SARS-CoV-2 Virus in Cancer Patients: A New Unknown in an Unsolved Equation.

INTRODUCTION: Cancer patients are more susceptible to infections, and infection can be more severe than in patients without cancer diagnosis. We conducted this retrospective study in patients admitted for SARS-CoV-2 infection in order to find differences in inflammatory markers and mortality in cancer patients compared to others. METHODS: We reviewed the electronic records of patients admitted for SARS-CoV-2 infection confirmed by PCR from March to September 2020. Data on socio-demographics, comorbidities, inflammatory makers, and cancer-related features were analyzed. RESULTS: 2,772 patients were admitted for SARS-CoV-2, to the Hospital Universitario Ramón y Cajal in Madrid during this period. Of these, 2,527 (91%) had no history of neoplastic disease, 164 (5.9%) patients had a prior history of cancer but were not undergoing oncological treatment at the time of infection, and 81 (2.9%) were in active treatment. Mortality in patients without a history of cancer was 19.5%, 28.6% for patients with a prior history of cancer, and 34% in patients with active cancer treatment. Patients in active oncology treatment with the highest mortality rate were those diagnosed with lung cancer (OR 5.6 95% CI: 2.2-14.1). In the multivariate study, active oncological treatment (OR 2.259 95% CI: 1.35-3.77) and chemotherapy treatment (OR 3.624 95% CI: 1.17-11.17), were statistically significant factors for the risk of death for the whole group and for the group with active oncological treatment, respectively. CONCLUSION: Cancer patients on active systemic treatment have an increased risk of mortality after SARS-CoV-2 infection, especially with lung cancer or chemotherapy treatment.

Correlation Between Endoglin and Malignant Phenotype in Human Melanoma Cells: Analysis of hsa-mir-214 and hsa-mir-370 in Cells and Their Extracellular Vesicles.

Endoglin (CD105) is an auxiliary receptor of transforming growth factor (TGF)-ß family members that is expressed in human melanomas. It is heterogeneously expressed by primary and metastatic melanoma cells, and endoglin targeting as a therapeutic strategy for melanoma tumors is currently been explored. However, its involvement in tumor development and malignancy is not fully understood. Here, we find that endoglin expression correlates with malignancy of primary melanomas and cultured melanoma cell lines. Next, we have analyzed the effect of ectopic endoglin expression on two miRNAs (hsa-mir-214 and hsa-mir-370), both involved in melanoma tumor progression and endoglin regulation. We show that compared with control cells, overexpression of endoglin in the WM-164 melanoma cell line induces; (i) a significant increase of hsa-mir-214 levels in small extracellular vesicles (EVs) as well as an increased trend in cells; and (ii) significantly lower levels of hsa-mir-370 in the EVs fractions, whereas no significant differences were found in cells. As hsa-mir-214 and hsa-mir-370 are not just involved in melanoma tumor progression, but they can also target endoglin-expressing endothelial cells in the tumor vasculature, these results suggest a complex and differential regulatory mechanism involving the intracellular and extracellular signaling of hsa-mir-214 and hsa-mir-370 in melanoma development and progression.

Evolution of the internet gender gaps in Spain and effects of the Covid-19 pandemic.

There is a widely accepted belief in new technologies that the digital divide in using a service will disappear as the service reaches an advanced level of maturity. The work presented here shows that this idea is debatable. Data from Spain, a country where daily internet users are 75.9 percent of the population, prove that the gender gap still exists. The paper explores if this gap can be entirely explained by the socioeconomic differences between men and women. We build a micro panel model and incorporate a set of socioeconomic variables (age, education, income, employment status, digital skills, and resident population) that allow us to isolate the effects of gender on the decision to become a daily Internet user. The results conclude that the Internet gap is a phenomenon with a specific gender component. Other things being equal a woman negatively affects the probability of using the Internet. Applying a similar model to 15 Internet services, we obtain that gender is always significant to explain the likelihood of being a user of each service. However, in some services (7 out of 15), the effect is favorable to women, and for other services (8), the gender effect favors men. The work concludes by analyzing the impact of the first wave of the Covid-19 pandemic on the use of Internet services, paying particular attention to its possible implications for the gender gap.

Endoglin in the Spotlight to Treat Cancer.

A spotlight has been shone on endoglin in recent years due to that fact of its potential to serve as both a reliable disease biomarker and a therapeutic target. Indeed, endoglin has now been assigned many roles in both physiological and pathological processes. From a molecular point of view, endoglin mainly acts as a co-receptor in the canonical TGFß pathway, but also it may be shed and released from the membrane, giving rise to the soluble form, which also plays important roles in cell signaling. In cancer, in particular, endoglin may contribute to either an oncogenic or a non-oncogenic phenotype depending on the cell context. The fact that endoglin is expressed by neoplastic and non-neoplastic cells within the tumor microenvironment suggests new possibilities for targeted therapies. Here, we aimed to review and discuss the many roles played by endoglin in different tumor types, as well as the strong evidence provided by pre-clinical and clinical studies that supports the therapeutic targeting of endoglin as a novel clinical strategy.

Serological and molecular study of Hepatitis E virus in pediatric patients in Mexico.

INTRODUCTION AND OBJECTIVES: Cases of viral hepatitis reported in Mexico are typically identified as hepatitis A, B and C. However, unspecified cases are reported annually. Hepatitis E virus (HEV) is an emergent agent that causes a self-limiting infection that can evolve to chronic in immunosuppressed individuals. In Mexico, HEV genotype 2 is considered endemic, though it's the prevalence is not well known. Therefore, the present study was designed to determine the prevalence of HEV among patients at the "Hospital Infantil de Mexico Federico Gomez". MATERIALS AND METHODS: The study included 99 patients, anti-HEV antibody (IgG and IgM) were detected by indirect ELISA and viral genome was identified using RT-PCR technique. Two PCR products of positive cases were sequenced. RESULTS: ELISA results were positive in 3% and 6%, for IgG and IgM respectively, 54.5% prevalence was found by PCR. Low lymphocyte count (p<0.05) and malnutrition (p<0.005) were significant factors for high PCR prevalence and could increase the possibility of infection. Two samples were sequenced and confirmed the presence of HEV genotype 3. CONCLUSIONS: This report reveals the incidence of HEV in pediatric patients in Mexico. Moreover, the identification of HEV genotype 3 in human samples suggests a potential zoonotic risk that requires further research.

Digit ratio (2D : 4D) and prosocial behaviour in economic games: no direct correlation with generosity, bargaining or trust-related behaviours.

Prenatal exposure to sex hormones exerts organizational effects on the brain which have observable behavioural correlates in adult life. There are reasons to expect that social behaviours-fundamental for the evolutionary success of humans-might be related to biological factors such as prenatal sex hormone exposure. Nevertheless, the existing literature is inconclusive as to whether and how prenatal exposure to testosterone and oestrogen, proxied by the second-to-fourth digit ratio (2D : 4D), may predict non-selfish behaviour. Here, we investigate this question using economic experiments with real monetary stakes and analyse five different dimensions of social behaviour in a comparatively large sample of Caucasian participants (n = 560). For both males and females, our results show no robust association between right- or left-hand 2D : 4D and generosity, bargaining or trust-related behaviours. Moreover, no differences in behaviour were found according to sex. We conclude that there is no direct correlation between 2D : 4D and these social behaviours.

Behavioral Health Risk Factors: the Interaction of Personal and Country Effects.

PURPOSE: This study investigated the relationship between the individual's self-assessed health status (SAHS) and health-risk factors (smoking, alcohol consumption and obesity), in 16 European countries. The associations were studied for the individual and for the country measures-and in particular, for the unexplored aspect of interaction between individual and country levels of the three risk factors. METHOD: Data for 47,114 adults, who participated in the Survey of Health Aging and Retirement Europe (SHARE), were analyzed using Multilevel Regression Analysis. The individual data were complemented by OECD data that provided country-specific risk measures: percentage of daily smokers, annual per-capita consumption of alcohol (liters), and percentage of obese individuals. RESULTS: We found that the individual's SAHS is negatively associated with smoking and with weight-risk factors and is positively associated with her/his alcohol consumption. The most pronounced associations relate to the weight variables, albeit they are attenuated in countries with higher percentages of obese individuals. Significant differences across countries were evidenced in the association between SAHS and smoking and between SAHS and alcohol consumption. CONCLUSION: Individual health levels are associated with individual risk factors and also with the behaviors in the country. Significant interactions might indicate that psychological factors are at work.

Towards chiral distributions of dopants in microporous frameworks: helicoidal supramolecular arrangement of (1R,2S)-ephedrine and transfer of chirality.

A molecular-mechanics computational study is performed in order to analyze the arrangement of (1R,2S)-(-)-ephedrine molecules within the 12-MR channels of the AFI aluminophosphate microporous framework and the influence on the spatial distribution of dopants embedded in the tetrahedral network. Results showed that ephedrine molecules arrange exclusively as dimers by π-π stacking of the aromatic rings within the AFI channels. Interestingly, the asymmetric nature of ephedrine and the presence of H-bond-forming groups (NH2 and OH) involve a preferential orientation where consecutive dimers within the channels are rotated by an angle of +30°; this is driven by the establishment of inter-dimer H-bonds. This preferential orientation leads to the development of a supramolecular enantiomerically-pure helicoidal (chiral) arrangement of ephedrine dimers. In addition, the computational results demonstrate that the particular molecular structure of ephedrine imparts a strong trend to attract negative charges to the vicinity of the NH2(+) positively-charged groups. Hence divalent dopants such as Mg, whose replacement by trivalent Al in the aluminophosphate network involves the generation of a negative charge, will tend to locate close to the NH2(+) molecular groups, suggesting that an imprinting of the organic arrangement to the spatial distribution of dopants would be feasible. Combined with the trend of ephedrine to arrange in a helicoidal fashion, an enantiomerically-pure helicoidal distribution of dopants would be expected, thus inducing a new type of chirality in microporous materials.

Therapeutic Exercise Parameters, Considerations and Recommendations for the Treatment of Non-Specific Low Back Pain: International DELPHI Study.

BACKGROUND: Therapeutic exercise (TE) recommendations for non-specific low back pain (LBP) are meant to support therapy choices for people who suffer from this condition. The aim of this study was to reach an agreement on the definition and use of TE in the care of people with LBP. METHODS: A Delphi study was carried out with a formal consensus procedure and sufficient scientific evidence, using an established methodology. Four rounds of anonymous questionnaires were administered to create useful suggestions and instructions in terms of the therapeutic activity for patients with LBP, and a group consensus conference. RESULTS: A consensus was reached on most of the questions after 35 physiotherapists completed the questionnaires. Participants agreed that proper TE requires correct posture, body awareness, breathing, movement control, and instruction. Patients with LBP were advised to participate in supervised sessions twice a week for 30 to 60 min for a period of 3 to 6 months. Participants added that tailored evaluation and exercise prescription, monitoring, and functional integration of exercise, as well as using specific equipment, would benefit patients with LBP. CONCLUSIONS: TE recommendations for patients with LBP should be dosed and customized based on their personal psychological needs, level of fitness, and kinesiophobia.

Differentiating people who use cannabis heavily through latent class analysis.

BACKGROUND: People who use cannabis daily or near-daily vary considerably in their daily dosage and use frequency, impacting both experienced effects and adverse consequences. This study identified heavy cannabis user groups according to consumption patterns and factors associated with class membership. METHODS: We conducted a cross-sectional study of 380 Spanish residents (61.8% male; average age = 30.3 years) who had used cannabis ≥ 3 days/week throughout the past year. Participants were recruited through chain referral and cannabis social clubs. We applied latent class analysis (LCA) to cluster participants according to use intensity. LCA indicators included frequency of weekly cannabis use, joints smoked each day, cannabis dosage, and if cannabis was consumed throughout the day or only at specific times. Associations between class membership and socio-demographics, use patterns, motives, supply sources, adverse outcomes, and use of other substances were measured using ANOVA and chi-squared tests. Multinomial regression identified the factors associated with latent class membership. RESULTS: Three latent classes (moderately heavy: 21.8%, heavy: 68.2%, very heavy: 10%) had average weekly cannabis intakes of 2.4, 5.5, and 18.3 g, respectively. Very heavy users were older ([Formula: see text]=17.77, p < 0.01), less educated [Formula: see text]=36.80, p < 0.001), and had used cannabis for longer (F = 4.62, p = 0.01). CAST scores (F = 26.51, p < 0.001) increased across the classes. The prevalence of past-month alcohol use was lower among the heaviest users ([Formula: see text]=5.95, p = 0.05). Cannabis was usually obtained from a club by very heavy users ([Formula: see text]=20.95, p < 0.001). CONCLUSIONS: People who use cannabis heavily present three groups according to frequency and quantity of cannabis consumption. Use intensity is associated with increased cannabis-related problems. Differences among heavy users must be considered in harm reduction interventions in cannabis clubs and indicated prevention.

Interobserver Variability in Contouring Hepatocellular Carcinoma at a Tertiary Center.

BACKGROUND/AIM: The optimal imaging test for delineation of the gross tumor volume (GTV) in hepatocellular carcinoma has not been defined. The hypothesis is that magnetic resonance imaging (MRI) allows for better visualization of the extent of tumor and will optimize the accuracy of tumor delineation for liver stereotactic radiotherapy compared with computed tomography (CT) only. We evaluated the interobserver agreement in GTV of hepatocellular carcinoma in a multicenter panel and compared MRI and CT in GTV delineation. MATERIALS AND METHODS: After the institutional review boards approved the study, we analyzed anonymous CT and MRI obtained from five patients with hepatocellular carcinoma. Eight radiation oncologists at our center used CT and MRI to delineate five GTVs of liver tumors. In both CT and MRI, the GTV volumes were compared. RESULTS: The median GTV volume on MRI was 2.4 cm3 (range=0.59-15.6 cm3) compared to 3.5 cm3 (range=0.52-24.9 cm3) on CT (p=0.36). The GTV volume as defined on MRI was larger or at least as large as the GTV volume on CT in two cases. Variance and standard deviation between observers in CT and MRI were minor (6 vs. 7.87 cm3, and 2.5 vs. 2.8 cm3 respectively). CONCLUSION: In cases with well-defined tumors, CT is easier and reproducible. In cases with no defined tumor in CT, other tools are needed and MRI can be complementary. The interobserver variability in target delineation of hepatocellular carcinoma in this study is noteworthy.

Endoglin, a Novel Biomarker and Therapeutical Target to Prevent Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGFß coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. EXPERIMENTAL DESIGN: ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis, were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. RESULTS: ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma-circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis. CONCLUSIONS: Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.

Use of crude extract of lentil plant (Lens culinaris Medikus) in peroxidase-based analyses: fast kinetic determination of hydrogen peroxide and sarcosine in urine.

Peroxidase-catalysed reactions are used in a wide variety of analytical applications, most of them based on the final quantification of hydrogen peroxide. Clinical tests for glucose, cholesterol, creatine, creatinine or uric acid in blood or urine and enzyme-linked immunosorbent assays for pesticides, hepatitis or acquired immune deficiency syndrome are good examples of such applications. The most widely used and commercially available peroxidase for biotechnological processes and analytical applications is horseradish peroxidase followed, although in much lower proportion, by soybean peroxidase. The high commercial interest in peroxidases has led to the search for new sources of these enzymes. This work describes the analytical use of lentil plant peroxidase (LPP), which is a new peroxidase extracted from lentil plants (Lens culinaris Medikus); an abundant post-harvest agricultural waste in the area of Castilla y León (Spain). A procedure for the quantification of hydrogen peroxide in urine is first proposed using crude extract of lentil plant instead of the purified enzyme. This procedure is then applied to the determination of sarcosine; a natural amino acid that has attracted considerable interest in clinical diagnostics since urinary sarcosine was proposed and later questioned as a biomarker for prostate cancer. Under the action of sarcosine oxidase, sarcosine is oxidized by molecular oxygen to give glycine, formaldehyde and hydrogen peroxide that is quantified according to the previously proposed procedure. The limit of detection for both hydrogen peroxide and sarcosine is around 5 × 10(-7) M. In the determination of sarcosine, the high selectivity of the overall enzymatic reaction, the simple sample treatment and instrumentation, the high-sample throughput and the use of LPP in the plant extract instead of the purified enzyme provide a rapid and inexpensive procedure with characteristics very suitable for routine analysis in a clinical laboratory.

The Need for New Treatments Targeting MPNST: The Potential of Strategies Combining MEK Inhibitors with Antiangiogenic Agents.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas that represent an important clinical challenge, particularly given their strong tendency to relapse and metastasize and their relatively poor response to conventional therapies. To date, targeted, noncytotoxic treatments have demonstrated limited clinical success with MPNSTs, highlighting the need to explore other key pathways to find novel, improved therapeutic approaches. Here, we review evidence supporting the crucial role of the RAS/MEK/ERK pathway and angiogenesis in MPNST pathogenesis, and we focus on the potential of therapies targeting these pathways to treat this disease. We also present works suggesting that the combination of MEK inhibitors and antiangiogenic agents could represent a promising therapeutic strategy to manage MPNSTs. In support of this notion, we discuss the preclinical rational and clinical benefits of this combination therapy in other solid tumor types. Finally, we describe other emerging therapeutic approaches that could improve patient outcomes in MPNSTs, such as immune-based therapies.

Interobserver variability in gross tumor volume contouring in non-spine bone metastases.

Background and Aim: The optimal imaging test for gross tumor volume (GTV) delineation in non-spine bone metastases has not been defined. The use of stereotactic body radiotherapy (SBRT) requires accurate target delineation. Magnetic resonance imaging (MRI) and/or 18fludesoxyglucose positron emission tomography (18FDG-PET) allow for better visualization of the extent of bone metastases and optimizes the accuracy of tumor delineation for stereotactic radiotherapy compared to computed tomography (CT) alone. We evaluated the interobserver agreement in GTV of non-spine bone metastases in a single center and compared MRI and/or 18FDG-PET and CT in GTV delineation. Methods: Anonymous CT and MRI and/or 18FDG-PET obtained from 10 non-spine bone metastases were analyzed by six radiation oncologists at our center. Images acquired by CT and MRI and/or 18FDG-PET were used to delineate 10 GTVs of non-spine bone metastases in the pelvis, extremities, and skull. The cases showed different characteristics: blastic and lytic metastases, and different primary cancers (lung, breast, prostate, rectum, urothelial, and biliary). In both CT and MRI and/or 18FDG-PET, the GTV volumes were compared. The index of agreement was evaluated according to Landis and Koch protocol. Results: The GTV volume as defined on MRI was in all cases larger or at least as large as the GTV volume on CT (P=0.25). The median GTV volume on MRI was 3.15 cc (0.027-70.64 cc) compared to 2.8 cc on CT (0.075-77.95 cc). Interobserver variance and standard deviation were lower in CT than MRI (576.3 vs. 722.2 and 24.0 vs. 26.9, respectively). The level of agreement was fair (kappa=0.36) between CT and MRI. The median GTV volume on 18FDG-PET in five patients was 5.8 cc (0.46-64.17 cc), compared to 4.1 cc on CT (0.99-54.2 cc) (P=0.236). Interobserver variance and standard deviation in CT, MRI, and 18FDG-PET were 576.3 versus 722.2 versus 730.5 and 24 versus 26.9 versus 27.0, respectively. The level of agreement was slight (kappa=0.08) between CT and 18FDG-PET. Conclusions: Interobserver variance in non-spine bone metastases was equal when MRI and PET were compared to CT. CT was associated with the lowest variance and standard deviation. Compared to CT GTVs, the GTVs rendered from MRI images had fair agreement, while the GTVs rendered from 18FDG-PET had only slight agreement. Relevance for Patients: The delimitation of the treatment volume in non-spine bone metastases with SBRT is important for the results determining its efficacy. It is therefore essential to know the variability and to manage it to achieve the highest quality of treatment.

Management of massive pulmonary embolism using recombinant activated Factor VII.

Massive pulmonary embolism with concomitant intracranial haemorrhage is a condition associated with high mortality. Emergency embolectomy is indicated in those cases in which medical treatment is not possible. The case of a 65-year-old woman with massive pulmonary embolism after cranial trauma with intracranial haemorrhage and two cardiac arrests prior to surgery is described. The patient suffered a right ventricular failure requiring 6h of extracorporeal circulation. After surgery a bleeding disorder happened despite conventional treatment. The patient was transferred to the ICU with packing. Despite the recent thrombotic event recombinant activated Factor VII (70 microg/kg) was used and the bleeding controlled. No other complications occurred and she was discharged 1 month later. As far as we know this is the first time that recombinant activated Factor VII has been used after a massive pulmonary embolism.

Results of a hydroxyapatite-coated modular femoral stem in primary total hip arthroplasty. A minimum 5-year follow-up.

The use of a modular metaphyseal-diaphyseal femoral stem in primary total hip arthroplasty is infrequent. We analyze 94 ESOP (Fournitures Hospitalieres, Heimsbrunn, France) cementless 2-piece modular stems after a minimum 5 years of follow-up. There were 2 aseptic femoral stem loosenings and no cases with thigh pain. Mean femoral canal filling was 90%. Radiographic ingrowth was obtained in 83 (P < .001). At 7 years, the survival rate for femoral aseptic loosening was 97.8% and no stem was at risk for revision (95% confidence interval, 94.8%-100%). This prosthesis provides good clinical results with absence of pain and excellent radiographic results. It is an option in femora with good bone quality. Femoral osteopenia and cortical widening were infrequent, and the modular metaphyseal-diaphyseal junction was not a problem in vivo.

A "healthy immigrant effect" or a "sick immigrant effect"? Selection and policies matter.

Previous literature on a variety of countries has documented a "healthy immigrant effect" (HIE). Accordingly, immigrants arriving in the host country are, on average, healthier than comparable natives. However, their health status dissipates with additional years in the country. HIE is explained through the positive self-selection of healthy immigrants as well as the positive selection, screening and discrimination applied by host countries. In this article we study the health trajectories of immigrants within the context of selection and migration policies. Using SHARE data we examine the HIE, comparing Israel and 16 European countries that have fundamentally different migration policies. Israel has virtually unrestricted open gates for Jewish people around the world, who in turn have ideological rather than economic considerations to move. European countries have selective policies with regards to the health, education and wealth of migrants, who also self-select themselves. Our results provide evidence that (1) immigrants who move to Israel have compromised health and are significantly less healthy than comparable natives. Their health disadvantage persists for up to 20 years of living in Israel, after which they become similar to natives; (2) immigrants who move to Europe have significantly better health than comparable natives. Their health advantage remains positive for many years. Even though during some time lapses they are not significantly different from natives, their health status never becomes worse than that of natives. Our results are important for migration policy and relevant for domestic health policy.

Gastrointestinal complications induced by sevelamer crystals.

BACKGROUND: Sevelamer is a phosphate binder widely used in chronic kidney disease (CKD) patients. Sevelamer, as well as other resin-based binders, can crystallize leading to the formation of concretions. Sevelamer crystals (SC) have been associated with gastrointestinal (GI) mucosal injury. We describe three new cases of GI lesions associated with SC and review previously reported cases. METHODS: We describe three new cases of GI lesions associated with SC and review previously reported cases. RESULTS: We found 16 previously reported cases of SC-induced GI lesions. The mean patient age was 61 years (interquartile range 51.5-71.75), 62.5% were females and 10 patients were diabetic. In 13 cases, SC was found inside the GI mucosa. Six patients had history of major abdominal surgery. GI bleeding was the most common clinical symptom (n = 7), with three patients presenting with acute abdomen requiring surgical intervention. Although, SC-induced lesions were observed in all GI segments, intestine was involved in 81% of the cases. Endoscopic examination revealed mainly erosions and ulcerations (n = 7) and pseudoinflammatory polyps (n = 5). No association between sevelamer doses and the severity of GI lesions was found. However, diabetics patients seemed to develop GI lesions with smaller doses of sevelamer as compared with non-diabetic patients, in spite of their fewer GI comorbidities. CONCLUSIONS: SC-induced GI lesions should be considered in CKD patients treated with sevelamer who present GI symptoms, especially lower GI bleeding, once other causes have been ruled out. Diabetics seem more prone to develop SC- associated GI lesions. Sevelamer therapy should be avoided if possible in patients with a history of major abdominal surgery or chronic constipation, because of the high risk of serious GI complications.

HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells.

Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is overexpressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor-negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel, or carboplatin by suppressing apoptosis and upregulating NF-κB Overexpressed HOXC10 increases S-phase-specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double-strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin-dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer. Cancer Res; 76(15); 4443-56. ©2016 AACR.