Dual targeting of cancer metabolome and stress antigens affects transcriptomic heterogeneity and efficacy of engineered T cells.

Few cancers can be targeted efficiently by engineered T cell strategies. Here, we show that γδ T cell antigen receptor (γδ TCR)-mediated cancer metabolome targeting can be combined with targeting of cancer-associated stress antigens (such as NKG2D ligands or CD277) through the addition of chimeric co-receptors. This strategy overcomes suboptimal γ9δ2 TCR engagement of αß T cells engineered to express a defined γδ TCR (TEGs) and improves serial killing, proliferation and persistence of TEGs. In vivo, the NKG2D-CD28WT chimera enabled control only of liquid tumors, whereas the NKG2D-4-1BBCD28TM chimera prolonged persistence of TEGs and improved control of liquid and solid tumors. The CD277-targeting chimera (103-4-1BB) was the most optimal co-stimulation format, eradicating both liquid and solid tumors. Single-cell transcriptomic analysis revealed that NKG2D-4-1BBCD28TM and 103-4-1BB chimeras reprogram TEGs through NF-κB. Owing to competition with naturally expressed NKG2D in CD8+ TEGs, the NKG2D-4-1BBCD28TM chimera mainly skewed CD4+ TEGs toward adhesion, proliferation, cytotoxicity and less exhausted signatures, whereas the 103-4-1BB chimera additionally shaped the CD8+ subset toward a proliferative state.

The rational modulation of autophagy sensitizes colorectal cancer cells to 5-fluouracil and oxaliplatin.

Colorectal cancer (CRC) is the third most common and deadliest cancer globally. Regimens using 5-fluorouracil (5FU) and Oxaliplatin (OXA) are the first-line treatment for CRC, but tumor recurrence is frequent. It is plausible to hypothesize that differential cellular responses are triggered after treatments depending on the genetic background of CRC cells and that the rational modulation of cell tolerance mechanisms like autophagy may reduce the regrowth of CRC cells. This study proposes investigating the cellular mechanisms triggered by CRC cells exposed to 5FU and OXA using a preclinical experimental design mimicking one cycle of the clinical regimen (i.e., 48 h of treatment repeated every 2 weeks). To test this, we treated CRC human cell lines HCT116 and HT29 with the 5FU and OXA, combined or not, for 48 h, followed by analysis for two additional weeks. Compared to single-drug treatments, the co-treatment reduced tumor cell regrowth, clonogenicity and stemness, phenotypes associated with tumor aggressiveness and poor prognosis in clinics. This effect was exerted by the induction of apoptosis and senescence only in the co-treatment. However, a week after treatment, cells that tolerated the treatment had high levels of autophagy features and restored the proliferative phenotype, resembling tumor recurrence. The pharmacologic suppression of early autophagy during its peak of occurrence, but not concomitant with chemotherapeutics, strongly reduced cell regrowth. Overall, our experimental model provides new insights into the cellular mechanisms that underlie the response and tolerance of CRC cells to 5FU and OXA, suggesting optimized, time-specific autophagy inhibition as a new avenue for improving the efficacy of current treatments.

Simultaneous evaluation of iris area and subfoveal choroidal thickness in Fuchs uveitis syndrome.

BACKGROUND/AIMS: To simultaneously evaluate iris area (IA) and subfoveal choroidal thickness (SFCT) in eyes with Fuchs Uveitis Syndrome (FUS). METHODS: We prospectively recruited a case series of patients with FUS at our institution, simultaneously measuring IA with anterior segment spectral domain optical coherence tomography (SD-OCT) and SFCT with enhanced depth imaging optical coherence tomography (EDI-OCT). Iris images were analyzed by ImageJ software. We tested the differences in intereye IA and SFCT with the healthy eye (HE) using the Wilcoxon test, and clinical interpretation was controlled by intraclass correlation coefficient (ICC) between two masked specialists. RESULTS: Sixteen patients with unilateral FUS were included. Six were female, and the age range was 37 to 67 (median age 48 years, IQR 41-60). ICC of 98.9%, with a lower confidence interval of 97%. Eyes with FUS had a significant thinning of the total iris median area (p < 0.002), restricted to the temporal and nasal areas compared to the HE (p < 0.01 and < 0.001, respectively). SFCT was also significantly thinner compared to the HE (p < 0.0001). A low correlation was found between iris and choroidal thinning in FUS eyes (rs = 0.21; p = 0.4). CONCLUSIONS: This study found reduced iris area and subfoveal choroidal thickness in eyes with FUS compared to the normal fellow eye.

Laminin Alpha 2 Enhances the Protective Effect of Exosomes on Human iPSC-Derived Cardiomyocytes in an In Vitro Ischemia-Reoxygenation Model.

Ischemic heart disease, a leading cause of death worldwide, manifests clinically as myocardial infarction. Contemporary therapies using mesenchymal stromal cells (MSCs) and their derivative (exosomes, EXOs) were developed to decrease the progression of cell damage during ischemic injury. Laminin alpha 2 (LAMA2) is an important extracellular matrix protein of the heart. Here, we generated MSC-derived exosomes cultivated under LAMA2 coating to enhance human-induced pluripotent stem cell (hiPSC)-cardiomyocyte recognition of LAMA2-EXOs, thus, increasing cell protection during ischemia reoxygenation. We mapped the mRNA content of LAMA2 and gelatin-EXOs and identified 798 genes that were differentially expressed, including genes associated with cardiac muscle development and extracellular matrix organization. Cells were treated with LAMA2-EXOs 2 h before a 4 h ischemia period (1% O2, 5% CO2, glucose-free media). LAMA2-EXOs had a two-fold protective effect compared to non-treatment on plasma membrane integrity and the apoptosis activation pathway; after a 1.5 h recovery period (20% O2, 5% CO2, cardiomyocyte-enriched media), cardiomyocytes treated with LAMA2-EXOs showed faster recovery than did the control group. Although EXOs had a protective effect on endothelial cells, there was no LAMA2-enhanced protection on these cells. This is the first report of LAMA2-EXOs used to treat cardiomyocytes that underwent ischemia-reoxygenation injury. Overall, we showed that membrane-specific EXOs may help improve cardiomyocyte survival in treating ischemic cardiovascular disease.

KRAS mutations in pancreatic cancer: could we talk about a risk factor for the development of thromboembolic phenomena?

The oncogenic KRAS mutation is associated with increased tissue factor expression and thus hypercoagulability. In this regard, numerous studies published in the last decade have shown that KRAS mutations are an important risk factor for the development of thromboembolic phenomena in neoplasms of the digestive tract, such as colorectal cancer. On the other hand, some recently published studies suggest that KRAS mutations are also associated with an increased risk of developing thromboembolic phenomena in pancreatic cancer. Based on these premises, we have conducted a single-centre retrospective study on a cohort of patients with pancreatic cancer. Our aim is to demonstrate whether there is an association between the presence of KRAS mutations in our cohort of pancreatic cancer patients and an increased risk of developing thromboembolic phenomena.

Extracellular vesicles as source for the identification of minimally invasive molecular signatures in glioblastoma.

The analysis of extracellular vesicles (EVs) as a source of cancer biomarkers is an emerging field since low-invasive biomarkers are highly demanded. EVs constitute a heterogeneous population of small membrane-contained vesicles that are present in most of body fluids. They are released by all cell types, including cancer cells and their cargo consists of nucleic acids, proteins and metabolites and varies depending on the biological-pathological state of the secretory cell. Therefore, EVs are considered as a potential source of reliable biomarkers for cancer. EV biomarkers in liquid biopsy can be a valuable tool to complement current medical technologies for cancer diagnosis, as their sampling is minimally invasive and can be repeated over time to monitor disease progression. In this review, we highlight the advances in EV biomarker research for cancer diagnosis, prognosis, and therapy monitoring. We especially focus on EV derived biomarkers for glioblastoma. The diagnosis and monitoring of glioblastoma still relies on imaging techniques, which are not sufficient to reflect the highly heterogenous and invasive nature of glioblastoma. Therefore, we discuss how the use of EV biomarkers could overcome the challenges faced in diagnosis and monitoring of glioblastoma.

Humoral responses against HDL are linked to lipoprotein traits, atherosclerosis, inflammation and pathogenic pathways during early arthritis stages.

OBJECTIVE: Chronic inflammation and immune dysregulation are crucial mechanisms for atherosclerosis in RA. Recent evidence suggests a link via humoral responses against high-density lipoproteins (HDL). This study aimed to characterize the specificity, clinical relevance and emergence of humoral responses against HDL along disease course, especially during the earliest phases of arthritis. METHODS: IgG and IgM serum levels of antibodies against HDL (anti-HDL) and apolipoprotein A1 (anti-ApoA1) were measured in 82 early RA patients, 14 arthralgia individuals and 96 controls. Established RA patients (n = 42) were included for validation. Atherosclerosis and vascular stiffness were measured by Doppler ultrasound. Lipoprotein content, particle numbers and size were measured by H-NMR. Cytokines were measured by immunoassays. A cardiometabolic-related protein panel was evaluated using high-throughput targeted proteomics. RESULTS: Anti-HDL and anti-ApoA1 responses were increased in early RA compared with controls (both P < 0.001) and were comparable to established disease. Only anti-ApoA1 antibodies were increased in arthralgia. IgG anti-HDL and anti-ApoA1 were associated with unfavourable lipoprotein traits in RA and arthralgia, respectively. A similar picture was observed for inflammatory mediators. No associations with clinical features or risk factors were found. IgG anti-HDL were independently associated with atherosclerosis occurrence in early RA, and outperformed patient stratification over conventional algorithms (mSCORE) and their anti-ApoA1 counterparts. Anti-HDL antibodies correlated with proteins involved in immune activation, remodelling and lipid metabolism pathways in early RA. CONCLUSION: Humoral responses against HDL particles are an early event along the arthritis course, although quantitative and qualitative differences can be noticed among stages. These differences informed distinct capacities as biomarkers and underlying pathogenic circuits.

Impact of time of culture specimen collection on the recovery of Neisseria gonorrhoeae after a positive nucleic acid amplification test.

OBJECTIVES: Culture of Neisseria gonorrhoeae remains essential for antimicrobial resistance (AMR) surveillance. We evaluated the effect of time of specimen collection on culture yield following a positive nucleic acid amplification test (NAAT). METHODS: We retrospectively assessed N. gonorrhoeae culture yield among asymptomatic individuals (largely men who have sex with men) who attended for sexual health screening and had a positive NAAT. Participants underwent either same-day testing and notification (Drassanes Exprés) or standard screening with deferred testing. RESULTS: Among 10 423 screened individuals, 809 (7.7%) tested positive for N. gonorrhoeae. A total of 995 different anatomical sites of infection culture was performed in 583 of 995 (58.6%) of anatomical sites (Drassanes Exprés 278 of 347, 80.1%; standard screening 305 of 648, 47.1%; p<0.001). Recovery was highest when culture specimens were collected within 3-7 days of screening with only a slight drop in recovery when the interval extended to 7 days . Recovery from pharynx was 38 of 149 (25.5%) within 3 days, 19 of 81 (23.4%) after 4-7 days (p=0.7245), 11 of 102 (10.7%) after 8-14 days (p<0.0036) and 1 of 22 (4.5%) with longer delays (p=0.00287). Recovery from rectum was 49 of 75 (65.3%) within 3 days, 28 of 45 (62.2%) after 4-7 days (p=0.7318), 41 of 69 (59.4%) after 8-14 days (p=0.4651) and 6 of 18 (33.3%) with longer delays (p=0.0131). Median culture specimen collection time was 1 day within Drassanes Exprés vs 8 days within standard screening. Consequently, the overall culture yield was slightly higher within Drassanes Exprés (102/278, 36.6% vs 99/305, 32.5%; p=0.2934). CONCLUSION: Reducing the interval between screening and collection of culture specimens increased N. gonorrhoeae recovery in extragenital samples. Implementing a same-day testing and notification programme increased collection of culture samples and culture yield in our setting, which may help AMR surveillance.

Correction: Ten simple rules for organizing a bioinformatics training course in low- and middle-income countries.

[This corrects the article DOI: 10.1371/journal.pcbi.1009218.].

Knowledge and expectations about miRNAs as biomarkers in head and neck squamous cell cancers.

Head and neck squamous cell cancer patients suffer from a high postoperative recurrence rate and poor prognosis. Thus, it is essential to better understand the underlying molecular mechanisms and identify the role of new biomarkers. Recent research has shown that the dysregulation of microRNAs is a potential biomarker as a screening or prognostic tool. Moreover, the literature reveals its promising usefulness to select the best treatment strategy and monitor tumour response. The purpose of this review is to identify and synthesize the available literature on microRNAs as biomarkers that could help manage patients with head and neck squamous cell cancer. A search in scientific databases was completed, including all relevant articles related to circulating microRNAs in head and neck squamous cell cancer published in English or Spanish. We focused on articles whose main findings were related to their usefulness in diagnosis and prognosis. Conclusion: Knowledge of microRNAs opens the possibilities that these molecules offer in terms of monitoring cancer disease in a less-invasive, simple manner, allowing for serial sampling to assess the response to treatment and minimal residual disease. It is yet to be determined whether liquid biopsy will replace the traditional biopsy in the future but it represents a change in the paradigm of management of head and neck squamous cell cancer.

Repeatability and reliability of the footwear assessment tool in Spanish patients: A transcultural adaptation.

BACKGROUND: The footwear assessment tool was designed to advise an appropriate footwear for each situation and patient. Footwear alterations structures can influence in musculoskeletal disorders, developing foot ulcers, increase the peak plantar pressure, bacterial growth, low back pain. METHODS: To validate the study 101 subjects were recruited. The study was tested by two expert podiatrists using the tool for the assessment of footwear characteristics that is composed by five domains, fit, general features, general structure, motion control properties and cushioning system. Each domain analyzes different shoe items. RESULTS: An excellent agreement between the test-retest. A suitable Cronbach's α was suggested for the five domains of fit (α = 0.952), general features (α = 0.953), general structure (α = 0.947), motion control properties (α = 0.951), and cushioning system (α = 0.951). Test-retest reliability was excellent for all domains. There were no significant differences between any domain (p > 0.05). There was only statistically significant difference in the item forefoot height (p = 0.011). For all the domains items there were no statistically significant difference (p > 0.05). CONCLUSIONS: The tool for the assessment European footwear is a suitable repeatability and reliability footwear tool that can be used in Spanish language subjects.

Digital pathology with artificial intelligence analyses provides greater insights into treatment-induced fibrosis regression in NASH.

BACKGROUND & AIMS: Liver fibrosis is a key prognostic determinant for clinical outcomes in non-alcoholic steatohepatitis (NASH). Current scoring systems have limitations, especially in assessing fibrosis regression. Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence analyses provides standardized evaluation of NASH features, especially liver fibrosis and collagen fiber quantitation on a continuous scale. This approach was applied to gain in-depth understanding of fibrosis dynamics after treatment with tropifexor (TXR), a non-bile acid farnesoid X receptor agonist in patients participating in the FLIGHT-FXR study (NCT02855164). METHOD: Unstained sections from 198 liver biopsies (paired: baseline and end-of-treatment) from 99 patients with NASH (fibrosis stage F2 or F3) who received placebo (n = 34), TXR 140 µg (n = 37), or TXR 200 µg (n = 28) for 48 weeks were examined. Liver fibrosis (qFibrosis®), hepatic fat (qSteatosis®), and ballooned hepatocytes (qBallooning®) were quantitated using SHG/TPEF microscopy. Changes in septa morphology, collagen fiber parameters, and zonal distribution within liver lobules were also quantitatively assessed. RESULTS: Digital analyses revealed treatment-associated reductions in overall liver fibrosis (qFibrosis®), unlike conventional microscopy, as well as marked regression in perisinusoidal fibrosis in patients who had either F2 or F3 fibrosis at baseline. Concomitant zonal quantitation of fibrosis and steatosis revealed that patients with greater qSteatosis reduction also have the greatest reduction in perisinusoidal fibrosis. Regressive changes in septa morphology and reduction in septa parameters were observed almost exclusively in F3 patients, who were adjudged as 'unchanged' with conventional scoring. CONCLUSION: Fibrosis regression following hepatic fat reduction occurs initially in the perisinusoidal regions, around areas of steatosis reduction. Digital pathology provides new insights into treatment-induced fibrosis regression in NASH, which are not captured by current staging systems. LAY SUMMARY: The degree of liver fibrosis (tissue scarring) in non-alcoholic steatohepatitis (NASH) is the main predictor of negative clinical outcomes. Accurate assessment of the quantity and architecture of liver fibrosis is fundamental for patient enrolment in NASH clinical trials and for determining treatment efficacy. Using digital microscopy with artificial intelligence analyses, the present study demonstrates that this novel approach has greater sensitivity in demonstrating treatment-induced reversal of fibrosis in the liver than current systems. Furthermore, additional details are obtained regarding the pathogenesis of NASH disease and the effects of therapy.

Iridian anterior segment OCT in rubella uveitis syndrome and cytomegalovirus anterior uveitis: a comparative study.

PURPOSE: To compare iris affectation in cytomegalovirus anterior uveitis (CMVAU), rubella virus-associated uveitis (RVU), and healthy contralateral eyes, using swept-source anterior segment optical coherence tomography (SS-AS-OCT). MATERIALS AND METHODS: A comparative, transversal, retrospective study examining 60 eyes from 30 patients-18 eyes (17 patients) with CMVAU, 14 eyes (13 patients) with RVU, and 28 healthy eyes-was performed. Six-millimeter cross-sectional SS-AS-OCT B-scans were obtained in each iris quadrant. Images were exported to ImageJ®. Qualitative and quantitative analyses were done: stromal thickness (ST), smooth index (SI), and optical density (OD) of pigment epithelium. Comparisons between measurements and clinical-demographic parameters were performed using SPSS®. RESULTS: Qualitative analysis showed extensive damage in iris stroma but was unable to differentiate between both uveitis. RVU eyes had a lower mean ST (315.72 µm ± 42.4) compared to those with CMVAU (348.6 µm ± 46) (p = 0.047) and a lower ST in the upper (338.9 µm ± 38.52)/(386.25 µm ± 47.2) (p = 0.005) and temporal (281.5 µm ± 57.3)/(326.43 µm ± 62.3) (p = 0.016) quadrants. Mean (0.94 ± 0.02)/(0.9 ± 0.03) (p = 0.001), temporal (0.94 ± 0.02)/(0.89 ± 0.03) (p < 0.001), and nasal SI (0.094 ± 0.02)/(0.9 ± 0.04) (p = 0.005) were higher in RVU. OD was similar in both uveitis. In healthy eyes, mean ST (376.8 µm ± 39.7) was higher and mean SI was lower (0.87 ± 0.04) than in RVU (p < 0.001) and CMVAU eyes (p = 0.032). Mean OD was higher in healthy eyes (911 ± 130) than in CMVAU eyes (800 ± 200) (p = 0.037). CONCLUSIONS: The quantitative analysis of the SS-AS-OCT iris images allows for the differentiation between healthy eyes and those with CMVAU and RVU, as well as between both uveitis.

Spontaneous portosystemic shunt embolization in liver transplant recipients with recurrent hepatic encephalopathy.

INTRODUCTION AND OBJECTIVES: Spontaneous portosystemic shunts (SPSS) are a common cause of recurrent hepatic encephalopathy (HE). Shunt occlusion is an effective and safe procedure when performed in patients with cirrhosis and preserved liver function. We aimed to describe our experience with SPSS embolization after liver transplantation (LT). PATIENTS: We identified five patients who underwent SPSS embolization after LT. Clinical, biochemical and technical procedure data were collected. RESULTS: At presentation, all patients had developed graft cirrhosis and HE after LT. Median Model for End-stage Liver Disease (MELD) at embolization was 9 (range 7-12), median Child-Pugh was 8 (range 7-9). Splenorenal and mesocaval shunt were the most frequent types of SPSS found. Three patients have been completely free of HE. Of the two patients who had HE recurrence after embolization, one patient had two episodes of HE which was controlled well with medications. The other patient required three embolizations because of recurrent HE. Median follow-up was 4.4 years (range 1.0-5.0) and MELD score at last follow up was 13 (range 10-18) and median Child-Pugh score B, 7 points (range 5-12). CONCLUSIONS: SPSS can be considered as a cause of HE after LT. SPSS embolization is feasible and safe in LT recipients.

Influence on Depression, Anxiety, and Satisfaction of the Relatives' Visit to Intensive Care Units prior to Hospital Admission for Elective Cardiac Surgery: A Randomized Clinical Trial.

Background: Intensive care units (ICUs) may produce stress on the relatives of patients that have long-term physiological and psychological implications. Objectives: This study aimed to evaluate the effects of the relatives´ visit prior to hospital admission(s) on the patient's scheduled cardiac surgery regarding depression, anxiety, and satisfaction of the patient's family in an ICU. Methods: A randomized clinical trial [NCT03605420] was carried out according to the CONSORT criteria. Thirty-eight relatives of ICU patients were recruited at an ICU and randomized into study groups. Experimental group participants (n = 19) consisted of relatives who received 1 ICU visit prior to the patient's admission. Control group participants (n = 19) consisted of patients' relatives who received standard care alone. A self-report test battery, including the Impact of Event Scale-Revised (IES-R) and the Hospital Anxiety and Depression Scale (HADS), was completed by the patient's relative prior to the patient's ICU admission and again three and 90 days after ICU discharge. Furthermore, the Family Satisfaction with Care in the Intensive Care Unit (FS-ICU) and Critical Care Family Needs Inventory (CCFNI) were administered to help determine the respondents' satisfaction three days after the patient's ICU discharge. Results: Statistically significant differences in FS-ICU results were found between control and experimental groups; no statistically significant differences were found in IES-R, HADS, and CCFNI results. Thus, members in the control group were more satisfied with the time elapsed to raise their concerns (p=0.005), emotional support provided (p=0.020), quality of care (p=0.035), opportunities to express concerns and ask questions (p=0.005), and general satisfaction with the ICU's decision-making (p=0.003). Conclusions: Relatives' satisfaction during patients' ICU admission may be impaired after their prior visit to the hospital admission. Relative's anxiety and depression scores did not seem to be significantly affected. Relatives´ visit prior to elective cardiac surgery hospital admission impaired their satisfaction in an ICU and may not be advisable for healthcare practice.

Increasing radiation doses in Anastrepha obliqua (Diptera: Tephritidae) larvae improve parasitoid mass-rearing attributes.

Doses of 40, 80, 120, and 160 Gy were applied to 5-, 6-, 7-, and 8-day-old Anastrepha obliqua larvae, which were exposed to the Neotropical-native braconids Doryctobracon crawfordi and Utetes anastrephae and the Asian braconid Diachasmimorpha longicaudata. These tests were performed to know the effect of the increase in host radiation on the emergence of the aforementioned parasitoids and the related consequences of oviposition on the host. The study was based on the fact that higher radiation doses may cause a decrease in the host immune activity. There was a direct relationship between the increase in radiation dose and the parasitoid emergence. Both, the weight and the mortality of the host larvae were not affected by radiation. Although the larval weight of the larvae was lower and the mortality was higher in the younger larvae. Both, the number of scars and immature stages per host puparium originated from the younger larvae were lower than those from older larvae. Only U. anastrephae superparasitized more at lower radiation. Superparasitism by D. longicaudata was more frequent at 160 Gy. Qualitative measurements of melanin in the larvae parasitized showed that the levels were lower with increasing radiation. As radiation doses increased, the antagonistic response of the A. obliqua larva was reduced. Host larvae aged 5- and 6-day-old irradiated at 120-160 Gy significantly improve parasitoid emergence. This evidence is relevant for the mass production of the three tested parasitoid species.

Ketoconazole Reverses Imatinib Resistance in Human Chronic Myelogenous Leukemia K562 Cells.

Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the oncogene BCR-ABL1, which encodes an oncoprotein with tyrosine kinase activity. Imatinib, a BCR-ABL1 tyrosine kinase inhibitor, performs exceptionally well with minimal toxicity in CML chemotherapy. According to clinical trials, however, 20-30% of CML patients develop resistance to imatinib. Although the best studied resistance mechanisms are BCR-ABL1-dependent, P-glycoprotein (P-gp, a drug efflux transporter) may also contribute significantly. This study aimed to establish an imatinib-resistant human CML cell line, evaluate the role of P-gp in drug resistance, and assess the capacity of ketoconazole to reverse resistance by inhibiting P-gp. The following parameters were determined in both cell lines: cell viability (as the IC50) after exposure to imatinib and imatinib + ketoconazole, P-gp expression (by Western blot and immunofluorescence), the intracellular accumulation of a P-gp substrate (doxorubicin) by flow cytometry, and the percentage of apoptosis (by the Annexin method). In the highly resistant CML cell line obtained, P-gp was overexpressed, and the level of intracellular doxorubicin was low, representing high P-gp activity. Imatinib plus a non-toxic concentration of ketoconazole (10 µM) overcame drug resistance, inhibited P-gp overexpression and its efflux function, increased the intracellular accumulation of doxorubicin, and favored greater apoptosis of CML cells. P-gp contributes substantially to imatinib resistance in CML cells. Ketoconazole reversed CML cell resistance to imatinib by targeting P-gp-related pathways. The repurposing of ketoconazole for CML treatment will likely help patients resistant to imatinib.

Strategies for the Biofunctionalization of Straining Flow Spinning Regenerated Bombyx mori Fibers.

High-performance regenerated silkworm (Bombyx mori) silk fibers can be produced efficiently through the straining flow spinning (SFS) technique. In addition to an enhanced biocompatibility that results from the removal of contaminants during the processing of the material, regenerated silk fibers may be functionalized conveniently by using a range of different strategies. In this work, the possibility of implementing various functionalization techniques is explored, including the production of fluorescent fibers that may be tracked when implanted, the combination of the fibers with enzymes to yield fibers with catalytic properties, and the functionalization of the fibers with cell-adhesion motifs to modulate the adherence of different cell lineages to the material. When considered globally, all these techniques are a strong indication not only of the high versatility offered by the functionalization of regenerated fibers in terms of the different chemistries that can be employed, but also on the wide range of applications that can be covered with these functionalized fibers.

Effect of foot health and quality of life in patients with Parkinson disease: A prospective case-control investigation.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder, characterised by the presence of motor disturbances. Therefore, it can be related to musculoskeletal and orthopaedic problems, particularly in the foot status, that are linked to a negative effect on overall health, mobility and social function. OBJECTIVE: The aim was to analyse the impact of foot health and quality of life in patients with Parkinson's disease and people without Parkinson's disease, with normalised reference scores, in the light of the values recorded with regard to foot health status and overall health. MATERIAL AND METHODS: This is a prospective case-control investigation. A sample of Parkinson's patients (n = 62) including 24 men and 38 women was recruited, and foot HQoL was measured using the Foot Health Status Questionnaire Spanish (Sp_FHSQ). RESULTS: The PD group recorded lower levels of foot health quality of life (HQoL) with lower scores on the Sp_FHSQ in general foot health, general health, physical activity, social capacity and vigour sub-scales. Regarding the rest of the sub-scales of the Sp_FHSQ, foot pain showed higher values in the PD group. Differences between the cases and control groups were analysed by means of a Mann-Whitney U test, showing statistical significance (P < 0.05). CONCLUSIONS: PD presents an increased negative impact on foot health and quality of life which appears to be related to the chronic neurodegenerative disease.

Repeatability and reliability of the diabetic foot self-care questionnaire in Arabic patients: A transcultural adaptation.

PURPOSE: The diabetic foot self-care questionnaire is considered a self-care evaluation tool with 16 questions for assessing diabetic foot health disorders. To date, the DFSQ has been validated in different languages, but an Arabic version was lacking. Consequently, the purpose of this study was to translate and validate the Arabic version of the DFSQ (DFSQ-AR). METHOD: A suitable method was developed for the translation protocol and cross-cultural validation from Spanish to Arabic. Regarding the total marks from each sub-scale, agreement degrees and confidence were analyzed using Cronbach's α and intraclass correlation coefficient (ICC), respectively. In addition, the mean ± standard deviation differences between pre and post-tests were calculated and completed using Bland-Altman distribution plots. RESULTS: Excellent agreement between the two versions was demonstrated based on Cronbach's α. Three sub-scales consisting of knowledge of foot hygiene, the appropriate use of footwear and socks, and podiatric self-care were added together to obtain the total score. Excellent retest reliability was shown for the total score. Test/retest reliability was excellent for the self-care and shoe and socks sub-scales. There were no significant differences among any domains (p > 0.05). There were no statistically significant differences (P = 0.000) for the mean ± standard deviations (SD) between pre- and post-tests (98.09 ± 15.42) [93.75-102.43] and 97.96 ± 13.88 [94.5-101.86] points, respectively). Bland-Altman plots or clinically pertinent variations were not statistically significantly different. CONCLUSIONS: The DFSQ-AR is considered a strong and valid questionnaire with adequate repeatability in the Arabic language population.