Speciation in kleptoparasites of oak gall wasps often correlates with shifts into new tree habitats, tree organs, or gall morphospace.

Host shifts to new plant species can drive speciation for plant-feeding insects, but how commonly do host shifts also drive diversification for the parasites of those same insects? Oak gall wasps induce galls on oak trees and shifts to novel tree hosts and new tree organs have been implicated as drivers of oak gall wasp speciation. Gall wasps are themselves attacked by many insect parasites, which must find their hosts on the correct tree species and organ, but also must navigate the morphologically variable galls with which they interact. Thus, we ask whether host shifts to new trees, organs, or gall morphologies correlate with gall parasite diversification. We delimit species and infer phylogenies for two genera of gall kleptoparasites, Synergus and Ceroptres, reared from a variety of North American oak galls. We find that most species were reared from galls induced by just one gall wasp species, and no parasite species was reared from galls of more than four species. Most kleptoparasite divergence events correlate with shifts to non-ancestral galls. These shifts often involved changes in tree habitat, gall location, and gall morphology. Host shifts are thus implicated in driving diversification for both oak gall wasps and their kleptoparasitic associates.

Real-world EGFR testing practices for non-small-cell lung cancer by thoracic pathology laboratories across Europe.

BACKGROUND: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs). MATERIALS AND METHODS: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021. RESULTS: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme. CONCLUSIONS: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

Morpho-functional analysis of patient-derived xenografts reveals differential impact of gastric cancer and chemotherapy on the tumor ecosystem, affecting immune check point, metabolism, and sarcopenia.

OBJECTIVES: Gastric cancer (GC) is an aggressive disease due to late diagnosis resulting from the lack of easy diagnostic tools, resistances toward immunotherapy (due to low PD-L1 expression), or chemotherapies (due to p53 mutations), and comorbidity factors, notably muscle atrophy. To improve our understanding of this complex pathology, we established patient-derived xenograft (PDX) models and characterized the tumor ecosystem using a morpho-functional approach combining high-resolution imaging with molecular analyses, regarding the expression of relevant therapeutic biomarkers and the presence of muscle atrophy. MATERIALS AND METHODS: GC tissues samples were implanted in nude mice. Established PDX, treated with cisplatin or not, were imaged by magnetic resonance imaging (MRI) and analyzed for the expression of relevant biomarkers (p53, PD-L1, PD-1, HER-2, CDX2, CAIX, CD31, a-SAM) and by transcriptomics. RESULTS: Three well-differentiated, one moderately and one poorly differentiated adenocarcinomas were established. All retained the architectural and histological features of their primary tumors. MRI allowed in-real-time evaluation of differences between PDX, in terms of substructure, post-therapeutic changes, and muscle atrophy. Immunohistochemistry showed differential expression of p53, HER-2, CDX2, a-SAM, PD-L1, PD-1, CAIX, and CD31 between models and upon cisplatin treatment. Transcriptomics revealed treatment-induced hypoxia and metabolic reprograming in the tumor microenvironment. CONCLUSION: Our PDX models are representative for the heterogeneity and complexity of human tumors, with differences in structure, histology, muscle atrophy, and the different biomarkers making them valuable for the analyses of the impact of platinum drugs or new therapies on the tumor and its microenvironment.

Signaling pathway deregulation and molecular alterations across pediatric medulloblastomas.

Medulloblastomas (MBs) account for 15% of brain tumors in children under the age of 15. To date, the overall 5-year survival rate for all children is only around 60%. Recent advances in cancer genomics have led to a fundamental change in medulloblastoma classification and is evolving along with the genomic discoveries, allowing to regularly reclassify this disease. The previous molecular classification defined 4 groups (WNT-activated MB, SHH-activated MB and the groups 3 and 4 characterized partially by NMYC and MYC driven MBs). This stratification moved forward recently to better define these groups and their correlation to outcome. This new stratification into 7 novel subgroups was helpful to lay foundations and complementary data on the understanding regarding molecular pathways and gene mutations underlying medulloblastoma biology. This review was aimed at answering the recent key questions on MB genomics and go further in the relevance of those genes in MB development as well as in their targeted therapies.

Letermovir breakthroughs during the French Named Patient Programme: interest of monitoring blood concentration in clinical practice.

OBJECTIVES: To analyse mechanisms of letermovir breakthrough during compassionate primary and secondary prophylaxis. METHODS: Mechanisms of letermovir breakthrough during compassionate primary and secondary prophylaxis were analysed in four patients from the French Named Patient Programme by the French National Reference Centre for Herpesviruses. RESULTS: Of three absolute resistance cases, two were associated with treatment interruption or low letermovir concentrations in blood. A fourth case of breakthrough was not associated with resistance. Next-generation sequencing (NGS) genotyping confirmed rapid emergence of resistant mutants, within 3 months of treatment initiation. CONCLUSIONS: Measurement of letermovir concentration and genotyping should be recommended for patient follow-up during letermovir therapy.

Effect of the alloy/mould contact on surface crystallisation of a biocompatible ZrCoAl bulk metallic glass.

Casting of metallic glasses (MG) sometimes induces surface crystallisation despite the fact that the surface is expected to be the region where the cooling rate is the highest. This phenomenon has been observed on various MG, even for those with large critical diameters. Such surface crystallisation can be detrimental when the target applications are focused on surface properties, such as corrosion resistance for biomedical applications. In this paper, a Zr56Co28Al16 bulk metallic glass (BMG) with a large critical diameter was used. We reveal that samples processed using common copper-mould suction casting present surface crystallisation up to 20 µm in thickness, greatly deteriorating corrosion resistance. Using in-house highly reproducible suction casting and injection micro-casting processes, the influence of the processing parameters (mould material and temperature, working atmosphere, applied pressure) were investigated. The origin of surface crystallisation was found to arise from the complex thermal history of the alloy depending on the alloy/mould contact quality. By ensuring a tight contact between the solidifying alloy and the mould, BMG samples without crystalline surface defects were obtained.

Radiative Rotational Lifetimes and State-Resolved Relative Detachment Cross Sections from Photodetachment Thermometry of Molecular Anions in a Cryogenic Storage Ring.

Photodetachment thermometry on a beam of OH^{-} in a cryogenic storage ring cooled to below 10 K is carried out using two-dimensional frequency- and time-dependent photodetachment spectroscopy over 20 min of ion storage. In equilibrium with the low-level blackbody field, we find an effective radiative temperature near 15 K with about 90% of all ions in the rotational ground state. We measure the J=1 natural lifetime (about 193 s) and determine the OH^{-} rotational transition dipole moment with 1.5% uncertainty. We also measure rotationally dependent relative near-threshold photodetachment cross sections for photodetachment thermometry.

The cryogenic storage ring CSR.

An electrostatic cryogenic storage ring, CSR, for beams of anions and cations with up to 300 keV kinetic energy per unit charge has been designed, constructed, and put into operation. With a circumference of 35 m, the ion-beam vacuum chambers and all beam optics are in a cryostat and cooled by a closed-cycle liquid helium system. At temperatures as low as (5.5 ± 1) K inside the ring, storage time constants of several minutes up to almost an hour were observed for atomic and molecular, anion and cation beams at an energy of 60 keV. The ion-beam intensity, energy-dependent closed-orbit shifts (dispersion), and the focusing properties of the machine were studied by a system of capacitive pickups. The Schottky-noise spectrum of the stored ions revealed a broadening of the momentum distribution on a time scale of 1000 s. Photodetachment of stored anions was used in the beam lifetime measurements. The detachment rate by anion collisions with residual-gas molecules was found to be extremely low. A residual-gas density below 140 cm(-3) is derived, equivalent to a room-temperature pressure below 10(-14) mbar. Fast atomic, molecular, and cluster ion beams stored for long periods of time in a cryogenic environment will allow experiments on collision- and radiation-induced fragmentation processes of ions in known internal quantum states with merged and crossed photon and particle beams.

Photodissociation of an Internally Cold Beam of CH

We have studied the photodissociation of CH^{+} in the Cryogenic Storage Ring at ambient temperatures below 10 K. Owing to the extremely high vacuum of the cryogenic environment, we were able to store CH^{+} beams with a kinetic energy of ∼60 keV for several minutes. Using a pulsed laser, we observed Feshbach-type near-threshold photodissociation resonances for the rotational levels J=0-2 of CH^{+}, exclusively. In comparison to updated, state-of-the-art calculations, we find excellent agreement in the relative intensities of the resonances for a given J, and we can extract time-dependent level populations. Thus, we can monitor the spontaneous relaxation of CH^{+} to its lowest rotational states and demonstrate the preparation of an internally cold beam of molecular ions.

Integrin α5ß1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma.

Integrin α5ß1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5ß1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5ß1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5ß1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5ß1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5ß1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5ß1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5ß1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.

A Rare Case of Ileocolic Obstruction Due to Lithophagia Associated with Cervical Oesophageal Perforation.

Lithophagia is a rare syndrome characterized by a repetitive ingestion of stones and pebbles. We herein report a case of a 61-year old mentally retarded man, with a past surgical history of multiple laparotomies for stone ingestion, presenting with cervical oesophagus perforation due to a large butterfly screw and massive impaction of 89 stones and other foreign bodies in the caecum, with consequent mechanical bowel obstruction.

IgM peak independently predicts treatment-free survival in chronic lymphocytic leukemia and correlates with accumulation of adverse oncogenetic events.

We examined the significance of IgM peaks in chronic lymphocytic leukemia (CLL), including its association with newly reported MYD88, BIRC3, NOTCH1 and SF3B1 mutations. A total of 27, 25, 41 and 57 patients with monoclonal IgM or IgG peaks (IgM and IgG groups), hypogammaglobulinemia (Hypo-γ group) and normal immunoglobulin serum levels (normal-γ group) were, respectively, included. IgM peaks were mainly associated with Binet stage C and the del(17p). Biased usage of IGHV3-48 was shared by both IgM and IgG groups. IGHV3-74 and IGHV4-39 gene rearrangements were specific for IgM and IgG peaks, respectively. SF3B1, NOTCH1, MYD88 and BIRC3 mutation frequencies were 12%, 4%, 2% and 2%, respectively, being over-represented in IgM, IgG and Hypo-γ groups for SF3B1, and being equal between normal-γ and IgM groups for MYD88. Overall, 76%, 87%, 49% and 42% of cases from IgM, IgG, Hypo-γ and normal-γ groups had at least one intermediate or poor prognosis genetic marker, respectively. By multivariate analysis, IgM peaks were associated with shorter treatment-free survival independently from any other univariate poor prognosis biological parameters, including IgG peaks, Hypo-γ, IGHV status, SF3B1 mutations, cytogenetics and lymphocytosis. Therefore, as with IgG peaks, IgM peaks aggravated the natural course of CLL, with increased accumulation of adverse genetic events.

Visual impairment registration: evaluation of agreement among ophthalmologists.

PURPOSE: To evaluate consistency among consultant ophthalmologists in registration of visual impairment of patients with glaucoma who had a significant visual field component to their visual loss. METHOD: Thirty UK NHS consultant ophthalmologists were asked to grade data sets comprising both visual acuity and visual fields as severely sight impaired, partially sight impaired, or neither. To assess intra-consultant agreement, a group of graders agreed to repeat the process. RESULTS: Kappa for inter-consultant agreement (n=30) for meeting the eligibility criteria for visual impairment registration was 0.232 (95% CI 0.142-0.345), the corresponding inter-class correlation score was 0.2 (95% CI 0.172 to 0.344). Kappa for intra-consultant agreement (n=16) ranged from 0.007 to 0.9118. CONCLUSIONS: When presented with the clinical data necessary to decide whether patients with severe visual field loss are eligible for vision impairment registration, there is very poor intra- and inter-observer agreement among consultant ophthalmologists with regard to eligibility. The poor agreement indicates that these criteria are open to significant subjective interpretation that may be a source of either under- or over-registration of visual impairment in this group of patients in the UK. This inconsistency will affect the access of visually impaired glaucoma patients to support services and may result in inaccurate recording of the prevalence of registerable visual disability among glaucoma patients with severe visual field loss. More objective criteria with less potential for misclassification should be introduced.

[Meckel's diverticulum and obstruction of the small intestine in adult patients: report of two cases]. / Diverticule de Meckel et occlusion de l'intestin grêle chez l'adulte: propos de deux cas.

Meckel's Diverticulum (MD) is the most frequent congenital anomaly of the ileum. However, its clinical manifestations in adult patients are rare. In this paper, we report cases with two different mechanisms of small intestine obstruction due to MD and we discuss diagnosis and management of these symptomatic lesions in adult patients.

Transient inhibition of transforming growth factor-beta1 in human diabetic CD34+ cells enhances vascular reparative functions.

OBJECTIVE: Peripheral blood CD34(+) cells from diabetic patients demonstrate reduced vascular reparative function due to decreased proliferation and diminished migratory prowess, largely resulting from decreased nitric oxide (NO) bioavailability. The level of TGF-beta, a key factor that modulates stem cell quiescence, is increased in the serum of type 2 diabetic patients. We asked whether transient TGF-beta1 inhibition in CD34(+) cells would improve their reparative ability. RESEARCH DESIGN AND METHODS: To inhibit TGF-beta1 protein expression, CD34(+) cells were treated ex vivo with antisense phosphorodiamidate morpholino oligomers (TGF-beta1-PMOs) and analyzed for cell surface CXCR4 expression, cell survival in the absence of added growth factors, SDF-1-induced migration, NO release, and in vivo retinal vascular reparative ability. RESULTS: TGF-beta1-PMO treatment of diabetic CD34(+) cells resulted in increased expression of CXCR4, enhanced survival in the absence of growth factors, and increased migration and NO release as compared with cells treated with control PMO. Using a retinal ischemia reperfusion injury model in mice, we observed that recruitment of diabetic CD34(+) cells to injured acellular retinal capillaries was greater after TGF-beta1-PMO treatment compared with control PMO-treated cells. CONCLUSIONS: Transient inhibition of TGF-beta1 may represent a promising therapeutic strategy for restoring the reparative capacity of dysfunctional diabetic CD34(+) cells.

Acute abdomen: a rare presentation of lung cancer metastasis.

Surgical emergencies caused by bowel metastases from carcinoma of the lung are very rare. We describe two cases of symptomatic gastrointestinal metastatic small cell carcinoma: the first one concerns a 69-year-old man with an acute abdomen and the second is a 72-year-old man complaining of a gastric ulcer symptoms. We also discuss the current management and the prognosis of these patients.

A laparoscopic approach to left diaphragmatic rupture after blunt trauma.

Diaphragmatic rupture after blunt trauma is rare, but indicates a powerful external impact. Associated lesions are often life-threatening and require a rapid diagnosis and management. We report a case of a 24-year-old man, admitted to the emergency department after a serious car accident. He complained of a left sided thoraco-abdominal pain with breathing difficulties. Chest X-ray showed a left diaphragmatic elevation. Computed tomography demonstrated a left haemo-pneumothorax, herniation of the stomach in the chest and a haemoperitonium. Laparoscopically, herniated organs were re-integrated in the abdominal cavity ; the diaphragmatic tear was repaired by both direct suture and synthetic prosthesis. Closure of a small bowel perforation found during the laparoscopic exploration was also performed. We consider this therapeutic modality to be an excellent approach in the management of acute left side diaphragmatic rupture in haemodynamically stable patients. Firstly, it permits an inspection of the thoracic cavity through the diaphragmatic tear and secondly, an easy repair of damaged structures in the abdominal cavity.

Spontaneous cystic artery rupture: a rare cause of haemoperitoneum.

We report the case of a 74-year-old man who presented an acute haemoperitoneum further to the rupture of the cystic artery. The bleeding was successfully controlled using embolization. This procedure was complicated by ischaemic necrosis and perforation of the gall-bladder requiring laparoscopic cholecystectomy. Spontaneous rupture of intra-abdominal arteries is a rare event. This usually occurs in abnormal arteries, presenting pseudo-aneurysm or, weakened by arterial hypertension, diabetes or corticotherapy. In the case of a cystic artery rupture, embolization can be safely done as long as the arterial anastomotic network with hepatic parenchyma is sufficient to supply the gall-bladder.

[Iron deficiency anaemia, pancreatitis and epigastric mass in a young female: a rare presentation of a large gastric trichobezoar]. / Anémie ferriprive, pancréatite et masse epigastrique chez une jeune patiente: une présentation clinique rare d'un volumineux trichobézoard gastrique.

We report the case of a 15-year old girl presenting with a gastric fullness sensation. The biological examination showed iron deficiency anaemia and elevation of the pancreatic enzymes. At endoscopy, a huge trichobezoar is found in the stomach. The endoscopic removal is impossible due to the compacity of the mass. Surgical resection is therefore performed. The postoperative course is uneventful and the biologic anomalies are rapidly corrected. A throughout anamnesis revealed a trichotillomania with trichophagia, this behavioural trouble found its origin in a familial conflict.

Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping.

Non-small cell lung cancers (NSCLC), in particular adenocarcinoma, are often mixed with normal cells. Therefore, low sensitivity of direct sequencing used for K-Ras mutation analysis could be inadequate in some cases. Our study focused on the possibility to increase the detection of K-Ras mutations in cases of low tumour cellularity. Besides direct sequencing, we used wild-type hybridisation probes and peptide-nucleic-acid (PNA)-mediated PCR clamping to detect mutations at codons 12 and 13, in 114 routine consecutive NSCLC frozen surgical tumours untreated by targeted drugs. The sensitivity of the analysis without or with PNA was 10 and 1% of tumour DNA, respectively. Direct sequencing revealed K-Ras mutations in 11 out of 114 tumours (10%). Using PNA-mediated PCR clamping, 10 additional cases of K-Ras mutations were detected (21 out of 114, 18%, P<0.005), among which five in samples with low tumour cellularity. In adenocarcinoma, K-Ras mutation frequency increased from 7 out of 55 (13%) by direct sequencing to 15 out of 55 (27%) by clamped-PCR (P<0.005). K-Ras mutations detected by these sensitive techniques lost its prognostic value. In conclusion, a rapid and sensitive PCR-clamping test avoiding macro or micro dissection could be proposed in routine analysis especially for NSCLC samples with low percentage of tumour cells such as bronchial biopsies or after neoadjuvant chemotherapy.