG12 mutation [median 8.3 and 9.2 months, respectively; hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.87-1.4]. Similar OS outcomes were also observed in the subgroup analysis of patients with a KRASG12 mutation versus those with a non-KRASG12RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRASG12 mutational status. Among patients with a KRASG12 mutation, the median OS was 9.4 months with FTD/TPI plus bevacizumab versus 7.2 months with FTD/TPI alone (HR 0.67, 95% CI 0.48-0.93), and in patients without a KRASG12 mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81). CONCLUSIONS: The presence of a KRASG12 mutation had no detrimental effect on OS among patients treated in SUNLIGHT. The benefit of FTD/TPI plus bevacizumab over FTD/TPI alone was confirmed independently of KRASG12 status.