Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME‐ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene‐based and pathway‐based analyses by applying the summary‐based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME‐ON and PLCO, after Bonferroni correction (p_pathway < 0.00625). The two most significant genes were NPAS2 (p_gene = 0.0062) and AANAT (p_gene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME‐ON (p_pathway = 0.021); this association was not confirmed in GECCO (p_pathway = 0.76) or the combined data (p_pathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.     

Update Breast Cancer 2022 Part 4 – Advanced-Stage Breast Cancer

For the treatment of patients with advanced HER2-negative hormone receptor-positive breast cancer, several substances have been introduced into practice in recent years. In addition, other drugs are under development. A number of studies have been published over the past year which have shown either an advantage for progression-free survival or for overall survival. This review summarizes the latest results, which have been published at current congresses or in specialist journals, and classifies them in the clinical treatment context. In particular, the importance of therapy with CDK4/6 inhibitors – trastuzumab deruxtecan, sacituzumab govitecan and capivasertib – is discussed. For trastuzumab deruxtecan, an overall survival benefit in HER2-negative breast cancer with low HER2 expression (HER2-low expression) was reported in the Destiny-Breast-04 study. Similarly, there was an overall survival benefit in the FAKTION study with capivasertib. The lack of overall survival benefit for palbociclib in the first line of therapy raises the question of clinical classification.Key words: advanced breast cancer, chemotherapy, endocrine therapy, antibody drug conjugates     

Data mining for signals in spontaneous reporting databases: proceed with caution

PURPOSE: To provide commentary and points of caution to consider before incorporating data mining as a routine component of any Pharmacovigilance program, and to stimulate further research aimed at better defining the predictive value of these new tools as well as their incremental value as an adjunct to traditional methods of post-marketing surveillance. METHODS/RESULTS: Commentary includes review of current data mining methodologies employed and their limitations, caveats to consider in the use of spontaneous reporting databases and caution against over-confidence in the results of data mining. CONCLUSIONS: Future research should focus on more clearly delineating the limitations of the various quantitative approaches as well as the incremental value that they bring to traditional methods of pharmacovigilance.     

Phentolamine blocks presynaptic serotonin autoreceptors in rabbit and rat brain cortex

Summary Possible antagonist effects of phentolamine at presynaptic serotonin autoreceptors were studied in slices of the occipito-parietal cortices of the rabbit and the rat. The slices were preincubated with ³H-serotonin and then superfused and stimulated electrically with single pulses or pulse trains. Nitroquipazine 1 mol/l, a compound that inhibits the high affinity neuronal uptake of serotonin, was present in the superfusion medium in all one pulse-experiments as well as in experiments in which the effect of unlabelled serotonin was examined.In rabbit cortical slices, unlabelled serotonin reduced the single pulse-evoked overflow of tritium. Its concentrationresponse curve was not changed by the selective ₂-adrenoceptor antagonist idazoxan 1 mol/l but was shifted to the right by phentolamine 1 and 10 mol/l. Phentolamine 10 mol/l also shifted to the right the concentration-inhibition curve of the selective 5-HT₁-receptor agonist 5-carboxamidotryptamine. When the slices were stimulated by trains of 30 pulses at 3 Hz, phentolamine 1 and 10 mol/l but not 0.1 mol/l increased the evoked overflow of tritium, the maximal increase amounting to 178%; its effect was enhanced in the presence of nitroquipazine 1 mol/l plus idazoxan 10 mol/l (a drug combination that, when given alone, slightly increased the evoked overflow of tritium). The serotonin receptor antagonist metitepin at concentrations of 0.01–1 mol/l also increased the overflow of tritium elicited by 30 pulses/3 Hz, the maximal increase amounting to 280%; its effect was potentiated in the presence of nitroquipazine 1 mol/l plus idazoxan 10 mol/l but was abolished or almost abolished in the presence of nitroquipazine 1 mol/l plus phentolamine 10 mol/l (a drug combination that, given alone, greatly increased the evoked overflow of tritium). When slices were stimulated by trains of 360 pulses at 3 Hz, there was no apparent antagonism of phentolamine 10 mol/l against the inhibitory effect of unlabelled serotonin. In rat brain cortex slices, unlabelled serotonin reduced the overflow of tritium elicited by 4 pulses delivered at 100 Hz. Again, phentolamine 10 mol/l shifted the concentration-response curve to the right.It is concluded that phentolamine blocks presynaptic serotonin autoreceptors in rabbit and rat brain cortex with pA₂ values of 6.44 and 5.95, respectively. Previous failures to detect the antagonistic effect against exogenous agonists were probably due to stimulation conditions that led to marked endogenous autoinhibition of serotonin release. At least the major part of the increase by phentolamine of the release of serotonin is due to autoreceptor blockade rather than blockade of the presynaptic a2-adrenoceptors at the cortical serotoninergic axons.Send offprint requests to N. Limberger at the above address     

Update Breast Cancer 2022 Part 5 – Early Stage Breast Cancer

The treatment of patients with early stage breast cancer has changed in recent years due to the introduction of pembrolizumab, olaparib, and abemaciclib. These and other drugs with the same class of active ingredient are currently in trial for various indications. This review article summarizes the latest results that have either been presented at major conferences such as the ESMO 2022 or published recently in international journals. This includes reports on newly discovered breast cancer genes, atezolizumab in neoadjuvant therapy in HER2-positive patients, long-term data from the APHINITY study, and on how preoperative peritumoral application of local anesthetics can influence the prognosis. We also present solid data on dynamic Ki-67 from the ADAPT studies.Key words: breast cancer, surgery, chemotherapy, therapy standard     

Species differences in the hydroxylation of aniline and N-ethylaniline by liver microsomes

Summary The velocity of the N- and p-hydroxylation of aniline and N-ethylaniline by NADPH-dependent hydroxylases in guinea pig liver microsomes was found to be as high as in rabbit liver microsomes. Microsomes prepared from cat livers were less active.The effect of 2,4-dichlorophenol, p-chloromercuribenzoate, semicarbazide, and 8-hydroxyquinoline on the microsomal hydroxylations was observed to be not uniform in the microsomes of the species studied.Carbon monoxide inhibited the p-hydroxylation of N-ethylaniline by the microsomes prepared from the livers of rabbits, guinea pigs, dogs, and rats. The N-hydroxylation of N-ethylaniline by microsomes from rat's liver was inhibited like the p-hydroxylation by carbon monoxide. The N-hydroxylation by dog and guinea pig microsomes was scarcely, if at all, inhibited by the same carbon monoxide pressure. These enzymes showed a lower affinity for oxygen than the N-hydroxylating enzyme in rat microsomes and the p-hydroxylating enzymes.With 1 Figure in the TextResults of this study were presented at a meeting of the Deutsche Pharmakologische Gesellschaft in Mainz on April 26, 1965.     

The formation in vivo of p-hydroxylaminopropiophenone from p-aminopropiophenone and its action in vivo and in vitro

Summary The N-hydroxylation of p-aminopropiophenone in dogs was demonstrated by the spectrum of p-nitrosopropiophenone in carbon tetrachloride extracts taken from the blood of dogs after injecting p-aminopropiophenone.The N-hydroxylation of p-aminopropiophenone proceeded rather rapidly. The p-hydroxylaminopropiophenone proved to be more active than phenylhydroxylamine in the enzymic cycle of hemiglobin formation in the red cell.By comparing the velocity of hemiglobin formation and the concentration of p-hydroxylamino- and p-nitrosopropiophenone in the blood of dogs following the injection of p-aminopropiophenone or the slow infusion of p-hydroxylaminopropiophenone it was ascertained that the hemiglobin formation following the injection of p-aminopropiophenone was mainly due to p-hydroxylaminopropiophenone.With 4 Figures in the Text     

Über das Verhalten von Herzglykosiden in der Niere als Ursache ihrer unterschiedlichen diuretischen Aktivität

Ohne Zusammenfassung     

Leberfunktionsprüfungen bei Vergiftungen mit Trinitrotoluol durch Bestimmung des Abbaus von p-Oxyphenylbrenztraubensäure

Zusammenfassung Bei Ratten wurden wiederholte akute und chronische Vergiftungen und bei Hunden chronische Vergiftungen mit Trinitrotoluol durchgeführt und die Leberfunktion durch Bestimmung des Abbaus von p-Oxyphenylbrenztraubensäure zu prüfen versucht. Obgleich alle Tiere, die infolge der Vergiftung starben, histologisch nachweisbare Schädigungen der Leber aufwiesen, konnte nur bei einigen Ratten, die wiederholt mit großen Dosen Trinitrotoluol vergiftet worden waren, die bei Leberschädigungen erwartete Zunahme der Ausscheidung von p-Oxyphenylbrenztraubensäure beobachtet werden. Während der chronischen Vergiftung von Ratten mit kleinen Dosen Trinitrotoluol nahm die Ausscheidung von p-Oxyphenylbrenztraubensäure in keinem Falle zu, bei mehreren Tieren dagegen ab. Es war also auch bei den — soweit die histologische Untersuchung einen diesbezüglichen Schluß erlaubt — stärkeren Schädigungen der Leber durch Trinitrotoluol ebenso wie bei den früheren Untersuchungen mit m-Dinitrobenzol eine quantitative Bestimmung der Störung der Leberfunktion bei Ratte und Hund nicht möglich. Daß die Änderungen der Ausscheidung der p-Oxyphenylbrenztraubensäure während der Vergiftung durch Änderungen der Leberfunktion bedingt werden, ist sehr wahrscheinlich und bietet einen weiteren Hinweis auf die Wirkung des Trinitrotoluols auf die Leber.Mit 1 Textabbildung.