Hospitalization-induced exacerbation of the ill effects of chemotherapy on rest-activity rhythm and quality of life of breast cancer patients: a prospective and comparative cross-sectional follow-up study

ABSTRACT

Chemotherapy administration may result in the disruption of circadian rhythms and impairment of quality of life (QoL) of cancer patients. Nevertheless, we have little knowledge on the long-term consequences of chemotherapy and the effects of hospitalization. In the present study, we employed the two-factor repeated-measure cross-sectional design to determine the effects of chemotherapy and hospitalization on rest-activity (RA) rhythm and QoL of breast cancer patients. Initially, we randomly selected 39 inpatients and 42 outpatients, scheduled to receive six cycles of chemotherapy, from the Regional Cancer Center (RCC), Raipur, India. Finally, 30 patients in each group were included in the current study. We monitored circadian RA rhythm and QoL using wrist actigraphy and QLQ-C30 and QLQ-BR23, respectively, during the 1st (C1), 3rd (C3) and 6th (C6) chemotherapy cycles. Results revealed that with the progression of chemotherapy cycles (from C1 to C6), all rhythm parameters, namely mesor, amplitude, acrophase, rhythm quotient (RQ), circadian quotient (CQ), peak activity (PA), dichotomy index and autocorrelation coefficient, significantly decreased in both cancer in- and outpatients. In both groups of patients and during C1–C6, all functional and global QoL measures of QLQ-C30 and QLQ-BR23 significantly decreased and the symptoms significantly increased, except constipation, body image, sexual functioning and future perspectives in outpatients. The hospitalization exacerbated the problems associated with the RA rhythm and the QoL of the patients. In conclusion, the current study highlighted the negative consequences of hospitalization among inpatients, irrespective of the stage of cancer. We, therefore, recommend that cancer patients should be administered with chemotherapy as outpatients. The proposed protocol might have a covert bearing on the expression of better physiological state leading to satisfactory treatment outcomes.     

Alterations of the Characteristics of the Circadian Rest‐Activity Rhythm of Cancer In‐Patients

The aim of the present study was to evaluate the characteristics of the circadian rest‐activity rhythm of cancer patients. Thirty‐one in‐patients, consisting of 19 males and 12 females, were randomly selected from the Regional Cancer Center, Pandit Jawaharlal Nehru Medical College, Raipur, India. The rest‐activity rhythm was studied non‐invasively by wrist actigraphy, and compared with 35 age‐matched apparently healthy subjects (22 males and 13 females). All subjects wore an Actiwatch (AW64, Mini Mitter Co. Inc., USA) for at least 4–7 consecutive days. Fifteen‐second epoch length was selected for gathering actigraphy data. In addition, several sleep parameters, such as time in bed, assumed sleep, actual sleep time, actual wake time, sleep efficiency, sleep latency, sleep bouts, wake bouts, and fragmentation index, were also recorded. Data were analyzed using several statistical techniques, such as cosinor rhythmometry, spectral analysis, ANOVA, Duncan's multiple‐range test, and t‐test. Dichotomy index (I<O) and autocorrelation coefficient (r24) were also computed. The results validated a statistically significant circadian rhythm in rest‐activity with a prominent period of 24 h for most cancer patients and control subjects. Results of this study further revealed that cancer patients do experience a drastic alteration in the circadian rest‐activity rhythm parameters. Both the dichotomy index and r24 declined in the group of cancer patients. The occurrence of the peak (acrophase, Ø) of the rest‐activity rhythm was earlier (p<0.001) in cancer patients than age‐ and gender‐matched control subjects. Results of sleep parameters revealed that cancer patients spent longer time in bed, had longer assumed and actual sleep durations, and a greater number of sleep and wake bouts compared to control subjects. Further, nap frequency, total nap duration, average nap, and total nap duration per 1 h awake span were statistically significantly higher in cancer patients than control subjects. In conclusion, the results of the present study document the disruption of the circadian rhythm in rest‐activity of cancer in‐patients, with a dampening of amplitude, lowering of mean level of activity, and phase advancement. These alterations of the circadian rhythm characteristics could be attributed to disease, irrespective of variability due to gender, sites of cancer, and timings of therapies. These results might help in designing patient‐specific chronotherapeutic protocols.     

Zinc regulates the activity of kinase-phosphatase pair (BasPrkC/BasPrpC) in Bacillus anthracis

Bacillus anthracis Ser/Thr protein kinase PrkC (BasPrkC) is important for virulence of the bacterium within the host. Homologs of PrkC and its cognate phosphatase PrpC (BasPrpC) are the most conserved mediators of signaling events in diverse bacteria. BasPrkC homolog in Bacillus subtilis regulates critical processes like spore germination and BasPrpC modulates the activity of BasPrkC by dephosphorylation. So far, biochemical and genetic studies have provided important insights into the roles of BasPrkC and BasPrpC; however, regulation of their activities is not known. We studied the regulation of BasPrkC/BasPrpC pair and observed that Zn²⁺ metal ions can alter their activities. Zn²⁺ promotes BasPrkC kinase activity while inhibits the BasPrpC phosphatase activity. Concentration of Zn²⁺ in growing B. anthracis cells was found to vary with growth phase. Zn²⁺ was found to be lowest in log phase cells while it was highest in spores. This variation in Zn²⁺ concentration is significant for understanding the antagonistic activities of BasPrkC/BasPrpC pair. Our results also show that BasPrkC activity is modulated by temperature changes and kinase inhibitors. Additionally, we identified Elongation Factor Tu (BasEf-Tu) as a substrate of BasPrkC/BasPrpC pair and assessed the impact of their regulation on BasEf-Tu phosphorylation. Based on these results, we propose Zn²⁺ as an important regulator of BasPrkC/BasPrpC mediated phosphorylation cascades. Thus, this study reveals additional means by which BasPrkC can be activated leading to autophosphorylation and substrate phosphorylation.     

Genome Sequencing Unveils a Novel Sea Enterotoxin-Carrying PVL Phage in Staphylococcus aureus ST772 from India

Staphylococcus aureus is a major human pathogen, first recognized as a leading cause of hospital-acquired infections. Community-associated S. aureus (CA-SA) pose a greater threat due to increase in severity of infection and disease among children and healthy adults. CA-SA strains in India are genetically diverse, among which is the sequence type (ST) 772, which has now spread to Australia, Europe and Japan. Towards understanding the genetic characteristics of ST772, we obtained draft genome sequences of five relevant clinical isolates and studied the properties of their PVL-carrying prophages, whose presence is a defining hallmark of CA-SA. We show that this is a novel prophage, which carries the structural genes of the hlb-carrying prophage and includes the sea enterotoxin. This architecture probably emerged early within the ST772 lineage, at least in India. The sea gene, unique to ST772 PVL, despite having promoter sequence characteristics typical of low expression, appears to be highly expressed during early phase of growth in laboratory conditions. We speculate that this might be a consequence of its novel sequence context. The crippled nature of the hlb-converting prophage in ST772 suggests that widespread mobility of the sea enterotoxin might be a selective force behind its ‘transfer’ to the PVL prophage. Wild type ST772 strains induced strong proliferative responses as well as high cytotoxic activity against neutrophils, likely mediated by superantigen SEA and the PVL toxin respectively. Both proliferation and cytotoxicity were markedly reduced in a cured ST772 strain indicating the impact of the phage on virulence. The presence of SEA alongside the genes for the immune system-modulating PVL toxin may contribute to the success and virulence of ST772.     

Effect of Portal Glucose Sensing on Systemic Glucose Levels in SD and ZDF Rats

BackgroundThe global epidemic of Type-2-Diabetes (T2D) highlights the need for novel therapeutic targets and agents. Roux-en-Y-Gastric-Bypass (RYGB) is the most effective treatment. Studies investigating the mechanisms of RYGB suggest a role for post-operative changes in portal glucose levels. We investigate the impact of stimulating portal glucose sensors on systemic glucose levels in health and T2D, and evaluated the role of sodium-glucose-cotransporter-3 (SGLT3) as the possible sensor.MethodsSystemic glucose and hormone responses to portal stimulation were measured. In Sprague-Dawley (SD) rats, post-prandial state was simulated by infusing glucose into the portal vein. The SGLT3 agonist, alpha-methyl-glucopyranoside (αMG), was then added to further stimulate the portal sensor. To elucidate the neural pathway, vagotomy or portal denervation was followed by αMG+glucose co-infusion. The therapeutic potential of portal glucose sensor stimulation was investigated by αMG-only infusion (vs. saline) in SD and Zucker-Diabetic-Fatty (ZDF) rats. Hepatic mRNA expression was also measured.ResultsαMG+glucose co-infusion reduced peak systemic glucose (vs. glucose alone), and lowered hepatic G6Pase expression. Portal denervation, but not vagotomy, abolished this effect. αMG-only infusion lowered systemic glucose levels. This glucose-lowering effect was more pronounced in ZDF rats, where portal αMG infusion increased insulin, C-peptide and GIP levels compared to saline infusions.ConclusionsThe portal vein is capable of sensing its glucose levels, and responds by altering hepatic glucose handling. The enhanced effect in T2D, mediated through increased GIP and insulin, highlights a therapeutic target that could be amenable to pharmacological modulation or minimally-invasive surgery.     

Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt

The mitochondrial matrix protease CLPP plays a central role in the activation of the mitochondrial unfolded protein response (UPR^mt) in Caenorhabditis elegans. Far less is known about mammalian UPR^mt signaling, although similar roles were assumed for central players, including CLPP. To better understand the mammalian UPR^mt signaling, we deleted CLPP in hearts of DARS2‐deficient animals that show robust induction of UPR^mt due to strong dysregulation of mitochondrial translation. Remarkably, our results clearly show that mammalian CLPP is neither required for, nor it regulates the UPR^mt in mammals. Surprisingly, we demonstrate that a strong mitochondrial cardiomyopathy and diminished respiration due to DARS2 deficiency can be alleviated by the loss of CLPP, leading to an increased de novo synthesis of individual OXPHOS subunits. These results question our current understanding of the UPR^mt signaling in mammals, while introducing CLPP as a possible novel target for therapeutic intervention in mitochondrial diseases.     

Interaction properties of biosynthesized cadmium sulphide quantum dots with human serum albumin: further investigation of antibacterial activities and sensing applications

The synthesis of small-sized quantum dots (QDs) (1–10 nm) via the green route has garnered great interest regarding their prospective use in many biological applications (diagnosis, drug delivery and in vivo sensing); this is difficult to achieve using chemical synthesis methods, which produce larger size QD particles and also require hazardous reagents. Here, we synthesized biogenic cadmium sulphide (CdS) QDs using green tea extract as the reducing agent to produce particles that were homogeneous and a smaller size of 2–4 nm. We also elucidated the (a) protein binding, (b) antibacterial use and (c) sensing applications of biogenic CdS QDs in this present work. The biosynthesized CdS QDs were found to have extensive antibacterial activity against both Gram-negative Escherichia coli and Gram-positive Enterococcus faecalis bacterial strains. The introduction of QDs in biological medium can lead to the formation of protein–QD complexes; therefore we investigated the binding interaction of CdS QDs with the carrier protein human serum albumin (HSA) in vitro. The synthesized CdS QDs quenched the intrinsic fluorescence of HSA through a static quenching mechanism and the binding constant (K_b) was in the order of 10⁴ M⁻¹. It was also observed that the presence of biogenic CdS QDs affected the HSA–ligand interactions in vitro. The synthesized CdS made highly effective sensors for tetracycline, rifampicin, and bilirubin with limit of detection (LOD) values of 99, 141 and 29 ng/ml, respectively.