Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Generation of goats by nuclear transfer: a retrospective analysis of a commercial operation (1998-2010).

At LFB USA, Inc., the ultimate use for transgenic cloned goats is for the production of recombinant human protein therapeutics in their milk. This retrospective analysis of the Somatic Cell Nuclear Transfer (SCNT) program, spanning from 1998 to 2010, examined parameters potentially affecting the outcomes and efficiencies in this commercial operation. Over 37,000 + ova were utilized in the SCNT protocol producing a total of 203 cloned goats. Fifty one (51) clones were produced from non-transfected (transgenic and non-transgenic animal donor) cell lines and 152 clones were produced from transfected cell lines. Comparisons and summaries of (a) transfected versus non-transfected cell lines, (b) relationship of SCNT parameters to offspring produced, (c) skin versus fetal cells, (d) fresh versus cryopreserved cells, (e) parameters from all cell lines used versus those producing SCNT offspring, (f) variation among cell sources, (g) methods of SCNT parturition management and effects on live offspring, and lastly (h) SCNT variation by program are reported. Findings indicate that (a) non-transfected cell lines were more efficient versus transfected cell lines in generating viable cloned offspring on a per reconstructed embryo transferred basis, (b) transfected fetal fibroblasts had improved efficiency versus transfected skin fibroblasts, (c) the percentage of non-transfected cell lines that produced offspring was statistically higher than transfected cell lines, (d) and induction of parturition improved the percentage of viable offspring. In summary, this retrospective analysis on the SCNT process has identified certain parameters for improved efficiency in producing viable cloned goats in a commercial setting.

Childhood adversity and borderline personality disorder: a meta-analysis.

OBJECTIVE: The aim of this meta-analysis was to better understand the magnitude and consistency of the association between childhood adversity and borderline personality disorder (BPD) across case-control, epidemiological and prospective cohort studies. METHOD: Following the review protocol (reference: CRD42017075179), search terms pertaining to adversity and BPD were entered into three search engines. Random-effects meta-analysis synthesised the size and consistency of the effects. RESULTS: A total of 97 studies compared BPD to non-clinical (k = 40) and clinical (k = 70) controls. Meta-analysis of case-control studies indicated that individuals with BPD are 13.91 (95% CI 11.11-17.43) times more likely to report childhood adversity than non-clinical controls. This effect was smaller when considering retrospective cohort (OR: 2.59; 95% CI 0.93-7.30) and epidemiological (OR: 2.56, 95% CI 1.24-5.30) studies. Findings were significant across adversity subtypes with emotional abuse (OR: 38.11, 95% CI: 25.99-55.88) and neglect (OR: 17.73, 95% CI = 13.01-24.17) demonstrating the largest effects. Individuals with BPD were 3.15 (95% CI 2.62-3.79) times more likely to report childhood adversity than other psychiatric groups. CONCLUSIONS: This meta-analysis corroborates theoretical proposals that exposure to adverse life experiences is associated with BPD. It highlights the importance of considering childhood adversity when treating people diagnosed with BPD.

Do stroke patients screened as lower-nutritional-risk still receive dietitian assessment if indicated? A retrospective evaluation of two dietetic models of care for adult stroke patients.

BACKGROUND: Dietetic models of care at Logan Hospital changed from all patients with a confirmed stroke receiving dietitian assessment (Old pathway) to only those patients screened as high-nutritional-risk (Modified pathway). However, it was unknown whether all low-nutritional-risk patients who were indicated for dietitian assessment for nutrition support actually received assessment. This pre-post retrospective study evaluated whether the Old pathway and the Modified pathway were equally effective in identifying low-nutritional-risk stroke patients who were indicated for dietitian assessment and compared the time spent providing Dietetic care. METHODS: For both pathways, medical charts were reviewed for low-nutritional-risk patients admitted between December 2012 and November 2017 with a confirmed stroke, who were given a standard food and fluid diet code and scored MST < 2 (Malnutrition Screening Tool) on admission. Data collected included demographics, anthropometrics, malnutrition assessment, dietetic intervention and time spent caring for patients. Malnutrition-related clinical indicators were used to classify patients as either Dietitian Assessment for Nutrition Support Indicated or Not Indicated. RESULTS: Low-nutritional-risk patients were similar on the Old (n = 180) and Modified (n = 206) pathways [mean (SD) 66 (13) years, 63% male, 4% malnutrition]. Those classified as Dietitian Assessment for Nutrition Support Indicated (n = 61 of 180) were older, had a longer length of stay (P < 0.05), and were all identified by the Dietitian on both pathways. Ten minutes less dietetic time per patient was required on the Modified pathway (P < 0.001). CONCLUSIONS: The Modified Nutrition Stroke pathway performed more efficiently than the Old pathway and was equally effective at ensuring that stroke patients who were determined as being low-nutritional-risk received dietitian assessment during admission if indicated.

Generation of transgenic goats by pronuclear microinjection: a retrospective analysis of a commercial operation (1995-2012).

Production of transgenic founder goats involves introducing and stably integrating an engineered piece of DNA into the genome of the animal. At LFB USA, the ultimate use of these transgenic goats is for the production of recombinant human protein therapeutics in the milk of these dairy animals. The transgene or construct typically links a milk protein specific promoter sequence, the coding sequence for the gene of interest, and the necessary downstream regulatory sequences thereby directing expression of the recombinant protein in the milk during the lactation period. Over the time period indicated (1995-2012), pronuclear microinjection was used in a number of programs to insert transgenes into 18,120, 1- or 2- cell stage fertilized embryos. These embryos were transferred into 4180 synchronized recipient females with 1934 (47%) recipients becoming pregnant, 2594 offspring generated, and a 109 (4.2%) of those offspring determined to be transgenic. Even with new and improving genome editing tools now available, pronuclear microinjection is still the predominant and proven technology used in this commercial setting supporting regulatory filings and market authorizations when producing founder transgenic animals with large transgenes (> 10 kb) such as those necessary for directing monoclonal antibody production in milk.

A percutaneous needle biopsy technique for sampling the supraclavicular brown adipose tissue depot of humans.

Brown adipose tissue (BAT) has been proposed as a potential target tissue against obesity and its related metabolic complications. Although the molecular and functional characteristics of BAT have been intensively studied in rodents, only a few studies have used human BAT specimens due to the difficulty of sampling human BAT deposits. We established a novel positron emission tomography and computed tomography-guided Bergström needle biopsy technique to acquire human BAT specimens from the supraclavicular area in human subjects. Forty-three biopsies were performed on 23 participants. The procedure was tolerated well by the majority of participants. No major complications were noted. Numbness (9.6%) and hematoma (2.3%) were the two minor complications noted, which fully resolved. Thus, the proposed biopsy technique can be considered safe with only minimal risk of adverse events. Adoption of the proposed method is expected to increase the sampling of the supraclavicular BAT depot for research purposes so as to augment the scientific knowledge of the biology of human BAT.

Understanding breakage in curly hair.

BACKGROUND: In 2005, the L'Oréal Institute for hair and skin research carried out a multiethnic study to investigate hair breakage in women residing in the U.S.A. In this study it was reported that a large percentage (96%) of the African-American respondents experience breakage. A combination of structural differences and grooming-induced stresses seem to contribute to the higher breakage incidence in the African-American group as the chemical composition of African-American hair is not significantly different from other ethnic groups. Some authors have proposed that the repeated elongation, torsion and flexion actions may affect the components of the hair fibre. However, considering the different properties of cuticle and cortex, one would expect a different wearing mechanism of each, leading to the ultimate failure of hair. Knowing in detail how each part of the structure fails can potentially lead to better ways to protect the hair from physical insults. OBJECTIVE: To investigate crack propagation and fracture mechanisms in African-American hair. METHODS: Virgin hair of excellent quality was collected, with informed consent, from a female African-American volunteer. A series of controlled mechanical stresses was applied to 10-mm hair sections using a high-resolution mechanical stage (20 mN) up to the fracture of the fibre. The surface was monitored using scanning electron microscopy imaging during the stress application. X-ray tomographic microscopy images were acquired and quantified to detect changes in energy absorption as a function of applied stress that could be linked to increase in crack density. RESULTS: Analysis of the mechanical response of hair combined with the two imaging techniques led us to propose the following mechanism of hair breakage: cuticle sliding; failure of the cuticle-cortex interface; nucleation of intercellular cracks and growth of cracks at the cuticle-cortex junction; and propagation of intercellular cracks towards the surface of the hair and final breakage when these cracks merge at the cuticular junction. CONCLUSIONS: The combination of scanning electron microscopy and X-ray tomography provided new information about the fracture of hair. Mechanical damage from grooming and some environmental factors accumulate in hair creating internal cracks that eventually result in breakage at unpredictable sites and therefore a continuous care regimen for the hair throughout the life cycle of the fibres is recommended.

Apparatus for the room temperature measurement of low field Nernst and magneto-Seebeck coefficients.

Nernst coefficient measurements are a classic approach to investigate charge carrier scattering in both metals and semiconductors. However, such measurements are not commonly performed, despite the potential to inform material design strategies in applications such as thermoelectricity. As dedicated instruments are extremely scarce, we present here a room temperature apparatus to measure the low field Nernst coefficient (and magneto-Seebeck coefficient) in bulk polycrystalline samples. This apparatus is specifically designed to promote accurate and facile use, with the expectation that such an instrument will make Nernst measurements de rigueur. In this apparatus, sample loading and electrical contacts are all pressure-based and alignment is automatic. Extremely stable thermal control (10 mK of fluctuation when ΔT = 1 K) is achieved from actively cooled thermoelectric modules that operate as heaters or Peltier coolers. Magneto-Seebeck measurements are integrated into the system to correct for residual probe offsets. Data from the apparatus are provided on bulk polycrystalline samples of bismuth, InSb, and SnTe, including raw data to illustrate the process of calculating the Nernst coefficient. Finally, we review how Nernst measurements, in concert with Seebeck, Hall, and electrical resistivity, can be analyzed via the Boltzmann equation in the relaxation time approximation to self-consistently predict the Fermi level, effective mass, and energy-dependent relaxation time.

Primary abandonment of the sac in the management of scrotal hernias: a dual-institution experience of short-term outcomes.

PURPOSE: Management of scrotal hernias presents as a common challenge, with operative interventions to address these hernias associated with higher rates of morbidity compared to those of less-complex pathology. Surgeons have advocated for the use of techniques such as primary abandonment of the distal sac as a potential means to reduce complications for operative intervention, with preliminary findings demonstrating feasibility. We sought to assess outcomes related to primary sac abandonment among patients undergoing minimally invasive (MIS) repair of scrotal hernias. METHODS: A review of prospectively maintained databases among two academic hernia centers was conducted to identify patients who underwent MIS inguinal hernia repairs with primary sac abandonment. Patient demographics, hernia risk factors, intraoperative factors, and postoperative outcomes were evaluated. Short-term outcomes related to patient-reported experiences and surgical-site occurrences requiring procedural intervention were queried. RESULTS: Sixty-seven male patients [median age: 51.6 years; interquartile range (IQR): 45-65 years] underwent inguinal hernia repair with primary sac abandonment. Anatomic polypropylene mesh was used in 98.5% cases. Rates of postoperative complications were low and included postoperative urinary retention (6%), clinically identified or patient-reported seromas/hematomas within a 30-day follow-up period (23.9%), deep venous thrombosis (1.5%), and pelvic hematoma (1.5%). No seromas or hematomas necessitated procedural interventions, with resolution of symptoms within three months of their operation date. CONCLUSION: We report a multi-center experience of patients managed with primary abandonment of the sac technique during repair of inguinoscrotal hernias. Utilization of this technique appears to be safe and reproducible with a low burden of short-term complications.

The Shigella human challenge model.

Shigella is an important bacterial cause of infectious diarrhoea globally. The Shigella human challenge model has been used since 1946 for a variety of objectives including understanding disease pathogenesis, human immune responses and allowing for an early assessment of vaccine efficacy. A systematic review of the literature regarding experimental shigellosis in human subjects was conducted. Summative estimates were calculated by strain and dose. While a total of 19 studies evaluating nine strains at doses ranging from 10 to 1 × 1010 colony-forming units were identified, most studies utilized the S. sonnei strain 53G and the S. flexneri strain 2457T. Inoculum solution and pre-inoculation buffering has varied over time although diarrhoea attack rates do not appear to increase above 75-80%, and dysentery rates remain fairly constant, highlighting the need for additional dose-ranging studies. Expansion of the model to include additional strains from different serotypes will elucidate serotype and strain-specific outcome variability.

Patient perspectives on nipple-areola complex micropigmentation during the COVID-19 pandemic.

BACKGROUND: Micropigmentation is a well-recognised option for nipple-areola complex reconstruction, as part of the breast reconstruction pathway for patients following mastectomy. As a part of delayed breast reconstruction, this treatment was put on hold during the COVID-19 pandemic. AIMS: To assess the views of patients regarding micropigmentation in response to the COVID-19 pandemic, and whether their attitudes to seeking out this part of the reconstructive journey had been altered. METHODS: A questionnaire undertaken with 53 patients between August & September 2020 attending the Micropigmentation clinic. FINDINGS: 81.1% of patients reported COVID-19 had not impacted their decision, with a similar proportion happy to proceed with the treatment at the time of questioning. CONCLUSIONS: The results highlight the importance of nipple-areola complex to our patients' reconstructive journey.

Caught in the act: in vivo development of macrolide resistance to Campylobacter jejuni infection.

We report the first instance of macrolide resistance developing in vivo following appropriate antibiotic use in a healthy volunteer as a part of a controlled human infection with Campylobacter jejuni. In vivo development of macrolide resistance may be an important contributor to antibiotic resistance in C. jejuni.

Synthesis of a new element with atomic number Z = 117.

The discovery of a new chemical element with atomic number Z=117 is reported. The isotopes (293)117 and (294)117 were produced in fusion reactions between (48)Ca and (249)Bk. Decay chains involving 11 new nuclei were identified by means of the Dubna gas-filled recoil separator. The measured decay properties show a strong rise of stability for heavier isotopes with Z > or = 111, validating the concept of the long sought island of enhanced stability for superheavy nuclei.

Polyamine biosynthesis impacts cellular folate requirements necessary to maintain S-adenosylmethionine and nucleotide pools.

Folate (vitamin B9) is utilized for synthesis of both S-adenosylmethionine (AdoMet) and deoxythymidine monophosphate (dTMP), which are required for methylation reactions and DNA synthesis, respectively. Folate depletion leads to an imbalance in both AdoMet and nucleotide pools, causing epigenetic and genetic damage capable of initiating tumorigenesis. Polyamine biosynthesis also utilizes AdoMet, but polyamine pools are not reduced under a regimen of folate depletion. We hypothesized that high polyamine biosynthesis, due to the high demand on AdoMet pools, might be a factor in determining sensitivity to folate depletion. We found a significant correlation (P<0.001) between polyamine biosynthesis and the amount of folate required to sustain cell line proliferation. We manipulated polyamine biosynthesis by genetic and pharmacological intervention and mechanistically demonstrated that we could thereby alter AdoMet pools and increase or decrease demand on folate availability needed to sustain cellular proliferation. Furthermore, growing a panel of cell lines with 100 nM folate led to imbalanced nucleotide and AdoMet pools only in cells with endogenously high polyamine biosynthesis. These data demonstrate that polyamine biosynthesis is a critical factor in determining sensitivity to folate depletion and may be particularly important in the prostate, where biosynthesis of polyamines is characteristically high due to its secretory function.

Oral delivery of Hyperimmune bovine serum antibodies against CS6-expressing enterotoxigenic Escherichia coli as a prophylactic against diarrhea.

BACKGROUND: . Oral administration of bovine antibodies active against enterotoxigenic Escherichia coli (ETEC) have demonstrated safety and efficacy against diarrhea in human challenge trials. The efficacy of bovine serum immunoglobulins (BSIgG) against recombinant colonization factor CS6 or whole cell ETEC strain B7A was assessed against challenge with the CS6-expressing B7A. METHODS: . This was a randomized, double-blind, placebo-controlled trial in which healthy adults received oral hyperimmune BSIgG anti-CS6, anti-B7A whole cell killed or non-hyperimmune BSIgG (placebo) in a 1:1:1 ratio then challenged with ETEC B7A. Two days pre-challenge, volunteers began a thrice daily, seven day course of immunoprophylaxis. On day 3, subjects received 1 × 1010 CFUs of B7A. Subjects were observed for safety and the primary endpoint of moderate-severe diarrhea (MSD). RESULTS: . A total of 59 volunteers received product and underwent ETEC challenge. The BSIgG products were well-tolerated across all subjects. Upon challenge, 14/20 (70%) placebo recipients developed MSD, compared to 12/19 (63%; p = .74) receiving anti-CS6 BSIgG and 7/20 (35%; p = .06) receiving anti-B7A BSIgG. Immune responses to the ETEC infection were modest across all groups. CONCLUSIONS: . Bovine-derived serum antibodies appear safe and well tolerated. Antibodies derived from cattle immunized with whole cell B7A provided 50% protection against MSD following B7A challenge; however, no protection was observed in subjects receiving serum antibodies targeting CS6. The lack of observed efficacy in this group may be due to low CS6 surface expression on B7A, the high dose challenge inoculum and/or the use of serum derived antibodies versus colostrum-derived antibodies.

Microvascular free tissue transfer for gene delivery: in vivo evaluation of different routes of plasmid and adenoviral delivery.

Transfer of healthy autologous tissue as a microvascular free flap facilitates reconstruction during ablative cancer surgery. In addition to filling surgical defects, free flaps might concentrate viral vectors at the tumour bed and mediate local therapeutic effects. We evaluated the magnitude, topography and duration of luciferase gene expression after plasmid and adenoviral delivery in rat superficial inferior epigastric (SIE) flaps. For plasmid delivery, luciferase expression was significantly increased by all transduction routes (topical, intraflap injection, intravascular) (P<0.01) at day 1, but not at day 7. The spread of luciferase expression was significantly different between the 4 groups at 1 day (P=0.026) and was greatest for flaps transduced by intravascular injection. For adenoviral transduction, total radiance was significantly different between the transduced groups at 1, 14 and 28 days (P<0.05 for all comparisons). The highest levels of radiance were seen in the intravascular group. There was a statistically significant difference in the spread of light emission between the 3 groups at 1 (P=0.009) and 14 (P=0.013) days, but this was no longer evident at 28 days. Intravascular adenoviral delivery yields high-level, diffuse and durable gene expression in rat SIE flaps and is suitable for examination in therapeutic models.

Typing of Campylobacter jejuni isolates from dogs by use of multilocus sequence typing and pulsed-field gel electrophoresis.

Campylobacter is a major cause of human gastroenteritis worldwide. Risk of Campylobacter infection in humans has been associated with many sources, including dogs. This study aimed to investigate whether C. jejuni carried by dogs could potentially be a zoonotic risk for humans and if there were common sources of C. jejuni infection for both humans and dogs. Multilocus sequence typing (MLST) together with macrorestriction analysis of genomic DNA using SmaI and pulsed-field gel electrophoresis (PFGE) were both used to analyze 33 C. jejuni isolates obtained from various dog populations, including those visiting veterinary practices and from different types of kennels. MLST data suggested that there was a large amount of genetic diversity between dog isolates and that the majority of sequence types found in isolates from these dogs were the same as those found in isolates from humans. The main exception was ST-2772, which was isolated from four samples and could not be assigned to a clonal complex. The most commonly identified clonal complex was ST-45 (11 isolates), followed by ST-21 (4 isolates), ST-508 (4 isolates), and ST-403 (3 isolates). The profiles obtained by macrorestriction PFGE were largely in concordance with the MLST results, with a similar amount of genetic diversity found. The diversity of sequence types found within dogs suggests they are exposed to various sources of C. jejuni infection. The similarity of these sequence types to C. jejuni isolates from humans suggests there may be common sources of infection for both dogs and humans. Although only a small number of household dogs may carry C. jejuni, infected dogs should still be considered a potential zoonotic risk to humans, particularly if the dogs originate from kennelled or hunt kennel dog populations, where the prevalence may be higher.

Spermidine requirement for cell proliferation in eukaryotic cells: structural specificity and quantitation.

Six structural homologs of spermidine and five of its precursor, putrescine, were studied for their ability to prevent cytostasis of cultured L1210 leukemia cells induced by alpha-difluoromethylornithine (DFMO), a specific inhibitor of putrescine biosynthesis. High-performance liquid chromatography and competition studies with spermidine indicated that the homologs, which vary in the length of the carbon chain separating the amines, penetrated the cells. The structural specificity of the spermidine carrier was defined. Three of the six spermidine homologs supported cell growth during a 48-hour incubation in the presence of DFMO, indicating that a two-carbon extension of spermidine structure was tolerated for biological function. Two of the five putrescine homologs supported growth after being converted by the cells to their respective spermidine homologs. The central nitrogen of spermidine appears to be essential for function since diamines of chain length comparable to that of spermidine did not prevent DFMO cytostasis. No more than 15 percent of the spermidine normally present in L1210 cells was required for cell proliferation in the presence of DFMO.