A scheme for generating two simultaneous hard-x-ray free-electron laser pulses with a controllable difference in photon energy is described and then demonstrated using the self-seeding setup at the ...Linac Coherent Light Source (LCLS). The scheme takes advantage of the existing LCLS equipment, which allows two independent rotations of the self-seeding diamond crystal. The two degrees of freedom are used to select two nearby crystal reflections, causing two wavelengths to be present in the forward transmitted seeding x-ray pulse. The free-electron laser system must support amplification at both desired wavelengths.
We conducted a phase I-II study to evaluate Nilotinib (NIL) safety and pharmacokinetics in 22 SR-cGVHD patients; we also evaluated ORR by using in parallel NIH criteria and an exploratory approach, ...combining objective improvement (OI) without failure criteria (GITMO criteria). Results: 22 patients were enrolled. After dose escalation up to 600 mg/day, MTD was not reached. Main toxicities were asthenia, headache, nausea, pruritus, cramps, and mild anemia. Mean and median plasma concentrations of NIL (C-NIL) were 817 (SD ± 450) and 773 ng/ml. ORR at 6 months, according to 2005 and 2014 NIH and GITMO criteria were 27.8%, 22.2%, and 55.6% respectively; close correspondence has been observed for ORR, according to 2014 NIH criteria, both assessed in a conventional way and assisted by dedicated software (CROSY). At 48 months OS was 75% while FFS, according to NIH and GITMO criteria, was 30 and 25%. In conclusion the safety profile of NIL and long-term outcome makes NIL an attractive option in SR-cGVHD. Exploratory GITMO criteria could represent an alternative tool for easy response evaluation in patients with prevalent skin and lung involvement, but require validation in a larger population; CROSY software showed excellent reliability in capturing ORR according to the 2014 NIH criteria.
New capabilities at X-ray free-electron laser facilities allow the generation of two-colour femtosecond X-ray pulses, opening the possibility of performing ultrafast studies of X-ray-induced ...phenomena. Particularly, the experimental realization of hetero-site-specific X-ray-pump/X-ray-probe spectroscopy is of special interest, in which an X-ray pump pulse is absorbed at one site within a molecule and an X-ray probe pulse follows the X-ray-induced dynamics at another site within the same molecule. Here we show experimental evidence of a hetero-site pump-probe signal. By using two-colour 10-fs X-ray pulses, we are able to observe the femtosecond time dependence for the formation of F ions during the fragmentation of XeF2 molecules following X-ray absorption at the Xe site.
Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular synovitis (PVNS) are related conditions with features of both reactive inflammatory disorders and clonal neoplastic proliferations. ...Chromosomal translocations involving chromosome 1p13 have been reported in both TGCT and PVNS. We confirm that transiocations involving p1pl3 are present in a majority of cases of TGCT and PVNS and show that CSF1 is the gene at the chromosome lp13 breakpoint. In some cases of both TGCT and PVNS, CSF1 is fused to COL6A3 (2q35). The CSF1 translocations result in overexpression of CSF1. In cases of TGCT and PVNS carrying this translocation, it is present in a minority of the intratumoral cells, leading to CSF1 expression only in these cells, whereas the majority of cells express CSFIR but not CSF1, suggesting a tumor-landscaping effect with aberrant CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of nonneoplastic cells that form a tumorous mass.
Summary Background If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary ...lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. Methods Patients with T1–2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov , number NCT00014612. Findings Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1–8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00–0·92) after axillary lymph node dissection versus 1·19% (0·31–2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00–5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. Interpretation Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1–2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. Funding EORTC Charitable Trust.
The SARS-CoV-2 pandemic has profoundly affected the social fabric and the economic and health care viability and functioning of most countries. Aside from its deeply destructive impact on health care ...systems and national economies, the pandemic has jeopardized people's emotional and psychological well-being as well. The authors aimed to shed a light on how the pandemic has been affecting patients with addiction issues and body dysmorphic disorder (BDD), which is characterized by negative thoughts about appearance and body misperceptions. People with body dysmorphic disorder are in fact at increased risk of developing substance use disorders, and such a destructive association has only been made more severe by pandemic-related restrictions, emotional distress and anxiety, as well as longer exposure to social media and online interactions. This is a major cause for concern, because substance use worsens symptoms of BDD and contributes to unfavorable treatment outcomes.
Summary A total of 507,671 people ≥65 experienced hip fractures between 2000 and 2005. In 2005, 94,471 people ≥65 were hospitalized due to hip fractures, corresponding to a 28.5% increase over 6 ...years. Most fractures occurred in patients ≥75 (82.9%; n = 420,890; +16% across 6 years), particularly in women (78.2%; n = 396,967). Introduction We aimed to analyze incidence and costs of hip fractures in Italy over the last 6 years. Methods We analyzed the national hospitalization and DRG databases concerning fractures occurred in people ≥65 between 2000 and 2005. Results A total of 507,671 people ≥65 experienced hip fractures across 6 years, resulting in about 120,000 deaths. In year 2005 94,471 people aged ≥65 were hospitalized due to hip fractures, corresponding to a 28.5% increase over 6 years. The majority of hip fractures occurred in patients ≥75 (82.9%; n = 420,890; +16% across 6 years) and particularly in women (78.2%; n = 396,967). Among women, 84.2% of fractures (n = 334,223; +28.0% over 6 years) were experienced by patients ≥75, which is known to be the age group with the highest prevalence of osteoporosis, accounting for 68.6% of the overall observed increase in the total number of fractures. Hip fractures in men ≥75 increased by 33.1% (up to 16,540). Hospitalization costs increased across the six examined years (+36.1%) reaching 467 million euros in 2005, while rehabilitation costs rose up to 531 million in the same year. Conclusions Hip fractures of the elderly are increasing and represent a major health problem in industrialized countries such as Italy.
Rapamycin enhances autophagic flux of Schwann cells, reduces prooxidant and proinflammatory proteins, and prevents neuropathic pain; autophagy deficiency induces exacerbated pain and delays recovery.
...Axonal degeneration in peripheral nerves after injury is accompanied by myelin degradation initiated by Schwann cells (SCs). These cells activate autophagy, a ubiquitous cytoprotective process essential for degradation and recycling of cellular constituents. Concomitantly to nerve insult and axonal degeneration, neuropathic pain (NeP) arises. The role of SC autophagy in the mechanisms underlying NeP is still unknown. In this study, we examined the role of the autophagy during the early phase of Wallerian degeneration in NeP induction and chronification by using a murine model of peripheral nerve lesion (chronic constriction injury). We demonstrate that the autophagy inducer rapamycin, administered in the first week after nerve damage, induces long-lasting analgesic and antiinflammatory effects, facilitates nerve regeneration, and prevents pain chronification. Conversely, when autophagy is altered, by means of autophagic inhibitor 3-methyladenine administration or as occurs in activating molecule in Beclin-1-regulated autophagy transgenic mice (Ambra1+/gt), NeP is dramatically enhanced and prolonged. Immunohistochemical and ultrastructural evaluations show that rapamycin is able to increase autophagic flux in SCs, to accelerate myelin compaction, and to reduce inflammatory and immune reaction. Proteomic analysis combined with bioinformatic analysis suggests that a redox-sensitive mechanism could be responsible for SC autophagy activation. These data suggest that a deficiency of autophagic activity in SCs can be an early event in the origin of NeP chronification and that autophagy modulation may represent a powerful pharmacological approach to prevent the onset and chronification of NeP in the clinical setting.
Context.
It is known that high-mass stars form as the result of the fragmentation of massive molecular clumps. However, it is not clear whether this fragmentation gives rise to cores that are massive ...enough to directly form high-mass stars, or if leads to cores of low and intermediate masses that generate high-mass stars by acquiring material from their environment.
Aims.
Detailed studies of massive clumps at the early stage of star formation are needed to collect observational evidence that sheds light on the fragmentation processes from clump to core scales. The infrared-quiet massive clump AGAL G035.1330−00.7450 (AGAL35) located at a distance of 2.1 kpc is a promising object for studying the fragmentation and the star formation activity at early stages.
Methods.
Using millimeter observations of continuum and molecular lines obtained from the Atacama Large Millimeter Array database at Bands 6 and 7, we studied the substructure of the source AGAL35. The angular resolution of the data at Band 7 is about 0.′′7, which allowed us to resolve structures of about 0.007 pc (~1500 au).
Results.
The continuum emission at Bands 6 and 7 shows that AGAL35 harbors four dust cores, labeled C1 to C4, with masses lower than 3
M
⊙
. Cores C3 and C4 exhibit well-collimated, young, and low-mass molecular outflows related to molecular hydrogen emission-line objects that were previously detected. Cores C1 and C2 present CH
3
CN
J
= 13–12 emission, from which we derive rotational temperatures of about 180 and 100 K, respectively. These temperatures allow us to estimate masses of about 1.4 and 0.9
M
⊙
for C1 and C2, respectively, which are about an order of magnitude lower than those estimated in previous works and agree with the Jeans mass of this clump. In particular, the moment 1 map of CH
3
CN emission suggests the presence of a rotating disk towards C1, which is confirmed by the CH
3
OH and CH
3
OCHO (20–19) emissions. On the other hand, the CN N = 2–1 emission shows a clumpy and filamentary structure that seems to connect all the cores. These filaments might be tracing the remnant gas of the fragmentation processes taking place within the massive clump AGAL35 or the gas that is being transported toward the cores, which would imply a competitive accretion scenario.
Conclusions.
The massive clump AGAL35 harbors four low- to intermediate-mass cores with masses lower than 3
M
⊙
, which is about an order of magnitude smaller than the masses estimated in previous works. This study shows that in addition to the importance of high-resolution and sensitivity observations for a complete detection of all fragments, it is very important to accurately determine the temperature of these cores for a correct mass estimation. Finally, although no high-mass cores were detected toward AGAL35, the filamentary structure connecting all the cores means that high-mass stars might form through the competitive accretion mechanism.
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