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Conclusion. Treatment of anaemia with recombinant human erythropoietin beta (rHuEpo) in patients with squamous cell carcinoma of the head and neck (HNSCC) undergoing curative radiotherapy does not improve cancer control. In fact, incompletely resected patients with HNSCC receiving radiation in combination with rHuEpo showed poorer loco-regional progression-free survival than patients receiving radiation in combination with placebo. It could be hypothesized that the effects of rHuEpo on tumour cell growth might only be manifested in vivo and after cell trauma, and that treating anaemia with rHuEpo might contribute to poor outcome after incomplete surgical resection. Objective. The aim of the present study was to examine the effect of rHuEpo alone and in combination with surgical trauma on the growth of human squamous cell carcinoma in vivo, xenografted onto nude mice. Materials and methods. The surgical trauma was inflicted through subcutaneous transection of the tumour with a needle. Immunohistochemical staining verified expression of the EPO receptor in tumour cells. Results. rHuEpo alone had no effect on the growth of xenografted HNSCC. However, a significant increase in tumour growth was observed after surgical trauma in combination with rHuEpo compared with surgery alone (p = 0.0008). [ABSTRACT FROM AUTHOR]

Abstract Background Mononuclear platinum anticancer agents hold a pivotal place in the treatment of many forms of cancers, however, there is a potential to improve response to evade resistance development and toxic side effects. BBR3464 is a promising trinuclear platinum anticancer agent, which is a polyamine mimic. The aim was to investigate the influence of polyamine pool reduction on the cytotoxic effects of the trinuclear platinum complex BBR3464 and cisplatin. Polyamine pool reduction was achieved by treating cells with either the polyamine biosynthesis inhibitor α-difluoromethylornithine (DFMO) or the polyamine analogue N1,N11-diethylnorspermine (DENSPM). Methods A human squamous cell carcinoma cell line, LU-HNSCC-4, established from a primary head and neck tumour was used to evaluate cellular effects of each drug alone or combinations thereof. High-performance liquid-chromatography was used to quantify intracellular polyamine contents. Inductively coupled mass spectroscopy was used to quantify intracellular platinum uptake. Cells were exposed to DFMO or DENSPM during 48 h at concentrations ranging from 0 to 5 mM or 0 to 10 μM, respectively. Thereafter, non-treated and treated cells were exposed to cisplatin or BBR3464 during 1 h at concentrations ranging from 0 to 100 μM. A 96-well assay was used to determine cytotoxicity after five days after treatment. Results The cytotoxic effect of BBR3464 on LU-HNSCC-4 cells was increased after cells were pre-treated with DENSPM or DFMO, and the interaction was found to be synergistic. In contrast, the interaction between cisplatin and DFMO or DENSPM was near-additive to antagonistic. The intracellular levels of the polyamines putrescine and spermidine were decreased after treatment with DFMO, and treatment with DENSPM resulted in an increase in putrescine level and concomitant decrease in spermidine and spermine levels. The uptake of BBR3464 was significantly increased after pre-treatment of the cells with DFMO, and varied dependent on the concentration of DENSPM. The uptake of cisplatin was unchanged. Conclusions Taken together, these results demonstrate that combinations of polyamine synthesis inhibitors with BBR3464 appear to be a promising approach to enhance the anticancer activity against HSCC.

Background: Cyanobacteria are emerging as green cell factories for sustainable biofuel and chemical production, due to their photosynthetic ability to use solar energy, carbon dioxide and water in a direct process. The model cyanobacterial strain Synechocystis sp. PCC 6803 has been engineered for the isobutanol and 3-methyl-1-butanol production by introducing a synthetic 2-keto acid pathway. However, the achieved productions still remained low. In the present study, diverse metabolic engineering strategies were implemented in Synechocystis sp. PCC 6803 for further enhanced photosynthetic isobutanol and 3-methyl-1-butanol production., Results: Long-term cultivation was performed on two selected strains resulting in maximum cumulative isobutanol and 3-methyl-1-butanol titers of 1247 mg L -1 and 389 mg L -1 , on day 58 and day 48, respectively. Novel Synechocystis strain integrated with a native 2-keto acid pathway was generated and showed a production of 98 mg isobutanol L -1 in short-term screening experiments. Enhanced isobutanol and 3-methyl-1-butanol production was observed when increasing the kivd S286T copy number from three to four. Isobutanol and 3-methyl-1-butanol production was effectively improved when overexpressing selected genes of the central carbon metabolism. Identified genes are potential metabolic engineering targets to further enhance productivity of pyruvate-derived bioproducts in cyanobacteria., Conclusions: Enhanced isobutanol and 3-methyl-1-butanol production was successfully achieved in Synechocystis sp. PCC 6803 strains through diverse metabolic engineering strategies. The maximum cumulative isobutanol and 3-methyl-1-butanol titers, 1247 mg L -1 and 389 mg L -1 , respectively, represent the current highest value reported. The significantly enhanced isobutanol and 3-methyl-1-butanol production in this study further pave the way for an industrial application of photosynthetic cyanobacteria-based biofuel and chemical synthesis from CO 2 ., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Postpartum haemorrhage is a leading cause of maternal death worldwide. Oxytocin, currently the drug of choice for prevention of PPH, requires constant refrigeration. In pursuit of an alternative medicine, Ferring Pharmaceuticals have developed a heat-stable formulation of carbetocin, an oxytocin analogue. This study aimed to define that formulation, and to investigate its stability under ICH climate zone IV conditions (30°C/75% relative humidity) for at least 3 years and at extreme temperatures, such as 60°C, for shorter periods of time. The development resulted in a heat-stable carbetocin formulation consisting of 0.1 mg/mL carbetocin in sodium succinate buffer, mannitol, and methionine. The optimum pH was determined to be pH 5.45 (5.25-5.65). The generated stability data of this formulation show that ≥95% purity of the peptide was maintained for a minimum of 3 years at 30°C, 6 months at 40°C, 3 months at 50°C and 1 month at 60°C. In addition, the heat-stable carbetocin formulation was not sensitive to freezing or light. The reported highly stable peptide formulation facilitates the distribution in low and middle-income countries, where maintaining cold chain distribution is difficult. Ferring Pharmaceuticals, the World Health Organization, and MSD for Mothers have established a collaboration to develop this heat-stable formulation of carbetocin for the prevention of post-partum hemorrhage in women after vaginal childbirth, with the aim of making the medicine available in the public sector of developing countries that have a high burden of maternal mortality., (© 2018 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)

This study explores the relative contribution of parental and teacher support to adolescents' psychosomatic health complaints, with a particular focus on gender and age differences. Based on a survey of 49,172 ninth- and eleventh-grade students in Stockholm (2006-2014), structural equation modeling results demonstrated negative associations between parental and teacher support on psychosomatic health complaints. Parental support had a stronger association with the outcome among girls than boys. It was also more important than teacher support for psychosomatic health complaints. Parental support was more important for younger girls' health compared to older girls, with opposite patterns for teacher support. These findings highlight the need to consider gender and age to understand the links between social support and health during adolescence., (© 2016 The Authors Journal of Research on Adolescence published by Wiley Periodicals, Inc. on behalf of Society for Research on Adolescence.)

Preclinical studies have indicated that there is only partial cross-resistance between cisplatin and oxaliplatin. The molecular background for this is incompletely known. To investigate the differences in resistance, we rendered a colon cancer cell line (S1) resistant against cisplatin and oxaliplatin and characterized the subclones with regard to cross-resistance, platinum uptake, and gene expression profiles. Four oxaliplatin and four cisplatin-resistant cell lines were produced from S1 by step-wise increasing the concentrations of the drugs in the growth medium. Cytotoxicity was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and platinum accumulation in cell lysates and DNA preparations by inductively coupled plasma mass spectroscopy. Gene expression was investigated by cDNA microarrays. The protein expression of the ATP-binding cassette B1 (ABCB1) was measured by immunohistochemistry. The cisplatin-resistant cell lines were 1.5-6.2-fold resistant against cisplatin and the oxaliplatin-resistant sublines 2.6-17-fold resistant against oxaliplatin. There was a limited degree of cross-resistance. Oxaliplatin resistance could be explained to a larger degree by reduced drug accumulation whereas mechanisms for increased tolerance against platinum incorporation in DNA seemed to be of higher importance for resistance against cisplatin. A greater number of ABC transporters were upregulated in the oxaliplatin-resistant cell lines compared with those selected for cisplatin resistance. ABCB1 was highly overexpressed in the three most oxaliplatin-resistant sublines, but significantly underexpressed in the two most cisplatin-resistant cell lines. This was also confirmed by immunohistochemistry. However, functional tests did not show any increase in ABCB1 transport activity in the oxaliplatin-resistant sub-lines compared with S1.

Conclusion: Treatment of anaemia with recombinant human erythropoietin beta (rHuEpo) in patients with squamous cell carcinoma of the head and neck (HNSCC) undergoing curative radiotherapy does not improve cancer control. In fact, incompletely resected patients with HNSCC receiving radiation in combination with rHuEpo showed poorer loco-regional progression-free survival than patients receiving radiation in combination with placebo. It could be hypothesized that the effects of rHuEpo on tumour cell growth might only be manifested in vivo and after cell trauma, and that treating anaemia with rHuEpo might contribute to poor outcome after incomplete surgical resection., Objective: The aim of the present study was to examine the effect of rHuEpo alone and in combination with surgical trauma on the growth of human squamous cell carcinoma in vivo, xenografted onto nude mice., Materials and Methods: The surgical trauma was inflicted through subcutaneous transection of the tumour with a needle. Immunohistochemical staining verified expression of the EPO receptor in tumour cells., Results: rHuEpo alone had no effect on the growth of xenografted HNSCC. However, a significant increase in tumour growth was observed after surgical trauma in combination with rHuEpo compared with surgery alone (p = 0.0008).

The current study was designed to compare the radiosensitizing effects of oxaliplatin and 5-fluorouracil (5FU) in a human colon cancer cell line. A human colon cancer cell line (S1) was treated with various doses of oxaliplatin, 5FU, radiation, and combinations thereof. Various clinically used schedules were mimicked. 5FU was either incubated during 1 h ("bolus") or 24 h ("continuous infusion"). When combining oxaliplatin and 5FU, an isobologram analysis revealed synergistic effects, regardless of 5FU schedule. The IC(10) and IC(50)-doses for the drugs where then combined with radiotherapy. With equitoxic drug doses (IC(50)), radiosensitization was observed in the following order: oxaliplatin > 5FU 24 h > 5FU 1 h exposure. The degree of potentiation corresponded to approximately 0.8 Gy, 0.7 Gy, and 0.2 Gy, respectively. In this experimental setting, oxaliplatin seemed to be a better radiosensitizer than 5FU, and longer incubation time with 5FU was better than short exposure.

Reactions of cis-[PtCl(NH(3))(CyNH(2))(OH(2))](+) (Cy=cyclohexyl) with thione-containing single-stranded oligonucleotides d(T(8)XT(8)) and d(XT(16)) (X=(s6)I or (s4)U) and the mononucleotides 4-thiouridine ((s4)UMP) and 6-mercaptoinosine ((s6)IMP) have been studied in aqueous solution at pH 4.1. The reaction kinetics was followed using HPLC methodology as a function of ionic strength in the interval 5.0 mM

Reactions of cis-[Pt(NH(3))(NH(2)C(6)H(11))Cl(OH(2))](+) with d(Tp(S)T) and d(T(n)()p(S)T(16)(-)(n)()), n = 1, 4, 8, 12, and 15, were investigated by use of HPLC in an aqueous medium with pH 4.1 +/- 0.1 and sodium and magnesium ion concentrations varying between 1.5 mM and 0.50 M. Platination of the oligonucleotide fragments is favored over platination of d(Tp(S)T) in the whole salt concentration interval studied. The maximum rate enhancement after incorporation of the p(S)-site into the polymeric DNA environment is observed for d(T(8)p(S)T(8)), which reacts up to ca. 500 times faster than d(Tp(S)T), after suitable changes of the cation concentrations in the reaction medium. The platination rates of the oligonucleotide fragments d(T(n)()p(S)T(16)(-)(n)()) decrease with increasing salt concentration. For a given phosphorothioate position, the rate also decreases when the cations in the medium are changed from Na(+) or K(+) to Mg(2+), even at constant ionic strength. The reactions with embedded p(S)-sites in d(T(n)()p(S)T(16)(-)(n)()), n = 4, 8, and 12, were found to be kinetically favored over reactions with the 5'- and 3'-end positions. In a reaction medium containing monovalent cations there is a strong preference for platination of d(T(8)p(S)T(8)), whereas d(T(4)p(S)T(12)) and d(T(12)p(S)T(4)) show intermediate reactivity compared with fragments with n = 1 and 15. In contrast, no kinetic discrimination is found between the p(S)-sites in d(T(n)()p(S)T(16)(-)(n)()), n = 4, 8, and 12, in the presence of Mg(2+). The results are interpreted in terms of a general mechanism where preaccumulation of the cationic Pt(II) complex on the oligomers is required for product formation. The kinetics are consistent with a reaction model that includes release of cations from the DNA surface during the adduct formation process.