High solid fed‐batch butanol fermentation with simultaneous product recovery: Part II—process integration

In these studies, liquid hot water (LHW) pretreated and enzymatically hydrolyzed Sweet Sorghum Bagasse (SSB) hydrolyzates were fermented in a fed‐batch reactor. As reported in the preceding paper, the culture was not able to ferment the hydrolyzate I in a batch process due to presence of high level of toxic chemicals, in particular acetic acid released from SSB during the hydrolytic process. To be able to ferment the hydrolyzate I obtained from 250 g L^?1 SSB hydrolysis, a fed‐batch reactor with in situ butanol recovery was devised. The process was started with the hydrolyzate II and when good cell growth and vigorous fermentation were observed, the hydrolyzate I was slowly fed to the reactor. In this manner the culture was able to ferment all the sugars present in both the hydrolyzates to acetone butanol ethanol (ABE). In a control batch reactor in which ABE was produced from glucose, ABE productivity and yield of 0.42 g L^?1 h^?1 and 0.36 were obtained, respectively. In the fed‐batch reactor fed with SSB hydrolyzates, these productivity and yield values were 0.44 g L^?1 h^?1 and 0.45, respectively. ABE yield in the integrated system was high due to utilization of acetic acid to convert to ABE. In summary we were able to utilize both the hydrolyzates obtained from LHW pretreated and enzymatically hydrolyzed SSB (250 g L^?1) and convert them to ABE. Complete fermentation was possible due to simultaneous recovery of ABE by vacuum. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:967–972, 2018     

Marital instability among British Pakistanis: transnationality,conjugalities and Islam

This article offers insights into the dynamics underlying an increase in marital instability in British Pakistani families, thus challenging stereotypes of British South Asian populations as representing ‘old-fashioned’ families, with their lower rates of divorce in contrast with the wider British population. In addition to problems of compatibility, domestic violence and infidelity, we explore dynamics that may be more specific to the British Pakistani population, namely the transnational nature of many marriages, attitudes to parental involvement in arranging marriages, and the place of Islam. We suggest that, while arranged marriages were conventionally seen as safer than love marriages, both young people and their parents may now be viewing arranged marriages as riskier. In an arranged marriage that brings family approval but not personal fulfilment, young people are increasingly supported to divorce and remarry, with a greater degree of personal say in spouse selection.     

Modulation of Testicular and Whole Blood Trace Element Concentrations in Conjunction with Testosterone Release Following Kisspeptin Administration in Male Rabbits (Oryctolagus cuniculus)

The present study investigated the role of kisspeptin-10 on reproductively significant trace elements in relation to testosterone release in male rabbits, Oryctolagus cuniculus. Groups of rabbits were exposed to single 1 μg kisspeptin dose (i.v., saphenous vein), while simultaneous groups were pretreated with a kisspeptin antagonist, peptide-234 (50 μg) 20 min before administering kisspeptin. Sequential blood sampling was done through marginal ear vein puncture at staggered time intervals: 0, 0.5, 1, 2, 4, and 24 h to determine serum testosterone. Testes and whole blood were collected at 4 and 24 h post dosage to determine trace element concentrations through atomic absorption spectrophotometry. In testes, zinc (Zn), manganese (Mn), and Fe concentrations showed significant increases at 24 h, while copper (Cu) concentration was found elevated at 4 and 24 h both (P?<?0.001). In whole blood, Zn and Cu concentrations were significantly elevated at 4 and 24 h, while Mn and cobalt (Co) concentrations showed increases only at 24 h (P?<?0.001). Blood iron concentration was not altered in the blood. In contrast, no change occurred in testicular Co, and chromium or nickel concentrations in either testes or blood. Compared to control and predose groups, serum testosterone levels increased gradually and peaked at 2 h (P?<?0.001) post kisspeptin treatment but declined thereafter. Pretreatment with antagonist abolished all increases in trace elements and testosterone concentrations. The present study provides first evidence that reproduction- and fertility-related peptide “kisspeptin” modulates testicular and blood trace elements and that this action is likely GPR54-dependent.     

Macrophage Migration Inhibitory Factor (MIF) and Thyroid Hormone Alterations in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (AAV)

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine known to be released from lymphocytes, macrophages and endothelial cells and also in animal models shown to be inducible with glucocorticoids (GC). In contrast, thyroxine seems to antagonize MIF activity. To investigate whether MIF is increased in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and possible correlations with GC dosing and thyroid hormone levels, 27 consecutive patients with active AAV were studied and followed prospectively. Disease activity was assessed using Birmingham Vasculitis Activity Score 2003 (BVAS) at baseline and at follow-up at 3 and 6 months, along with MIF, thyroid hormones free triiodothyronine (fT3) and free thyroxine (fT4), C-reactive protein (CRP) and creatinine. MIF was elevated significantly at baseline compared with follow-up at 3 and 6 months (8,618 pg/mL versus 5,696 and 6,212 respectively; P < 0.002) but did not correlate to CRP, GC dose, creatinine or organ involvement. fT3 was depressed significantly at baseline compared with follow-up (1.99 pg/mL versus 2.31 and 2.67 respectively; P = 0.01) and correlated inversely to the BVAS score at baseline. We found a significant correlation between the MIF/fT4 ratio at baseline versus MIF/fT4 ratio at 6 months (ρ = 0.52, P < 0.005) and a trend between the baseline MIF/fT3 ratio versus MIF/fT3 ratio at 6 months (ρ = 0.39, P = 0.05). These results suggest a possible role for MIF and thyroid status in AAV. Further studies could reveal whether the association between AAV and thyroid hormone levels in the context of elevated MIF may present a link as well as a target of treatment.     

Sabar: body politics among middle‐aged migrant Pakistani women

This article explores the relationship among suffering, Islamic moral concepts, subjectivity, and agency within a cohort of middle‐aged women who migrated from Pakistan to Britain in the 1960s and 1970s as the wives or daughters of industrial workers. These women were preoccupied with their ageing bodies and complained about the cumulative assaults on their health they had experienced, and which they felt had been neglected by health professionals and family alike. By examining how these women bear chronic illness through a discourse of sabar (patience or silent forbearance), I show how women were able to transform their illness into a selfless and virtuous consequence of shouldering the burdens of kinship. Sabar suggests passive acceptance or fatalism to some observers, but attending to how women situate their illness in a religious and eschatological frame, we see that they actively appropriate rather than passively imbibe the norm of sabar. Moreover, turning from narratives to everyday contexts of friendship, family, and inter‐generational relations, we see that there are tensions between self‐sublimation and self‐assertion in the practice of sabar. It is argued that ethnographic attention to subjectivity and reflexivity are crucial to understanding sabar as an agential capacity.     

Calibration of a burrow count index for the Indian desert jird, Meriones hurrianae

Population estimates, often difficult to acquire, warrantee the use of an index as an economical substitute for rapid assessments of populations. We estimated population size of the little known social, semi-fossorial Indian desert jird (Meriones hurrianae) in Kachchh, Gujarat, India under closed population capture-mark-recapture (CMR) framework to calibrate a burrow count index for the species. A total of 147 individuals were trapped in 16 colonies using baited Sherman traps and the number of burrow entrances at each colony was recorded. Data from colonies with low number of captures were pooled to estimate capture probability using Huggins heterogeneity models with gender, site, body weight and age category as covariates in Program MARK. Colony sizes ranged from 2 to 46 individuals. The number of burrow entrances was calibrated against CMR-based population estimates using least squares regression (n = 16, adjusted R ² = 0.96, t = 18.18, P < 0.001). The index was further validated using Jackknife (JK) analysis where JK-predicted population estimates strongly correlated with CMR estimates (r = 0.96, P < 0.001). In habitats and climatic conditions similar to Kachchh and within the range of colony sizes sampled, our calibrated index can be a valuable and effective tool for large scale surveys of the desert jird, which occupies a keystone trophic level in the semi-arid ecosystem.     

Translational Predictive Biomarker Analysis of the Phase 1b Sorafenib and Bevacizumab Study Expansion Cohort

Predictive biomarkers are needed to triage patients to the best therapy. We prospectively planned examination of sequential blood, biopsy, and functional imaging with which to confirm the mechanism and to identify potential predictive biomarkers in a phase Ib clinical trial expansion of patients with solid tumors receiving sorafenib/bevacizumab. The maximally tolerated doses of sorafenib at 200 mg twice daily with bevacizumab at 5 mg/kg every other week were given to biopsiable patients. Patients were randomized to receive either sorafenib or bevacizumab monotherapy for the first 28-day cycle with the second drug added with cycle 2. Biopsies, dynamic contrast-enhanced MRI, and fluorodeoxyglucose-proton emission tomography were done pre-therapy and at 2 and 6 weeks (2 weeks into combination therapy). Tumor and serum proteomics, Ras/Raf mutational analysis, and functional imaging results were examined individually and across the dataset to identify potential changes predictive of response to therapy and those that confirm the biochemical drug mechanism(s). Therapy with sorafenib/bevacizumab resulted in clinical benefit in 45% of this mixed solid tumor group. ERK activation and microvessel density were decreased with monotherapy treatment with sorafenib or bevacizumab, respectively; whereas a decreased signal over the group of total AKT, phospho(p)-VEGF receptor2, p-endothelial nitric-oxide synthase, b-RAF, and cleaved poly(ADP-ribose) polymerase was associated with earlier progression of disease. Tumor metabolic activity decreased in those patients with clinical benefits lasting longer than 4 months, and activity increased with progression of disease. Cleavage of caspase 3 and poly(ADP-ribose) polymerase was increased, and Ki67 expression decreased in patients with prolonged clinical benefits, consistent with decreased proliferation and increased apoptosis. The conglomerate analysis, incorporating pharmacodynamic and tumor biochemistry, demonstrated sorafenib/bevacizumab-targeted vascular activity in the tumor. Results suggest potential biomarkers for which changes, as a group, during early therapeutic exposure may predict clinical benefit.Sorafenib and bevacizumab have demonstrated clinical utility as single agents or in combination with chemotherapy for solid tumors. Sorafenib, initially developed as a c-Raf kinase inhibitor, also has potent inhibitory activity against the vascular endothelial growth factor receptor-2 (VEGFR2).¹ Clinical activity has been shown for bevacizumab, the humanized neutralizing monoclonal antibody against VEGF, also alone and in chemotherapy combinations (1–5). The role of combining two agents with overlapping target biology had not yet been studied.We tested the clinical hypothesis that signal interruption at collaborative pathway points, both vertical and horizontal interactions, may yield equal or greater effect than the agents in isolation in a phase I trial combining bevacizumab and sorafenib ({"type":"clinical-trial","attrs":{"text":"NCT00095459","term_id":"NCT00095459"}}NCT00095459), and we now report the translational analyses (6). Sorafenib was selected for its ability to target both receptor and cytosolic kinases important in a variety of activated cells in the tumor microenvironment, including stromal, endothelial, and malignant cells. Because such kinase inhibitor treatment has been shown to up-regulate production of proangiogenic cytokines, we added bevacizumab to reduce VEGF ligand availability and augment inhibition of endothelial cells. We observed the clinical benefit, including partial response and prolonged disease stabilization, using attenuated doses of the individual agents as determined by safety assessments during the trial; partial response or disease stabilization of at least 4 months occurred in 59% of the daily sorafenib cohort and in 55% of those on the intermittent, 5 of 7 days, sorafenib schedule (6, 7). These benefits lasted up to 37+ months with over 25% of patients receiving 12 or more months of therapy. The trial prospectively planned comprehensive translational assessment using a randomized drug addition design (Fig. 1A) to evaluate individual drug target specificity and combination drug effects to identify potential predictive biomarkers to examine in the ongoing phase II study of sorafenib/bevacizumab in ovarian cancer.Open in a separate windowFig. 1.Treatment schema (A) and Consort diagram (B).Predictive biomarkers are increasingly important for the advancement of targeted therapies. Such knowledge should allow more effective triage of patients to interventions more likely to provide clinical benefit. Biomarkers that predict drug response may consist of direct measures of activity, such as modulation of biochemical signals in the tumor (8) or those that yield pharmacodynamic measures, such as functional imaging (9, 10). Changes in metabolic activity and/or blood flow using dynamic imaging may fall into both categories with decreased glucose uptake due to reduced glucose delivery and/or reduced glucose metabolism and altered vascular permeability in response to attenuation of the VEGF drive. Aggregate analysis of these varied translational measures may yield a more detailed view of the cancer and the drug combination, allowing broader dissection into potential predictive biomarkers. Linking modulation of activity with clinical benefit is a first step in validating prospective biomarkers.We designed a novel drug administration schema from which to examine the contribution of both sorafenib and bevacizumab on the modulation of tumor and the tumor microenvironment behavior. The biochemical and imaging data demonstrate changes consistent with alteration of tumor vascularity, demonstrate direct association of target effect with clinical outcome across solid tumor types, and confirm the benefit of complementary pathway targeting. Reduction in blood flow, up-regulation of cytokine production, and inhibition of a set of anti-apoptotic anti-proliferative signaling events together may define potentially predictive changes to examine in early drug administration in subsequent trials.     

Risk of a Second Primary Cancer after Non-melanoma Skin Cancer in White Men and Women: A Prospective Cohort Study

Background

Previous studies suggest a positive association between history of non-melanoma skin cancer (NMSC) and risk of subsequent cancer at other sites. The purpose of this study is to prospectively examine the risk of primary cancer according to personal history of NMSC.

Methods and Findings

In two large US cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses'' Health Study (NHS), we prospectively investigated this association in self-identified white men and women. In the HPFS, we followed 46,237 men from June 1986 to June 2008 (833,496 person-years). In the NHS, we followed 107,339 women from June 1984 to June 2008 (2,116,178 person-years). We documented 29,447 incident cancer cases other than NMSC. Cox proportional hazard models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). A personal history of NMSC was significantly associated with a higher risk of other primary cancers excluding melanoma in men (RR = 1.11; 95% CI 1.05–1.18), and in women (RR = 1.20; 95% CI 1.15–1.25). Age-standardized absolute risk (AR) was 176 in men and 182 in women per 100,000 person-years. For individual cancer sites, after the Bonferroni correction for multiple comparisons (n = 28), in men, a personal history of NMSC was significantly associated with an increased risk of melanoma (RR = 1.99, AR = 116 per 100,000 person-years). In women, a personal history of NMSC was significantly associated with an increased risk of breast (RR = 1.19, AR = 87 per 100,000 person-years), lung (RR = 1.32, AR = 22 per 100,000 person-years), and melanoma (RR = 2.58, AR = 79 per 100,000 person-years).

Conclusion

This prospective study found a modestly increased risk of subsequent malignancies among individuals with a history of NMSC, specifically breast and lung cancer in women and melanoma in both men and women. Please see later in the article for the Editors'' Summary     

Microbial production of a biofuel (acetone–butanol–ethanol) in a continuous bioreactor: impact of bleed and simultaneous product removal

Acetone butanol ethanol (ABE) was produced in an integrated continuous one-stage fermentation and gas stripping product recovery system using Clostridium beijerinckii BA101 and fermentation gases (CO₂ and H₂). In this system, the bioreactor was fed with a concentrated sugar solution (250–500 g L^?1 glucose). The bioreactor was bled semi-continuously to avoid accumulation of inhibitory chemicals and products. The continuous system was operated for 504 h (21 days) after which the fermentation was intentionally terminated. The bioreactor produced 461.3 g ABE from 1,125.0 g total sugar in 1 L culture volume as compared to a control batch process in which 18.4 g ABE was produced from 47.3 g sugar. These results demonstrate that ABE fermentation can be operated in an integrated continuous one-stage fermentation and product recovery system for a long period of time, if butanol and other microbial metabolites in the bioreactor are kept below threshold of toxicity.