A role of point-of-care ultrasound in the emergency department diagnosis of vision loss due to traumatic cataract.

BACKGROUND: Ocular complaints, including acute or subacute vision loss, are commonly encountered in emergency departments (ED). These potentially time-sensitive complaints are difficult to diagnose and evaluate without adequate, specialized equipment and expertise. Additionally, a thorough evaluation often requires a more extensive and specialized physical exam, imaging, and ophthalmologic consultation, all of which may not be readily available in the acute setting. CASE PRESENTATION: This case report presented a patient in the emergency department with the chief complaint of vision loss. Point-of-care ultrasound (POCUS) using the 10-MHz-linear-array probe, in the ocular setting, demonstrated calcification of the lens, a finding consistent with cataract in the right eye. CONCLUSIONS: The use of POCUS can expedite the accurate identification of vision threatening pathology, such as cataracts, and streamline ED disposition and plan of care.

Efficacy and Safety of a Parenteral Nutrition Program for Patients with RAS Wild-Type Metastatic Colorectal Cancer Administered First-Line Cetuximab Plus Chemotherapy: A Propensity Score Matching Study.

Malnutrition is a common problem in patients with metastatic colorectal cancer (mCRC) receiving targeted therapy plus chemotherapy, resulting in severe toxicity and decreased survival rates. This retrospective study employing propensity score matching (PSM) examined the efficacy and safety of a supplemental home parenteral nutrition (HPN) program for patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy. This retrospective nationwide registry study included data from 14 medical centers/hospitals across Taiwan, and the data period ranged from November 2016 to December 2020. Patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy as their first-line therapy were included and divided into HPN and non-HPN program groups. HPN was initiated based on patient-specific factors, such as baseline nutritional status, treatment-related toxicities, and comorbidities. Clinical outcomes were evaluated using response to therapy, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). This study recruited 758 patients, of whom 110 and 648 were included in the HPN and non-HPN program groups, respectively. After 1:3 PSM, the data of 109 and 327 patients from the HPN and non-HPN program groups were analyzed, respectively. The HPN program group had a higher metastasectomy rate (33.9% vs. 20.2%, p = 0.005), and longer duration of treatment and DoR than the non-HPN program group (13.6 vs. 10.3 and 13.6 vs. 9.9 months, p = 0.001 and < 0.001, respectively). The HPN program group tended to have a longer median PFS (18.2 vs. 13.9 months, p = 0.102). Moreover, we noted a significant improvement in the median OS in the same group (53.4 vs. 34.6 months, p = 0.002). Supplemental HPN programs may be recommended for select patients with mCRC receiving targeted therapy plus chemotherapy to improve oncological outcomes.

Survival benefit of metastasectomy in first-line cetuximab therapy in patients with RAS wild-type metastatic colorectal cancer: a nationwide registry.

This multicenter study aimed to explore the survival benefit of metastasectomy by first-line cetuximab-based chemotherapy in real-world patients with RAS wild-type metastatic colorectal cancer (mCRC). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and metastasectomy rate. The exploratory endpoint was the optimal treatment cycle for better OS and PFS. Receiver operating characteristic curve with the area under curve (AUC) was used to identify the optimal cut-off cycle for survival outcomes. A total of 758 mCRC patients were enrolled in this study, with a median OS of 35.1 months, median PFS of 14.6 months, and metastasectomy rate of 21.4%. Left-sided mCRC had a significantly higher DCR (88.9% vs. 73.1%, P<0.001) and better OS (36.4 vs. 19.6 months, P<0.001). There were no significant differences in PFS and metastasectomy rate between left-sided and right-sided mCRC. However, mCRC patients who underwent metastasectomy over the course of treatment had better OS (54.9 vs. 28.6 months, P<0.001) and PFS (21.0 vs. 13.1 months, P<0.001) than those who did not. Notably, right-sided mCRC who benefited from first-line cetuximab-based chemotherapy to underwent metastasectomy also had favorable outcomes, on a par with left-sided mCRC. The optimal treatment cycle was 14 cycles (AUC: 0.779, P<0.001). Patients who received ≥14 cycles had higher metastasectomy rates (27.5% vs. 13.5%, P<0.001), favorable OS (42.6 vs. 23.4 months, P<0.001) and PFS (18.1 vs. 8.6 months, P<0.001), and, importantly, had comparable adverse events compared with patients who received <14 cycles of treatment. Patients who underwent metastasectomy after or during first-line cetuximab therapy have an improved OS in both left-sided and right-sided mCRC. Furthermore, patients receive ≥14 cycles of treatment whenever possible to achieve a higher likelihood of metastasectomy was associated with favorable survival outcomes.

Retrospective assessment of metabolic syndrome components in early adult life on vegetarian dietary status.

Background: Metabolic syndrome (MetS) encompasses several clinical presentations that include truncal obesity and insulin resistance at its core. MetS afflicts 23% of the adult US population, increasing their risk of diabetes and cardiovascular disease. Many studies have indicated the importance of a vegetarian diet in improving overall health and more specifically MetS components. Unfortunately, these findings have been inconsistent and cannot be extended to examine effects on MetS incidence in the younger adult population. Objective: This study aimed to conduct a retrospective analysis of a vegetarian vs. non-vegetarian dietary status in young adults (age 18-24) based on MetS components in later adulthood (age 20-30). This study focuses on elucidating any relationship between a vegetarian diet and MetS components of central obesity, hypertension, and hyperlipidemia. Methods: Waves 3 and 4 data were acquired from AddHealth. One-to-one propensity score matched vegetarians to non-vegetarians in a cohort of 535 women and 159 men. Logistical regression assessed the relationship between vegetarian status and MetS components, including truncal obesity (cm), hypertension (normal, pre-HT, HT1, and HT2), and hyperlipidemia (high and low). Results MetS components from ages 20 to 30 are not associated with vegetarian dietary status. Truncal obesity [N = 694; M = 92.82 cm; OR 0.999; p = 0.893; 95% CI (0.980, 1.017)]; hypertension [N = 694; OR 0.949; p = 0.638; 95% CI (0.764, 1.179)]; hyperlipidemia [N = 694; OR 0.840; p = 0.581; 95% CI (0.453, 1.559)]. Conclusion: Current study results were consistent with previous findings suggesting that consumption of a vegetarian diet cannot be directly linked to MetS outcomes. However, further investigation should be completed as MetS is a risk factor for several chronic diseases.

An Observational Study on the Use of a Patient Navigator to Help Improve Outcomes in Patients on Chronic Opioids.

BACKGROUND: In the United States, the prevalence of opioid use disorders has increased in recent years along with an attendant rise in the incidence of chronic pain disorders and prescription opioid use. Patient navigation services have been used to improve health outcomes in cancer and other chronic disease states, but it is unclear whether the implementation of patient navigation services can facilitate improved outcomes among patients receiving chronic opioid therapy. OBJECTIVES: The objective of this study was to compare the outcomes of patients receiving chronic opioid therapy plus patient navigation services and those receiving chronic opioid therapy as a part of usual care. STUDY DESIGN: This was a prospective, observational study. Consecutive patients receiving chronic opioid therapy were enrolled, with alternating assignments to patient navigation (n = 30) or usual care (n = 30). Participants in the patient navigation group received support from a non-physician, non-advanced practice provider staff member who initiated frequent contact via telephone, telemedicine, or in-clinic visits to discuss the patient's health goals. The minimum follow-up period was 90 days. Outcomes qualitatively compared across groups included final pain score, final morphine milligram equivalent (MME) per day, and discharge rates. Risk factors for discharge within the navigation group were assessed. Patient feedback was also solicited. SETTING: This study was conducted at a single independent pain clinic in the United States. RESULTS: Demographic features were similar between the navigator group and the control group. The control group had a higher average initial pain score (7.0/10) than the intervention group (5.9/10) and were receiving a higher initial dose of opioids (23.1 vs 19.0 MME/d). After an average follow-up of 108.7 days, patients in the navigator group had a 16% decrease in final opioid dose compared with a 23% increase in the control group. Furthermore, patients in the control group were discharged from the practice at a higher rate (23.3% vs 6.6%), suggesting increased opioid misuse in the control group compared with the navigator group. In the navigator group, higher levels of anxiety and depression were the primary predictors of discharge. LIMITATIONS: This was a single-center study with a small sample size. The generalizability of these results to other clinic settings is unknown. CONCLUSIONS: Patient navigation decreased opioid use and practice discharge compared with usual care in an independent pain clinic, suggesting a role for patient navigation in reducing opioid misuse and potentially reducing adverse events.

Identification of four serum miRNAs as potential markers to screen for thirteen cancer types.

INTRODUCTION: Cancer consistently remains one of the top causes of death in the United States every year, with many cancer deaths preventable if detected early. Circulating serum miRNAs are a promising, minimally invasive supplement or even an alternative to many current screening procedures. Many studies have shown that different serum miRNAs can discriminate healthy individuals from those with certain types of cancer. Although many of those miRNAs are often reported to be significant in one cancer type, they are also altered in other cancer types. Currently, very few studies have investigated serum miRNA biomarkers for multiple cancer types for general cancer screening purposes. METHOD: To identify serum miRNAs that would be useful in screening multiple types of cancers, microarray cancer datasets were curated, yielding 13 different types of cancer with a total of 3352 cancer samples and 2809 non-cancer samples. The samples were divided into training and validation sets. One hundred random forest models were built using the training set to select candidate miRNAs. The selected miRNAs were then used in the validation set to see how well they differentiate cancer from normal samples in an independent dataset. Furthermore, the interactions between these miRNAs and their target mRNAs were investigated. RESULT: The random forest models achieved an average of 97% accuracy in the training set with 95% bootstrap confidence interval of 0.9544 to 0.9778. The selected miRNAs were hsa-miR-663a, hsa-miR-6802-5p, hsa-miR-6784-5p, hsa-miR-3184-5p, and hsa-miR-8073. Each miRNA exhibited high area under the curve (AUC) value using receiver operating characteristic analysis. Moreover, the combination of four out of five miRNAs achieved the highest AUC value of 0.9815 with high sensitivity of 0.9773, indicating that these miRNAs have a high potential for cancer screening. miRNA-mRNA and protein-protein interaction analysis provided insights into how these miRNAs play a role in cancer.

Co-flow injection for serial crystallography at X-ray free-electron lasers.

Serial femtosecond crystallography (SFX) is a powerful technique that exploits X-ray free-electron lasers to determine the structure of macro-molecules at room temperature. Despite the impressive exposition of structural details with this novel crystallographic approach, the methods currently available to introduce crystals into the path of the X-ray beam sometimes exhibit serious drawbacks. Samples requiring liquid injection of crystal slurries consume large quantities of crystals (at times up to a gram of protein per data set), may not be compatible with vacuum configurations on beamlines or provide a high background due to additional sheathing liquids present during the injection. Proposed and characterized here is the use of an immiscible inert oil phase to supplement the flow of sample in a hybrid microfluidic 3D-printed co-flow device. Co-flow generation is reported with sample and oil phases flowing in parallel, resulting in stable injection conditions for two different resin materials experimentally. A numerical model is presented that adequately predicts these flow-rate conditions. The co-flow generating devices reduce crystal clogging effects, have the potential to conserve protein crystal samples up to 95% and will allow degradation-free light-induced time-resolved SFX.

Specific PIWI-Interacting RNAs and Related Small Noncoding RNAs Are Associated With Ovarian Aging in Ames Dwarf (df/df) Mice.

The Ames dwarf (df/df) mouse is a well-established model for delayed aging. MicroRNAs (miRNAs), the most studied small noncoding RNAs (sncRNAs), may regulate ovarian aging to maintain a younger ovarian phenotype in df/df mice. In this study, we profile other types of ovarian sncRNAs, PIWI-interacting RNAs (piRNAs) and piRNA-like RNAs (piLRNAs), in young and aged df/df and normal mice. Half of the piRNAs derive from transfer RNA fragments (tRF-piRNAs). Aging and dwarfism alter the ovarian expression of these novel sncRNAs. Specific tRF-piRNAs that increased with age might target and decrease the expression of the breast cancer antiestrogen resistance protein 3 (BCAR3) gene in the ovaries of old df/df mice. A set of piLRNAs that decreased with age and map to D10Wsu102e mRNA may have trans-regulatory functions. Other piLRNAs that decreased with age potentially target and may de-repress transposable elements, leading to a beneficial impact on ovarian aging in df/df mice. These results identify unique responses in ovarian tissues with regard to aging and dwarfism. Overall, our findings highlight the complexity of the aging effects on gene expression and suggest that, in addition to miRNAs, piRNAs, piLRNAs, tRF-piRNAs, and their potential targets can be central players in the maintenance of a younger ovarian phenotype in df/df mice.

Lung adenocarcinoma and lung squamous cell carcinoma cancer classification, biomarker identification, and gene expression analysis using overlapping feature selection methods.

Lung cancer is one of the deadliest cancers in the world. Two of the most common subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), have drastically different biological signatures, yet they are often treated similarly and classified together as non-small cell lung cancer (NSCLC). LUAD and LUSC biomarkers are scarce, and their distinct biological mechanisms have yet to be elucidated. To detect biologically relevant markers, many studies have attempted to improve traditional machine learning algorithms or develop novel algorithms for biomarker discovery. However, few have used overlapping machine learning or feature selection methods for cancer classification, biomarker identification, or gene expression analysis. This study proposes to use overlapping traditional feature selection or feature reduction techniques for cancer classification and biomarker discovery. The genes selected by the overlapping method were then verified using random forest. The classification statistics of the overlapping method were compared to those of the traditional feature selection methods. The identified biomarkers were validated in an external dataset using AUC and ROC analysis. Gene expression analysis was then performed to further investigate biological differences between LUAD and LUSC. Overall, our method achieved classification results comparable to, if not better than, the traditional algorithms. It also identified multiple known biomarkers, and five potentially novel biomarkers with high discriminating values between LUAD and LUSC. Many of the biomarkers also exhibit significant prognostic potential, particularly in LUAD. Our study also unraveled distinct biological pathways between LUAD and LUSC.

Colo-pancreaticoduodenectomy for locally advanced colon carcinoma-feasibility in patients presenting with acute abdomen.

BACKGROUND: En bloc right hemicolectomy plus pancreaticoduodenectomy (PD) is administered for locally advanced colon carcinoma that invades the duodenum and/or pancreatic head. This procedure may also be called colo-pancreaticoduodenectomy (cPD). Patients with such carcinomas may present with acute abdomen. Emergency PD often leads to high postoperative morbidity and mortality. Here, we aimed to evaluate the feasibility and outcomes of emergency cPD for patients with advanced colon carcinoma manifesting as acute abdomen. METHODS: We retrospectively reviewed 4898 patients with colorectal cancer who underwent curative colectomy during the period from 1994 to 2018. Among them, 30 had locally advanced right colon cancer and had received cPD. Among them, surgery was performed in 11 patients in emergency conditions (bowel obstruction: 6, perforation: 3, tumor bleeding: 2). Selection criteria for emergency cPD were the following: (1) age ≤ 60 years, (2) body mass index < 35 kg/m2, (3) no poorly controlled comorbidities, and (4) perforation time ≤ 6 h. Three patients did not meet the above criteria and received non-emergency cPD after a life-saving diverting ileostomy, followed by cPD performed 3 months later. We analyzed these patients in terms of their clinicopathological characteristics, the early and long-term postoperative outcomes, and compared findings between emergency cPD group (e-group, n = 11) and non-emergency cPD group (non-e-group, n = 19). After cPD, staged pancreaticojejunostomy was performed in all e-group patients, and on 15 of 19 patients in the non-e-group. RESULTS: The non-e-group was older and had a higher incidence of associated comorbidities, while other clinicopathological characteristics were similar between the two groups. None of the patients in the two groups succumbed from cPD. The postoperative complication rate was 63.6% in the e-group and 42.1% in the non-e-group (p = 0.449). The 5-year overall survival rate were 15.9% in the e-group and 52.6% in the non-e-group (p = 0.192). CONCLUSIONS: Emergency cPD is feasible in highly selected patients if performed by experienced surgeons. The early and long-term positive outcomes of emergency cPD are similar to those after non-emergency cPD in patients with acute abdominal conditions.

Determination of the UGT1A1 polymorphism as guidance for irinotecan dose escalation in metastatic colorectal cancer treated with first-line bevacizumab and FOLFIRI (PURE FIST).

AIM: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility of patients to irinotecan and its toxicity. This study is a multicenter, randomised clinical trial comparing the clinical outcomes and adverse events (AEs) in metastatic colorectal cancer (mCRC) patients treated with bevacizumab plus FOLFIRI with or without UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. METHODS: The control group received conventional biweekly FOLFIRI plus bevacizumab without UGT1A1 genotyping, whereas the study group received the same regimen with irinotecan dose escalation based on UGT1A1 genotyping. The primary end-point was progression-free survival (PFS), and secondary end-points were overall response rate (ORR), disease control rate (DCR), overall survival (OS), AEs and metastasectomy rate. RESULTS: Over a median follow-up of 26.0 months (IQR, 17.0-35.0 months), study group (n = 107) was superior to the control group (n = 106) in PFS, OS, ORR, DCR, and metastasectomy rate (all P < 0.05). Furthermore, there were no significant differences in AEs ≥ grade III between the two groups, even with the 1.36-fold increase in the relative dose intensity of irinotecan in the study group. Dose escalation of irinotecan, an independent factor of ORR (P < 0.001) and DCR (P = 0.006), improved PFS in mCRC patients with wild-type and mutant KRAS (P = 0.007 and P = 0.019, respectively). CONCLUSION: The current study revealed that mCRC patients, regardless of KRAS gene status, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favourable clinical outcome without significantly increased toxicities. CLINICAL TRIAL REGISTRATION: NCT02256800.

Vitamin D deficiency in proximal femur fracture patients of South-East Queensland.

OBJECTIVES: To determine the incidence of hypovitaminosis D in proximal femur fracture (PFF) patients and investigate whether sociodemographic factors or radiographic parameters are associated with vitamin D levels. METHODS: This is a consecutive case series of South-East Queensland patients presenting with low-energy PFFs. Vitamin D levels and sociodemographic factors (age, sex, postcode, medications and type of residence) were collected from medical records. Radiographic parameters included PFF type and cortical thickness of the femur. RESULTS: A total of 313 patients were included (mean age = 79.5 years), and 105 (34%) were deficient in vitamin D (<50 nmol/L). There was no association between vitamin D levels and sociodemographic factors or radiographic parameters. Eighty-four (84%) of vitamin D-deficient patients were not taking vitamin D supplements. CONCLUSIONS: Social and demographic factors are not correlated with vitamin D levels in this cohort. Routine vitamin D supplementation may be indicated in ageing patients although it is not always protective of low-energy fractures.

Correction: Ion concentration polarization (ICP) of proteins at silicon micropillar nanogaps.

[This corrects the article DOI: 10.1371/journal.pone.0223732.].

Ab initio phasing of the diffraction of crystals with translational disorder.

To date X-ray protein crystallography is the most successful technique available for the determination of high-resolution 3D structures of biological molecules and their complexes. In X-ray protein crystallography the structure of a protein is refined against the set of observed Bragg reflections from a protein crystal. The resolution of the refined protein structure is limited by the highest angle at which Bragg reflections can be observed. In addition, the Bragg reflections alone are typically insufficient (by a factor of two) to determine the structure ab initio, and so prior information is required. Crystals formed from an imperfect packing of the protein molecules may also exhibit continuous diffraction between and beyond these Bragg reflections. When this is due to random displacements of the molecules from each crystal lattice site, the continuous diffraction provides the necessary information to determine the protein structure without prior knowledge, to a resolution that is not limited by the angular extent of the observed Bragg reflections but instead by that of the diffraction as a whole. This article presents an iterative projection algorithm that simultaneously uses the continuous diffraction as well as the Bragg reflections for the determination of protein structures. The viability of this method is demonstrated on simulated crystal diffraction.

Rapid sample delivery for megahertz serial crystallography at X-ray FELs.

Liquid microjets are a common means of delivering protein crystals to the focus of X-ray free-electron lasers (FELs) for serial femtosecond crystallography measurements. The high X-ray intensity in the focus initiates an explosion of the microjet and sample. With the advent of X-ray FELs with megahertz rates, the typical velocities of these jets must be increased significantly in order to replenish the damaged material in time for the subsequent measurement with the next X-ray pulse. This work reports the results of a megahertz serial diffraction experiment at the FLASH FEL facility using 4.3 nm radiation. The operation of gas-dynamic nozzles that produce liquid microjets with velocities greater than 80 m s-1 was demonstrated. Furthermore, this article provides optical images of X-ray-induced explosions together with Bragg diffraction from protein microcrystals exposed to trains of X-ray pulses repeating at rates of up to 4.5 MHz. The results indicate the feasibility for megahertz serial crystallography measurements with hard X-rays and give guidance for the design of such experiments.

Fabrication of an anthropomorphic heterogeneous mouse phantom for multimodality medical imaging.

This work presents a comprehensive methodology for constructing a tissue equivalent mouse phantom using image modeling and 3D printing technology. The phantom can be used in multimodality imaging and irradiation experiments, quality control, and management. Computed tomography (CT) images of a mouse were acquired and imported into 3D modeling software. A skeleton and skin shell models were segmented in the modeling software and manufactured using 3D printing technology. The bone model was constructed with VERO-WHITE printing material with additional ingredients, including a photosensitive resin, polyurethane epoxy resin, and acrylate. Acrylonitrile butadiene styrene resin material was used to construct the skin shell. The skin shell was attached to the skeleton and filled with a specially formulated gel to act as a soft tissue substitute. The gel consisted of agarose, micro-pearl powder, sodium chloride, and magnevist solution (gadopentetate dimeglumine). A micro-container filled with 18F-fluorodeoxyglucose (18F-FDG) radioactive tracer was placed in the abdomen for micro and human positron emission tomography (PET)/CT imaging. The mouse phantom had tissue equivalency in dose attenuation with x-rays and relaxation times with magnetic resonance imaging (MRI). The CT Hounsfield Unit (HU) range for the gel soft tissue material was 31-36 HU. The 3D printed bone mimetic material had equivalent tissue/bone contrast compared with in vivo mouse measurements with a mean value of 130 ± 10 HU. At different magnetic field strengths, the T 1 relaxation time of the soft tissue was 382.75-506.48 ms, and T 2 was 51.11-70.76 ms. 18F-FDG tracer could be clearly observed in PET imaging. The 3D printed mouse phantom was successfully constructed with tissue-equivalent materials. Our model can be used for CT, MRI, and PET as a standard device for small-animal imaging and quality control.

Regularized Laplacian determinants of self-similar fractals.

We study the spectral zeta functions of the Laplacian on fractal sets which are locally self-similar fractafolds, in the sense of Strichartz. These functions are known to meromorphically extend to the entire complex plane, and the locations of their poles, sometimes referred to as complex dimensions, are of special interest. We give examples of locally self-similar sets such that their complex dimensions are not on the imaginary axis, which allows us to interpret their Laplacian determinant as the regularized product of their eigenvalues. We then investigate a connection between the logarithm of the determinant of the discrete graph Laplacian and the regularized one.

X-ray focusing with efficient high-NA multilayer Laue lenses.

Multilayer Laue lenses are volume diffraction elements for the efficient focusing of X-rays. With a new manufacturing technique that we introduced, it is possible to fabricate lenses of sufficiently high numerical aperture (NA) to achieve focal spot sizes below 10 nm. The alternating layers of the materials that form the lens must span a broad range of thicknesses on the nanometer scale to achieve the necessary range of X-ray deflection angles required to achieve a high NA. This poses a challenge to both the accuracy of the deposition process and the control of the materials properties, which often vary with layer thickness. We introduced a new pair of materials-tungsten carbide and silicon carbide-to prepare layered structures with smooth and sharp interfaces and with no material phase transitions that hampered the manufacture of previous lenses. Using a pair of multilayer Laue lenses (MLLs) fabricated from this system, we achieved a two-dimensional focus of 8.4 × 6.8 nm2 at a photon energy of 16.3 keV with high diffraction efficiency and demonstrated scanning-based imaging of samples with a resolution well below 10 nm. The high NA also allowed projection holographic imaging with strong phase contrast over a large range of magnifications. An error analysis indicates the possibility of achieving 1 nm focusing.

Neoadjuvant therapy of bevacizumab in combination with oxaliplatin and capecitabine (XELOX) for patients with metastatic colorectal cancer with unresectable liver metastases: a phase II, open-label, single-arm, noncomparative trial.

AIM: This phase II, open-label study evaluated the efficacy and safety of neoadjuvant therapy with bevacizumab plus XELOX (capecitabine and oxaliplatin) for untreated metastatic colorectal cancer with unresectable liver metastases and assessed conversion of unresectable to resectable metastases after neoadjuvant treatment. METHODS: Patients received bevacizumab 5 mg/kg and oxaliplatin 85 mg/m2 on day 1, and capecitabine 1000 mg/m2 twice daily on days 1-5 followed by 2 days of rest in a 14-day cycle for 12 cycles; bevacizumab was excluded in cycles 6 and 7. Patients were later divided into resected and unresected groups, depending upon whether they underwent curative resection after chemotherapy. Efficacy and safety were evaluated. RESULTS: Of 45 patients enrolled, 17.8% completed the study. The resection rate of liver metastases after neoadjuvant therapy was 42.2%. The median time to disease progression was 10.1 and 8.7 months in the resected and unresected groups, respectively (P = 0.1341). Response rate was significantly higher in the resected (47.4%) versus the unresected group (34.6%; P = 0.0010), and seven patients achieved complete response (resected group). Overall, 94.3% of adverse events were of mild or moderate severity, and grade ≥3 adverse events occurred in 4.3% and 7.3% of patients in the resected and unresected groups, respectively. The most common adverse events in both groups were palmar-plantar erythrodysesthesia syndrome, decreased appetite, thrombocytopenia, peripheral neuropathy, fatigue, diarrhea, vomiting, proteinuria and nausea. CONCLUSION: Neoadjuvant therapy with bevacizumab plus XELOX was well tolerated and effective in previously untreated metastatic colorectal cancer patients with initially unresectable liver metastases.

Flow-aligned, single-shot fiber diffraction using a femtosecond X-ray free-electron laser.

A major goal for X-ray free-electron laser (XFEL) based science is to elucidate structures of biological molecules without the need for crystals. Filament systems may provide some of the first single macromolecular structures elucidated by XFEL radiation, since they contain one-dimensional translational symmetry and thereby occupy the diffraction intensity region between the extremes of crystals and single molecules. Here, we demonstrate flow alignment of as few as 100 filaments (Escherichia coli pili, F-actin, and amyloid fibrils), which when intersected by femtosecond X-ray pulses result in diffraction patterns similar to those obtained from classical fiber diffraction studies. We also determine that F-actin can be flow-aligned to a disorientation of approximately 5 degrees. Using this XFEL-based technique, we determine that gelsolin amyloids are comprised of stacked ß-strands running perpendicular to the filament axis, and that a range of order from fibrillar to crystalline is discernable for individual α-synuclein amyloids.