Cancer and neurodegenerative diseases are two of the leading causes of premature death in modern societies. Their incidence continues to increase, and in the near future, it is believed that cancer will kill more than 20 million people per year, and neurodegenerative diseases, due to the aging of the world population, will double their prevalence. The onset and the progression of both diseases are defined by dysregulation of the same molecular signaling pathways. However, whereas in cancer, these alterations lead to cell survival and proliferation, neurodegenerative diseases trigger cell death and apoptosis. The study of the mechanisms underlying these opposite final responses to the same molecular trigger is key to providing a better understanding of the diseases and finding more accurate treatments. Here, we review the ten most common signaling pathways altered in cancer and analyze them in the context of different neurodegenerative diseases such as Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s (HD) diseases. Cancer and neurogenerative diseases are two of the leading causes of death in modern societies, and despite all the efforts made in understanding their onset and development, their prevalence continues to increase dramatically. Cancer, together with cardiovascular disease, is known to be the main cause of premature death . In the APP, APOE, PARKIN, and PINK1 have been identified as causal genes of AD and PD . Alz. Alz6]. D and PD ,12. On t PD [HTT .In cancer, cells acquired the ability to divide and growth uncontrollably ,34,35. UAlthough the mechanisms underlying cancer and neurodegenerative disorders are different, the onset and progression of both diseases share the same molecular signaling pathways. In this review, we provide a summary of the molecular alterations implicated in neurodegenerative diseases, based on the ten canonical signal pathways most altered in cancer . The objFirst discovered as a regulator of organ size, Hippo signalling is involved in many different processes, such as mechanotransduction, homeostasis, cellular differentiation, and tissue regeneration, among others ,38,39. BThe Hippo pathway has been well-studied in the developing brain , butChanges in YAP location are not exclusive of AD; it also has been found in postmortem brains of Huntington’s disease patients as reported ,56. In cAlthough YAP has lately gained relevance as the main effector of the Hippo signaling in the onset of neurodegenerative disorders, other components of the pathway, such as MST1 and LATS1/2, have been also identified and linked to the progression of different CNS diseases ,58. For Notch is a conserved pathway responsible for a wide range of physiological roles, including self-renewal, differentiation, angiogenesis, and proliferation ,60. NotcThe Notch signaling pathway regulates neurogenesis, neural maturation, and synaptic plasticity in the brain ,69,70. MNotch ligands were also involved in the onset and development of different neurodegenerative diseases. Among others, alterations in Jagged1 were observed in AD patients . Like thAlthough to a lesser extent, Notch signaling is also related to other neurodegenerative diseases, such as PD and Down syndrome ,78.Nrf2 (Nuclear factor-erythroid factor 2-related factor 2) holds key physiological functions in homeostasis maintenance and cell proliferation. It is a master regulator of redox balance and antioxidant-related activity . RecentlNrf2 has been widely studied within the CNS ,88,89. DThere are numerous efforts to determine the relevance of Nrf2 in the development of neurodegenerative disorders using transgenic mouse models. AD mouse models (APP/PS1 mouse) showed defective expression of Nrf2 and its downstream targets in the hippocampus and cortex, coinciding with the increase of Aβ aggregates ,94. InteNrf2 involvement in the progression of neurodegenerative disorders has also been linked to neuroinflammation and autophagy. p62, an autophagy marker, is closely related to the Nrf2 signaling pathway ,96. LossThe Wnt/β-catenin pathway is a highly conserved pathway that regulates key cellular functions including gene stability, differentiation, proliferation, apoptosis, stem cell renewal, and migration ,99,100. Despite the well-known role of WNT signaling in the developing brain ,109, wheDifferent players of the WNT pathway are altered in the postmortem brains of AD patients . DKK1, aDifferent mouse strains of neurogenerative disease also showed altered expression of WNT components ,110,112.In postmortem brains derived from patients suffering from other neurodegenerative disorders, such as Parkinson’s and Huntington’s diseases, scientists have found dysregulation of the WNT pathway. For example, genes regulated by WNT were found downrated in the SN of PD brains ,113,114.The TGFβ (transforming growth factor β) superfamily of growth factors includes TGFβ, activins, and BMPs. The activated TGFβ ligands interact with type II TGFβ receptors (TβRII), which subsequently recruit and phosphorylate type I TGFβ receptors (TβRI), thereby activating downstream signaling through either the SMAD-dependent canonical pathway or the SMAD-independent non-canonical pathway. The canonical pathway involves R-Smad (Smad2/3) phosphorylation complex with co-Smad (Smad4) to translocate to the nucleus and activate the expression of genes ,116. TheIn normal cells, the TGFβ pathway regulates key physiological functions in homeostasis, development, tissue, and cell growth . In cancThe TGFβ superfamily is involved in neuroinflammation and repair after brain injury . In the In the AD brain, the TGFβ pathway promotes amyloid deposition and is co-expressed with Tau in neurons and tangles . TβRII sTGFβ seems to be involved in the onset and development of Tau pathology. TGFβ levels have been correlated with NFTs in AD brain. Moreover, Smad2/3 co-expressed with Tau in both neurons and NFTs ,139.TGFβ has different implications in the development of PD. It is increased in the brains of PD patients . SeveralAlthough to a lesser extent, a potential role of TGFβ in the cortical neurons of HD patients has been described . TGFβ siC-Myc belongs to the MYC family that also encompasses N-Myc and L-Myc proteins in mammalian cells. Although highly homologous, they display more tissue-restricted expression . c-Myc hMyc is frequently dysregulated during tumorigenesis and is a central driver in multiple cancers, such as breast cancer , liver tAlthough the characterization of the MYC members has been very extensive in the study of different cancer types, its role in neurodegenerative diseases is still far from being understood. Similar to its functions in cancer progression, MYC has also been tightly linked with cell cycle re-entry in the onset and development of AD and other CNS disorders .Alterations of the different Myc members were found in the brains of AD and HD patients ,164. WheInsights into the relevance of c-Myc in the onset of neurodegenerative diseases were first reported by a study that generated a mouse strain expressing c-Myc in neurons . IncreasThe mitogen-activated protein kinase (MAPK) is a complex interconnected signaling cascade that converges in the amplification of key molecules that sustain cell proliferation, growth, and survival processes . The MAPV600E are by far the most identified mutation in human tumors. This mutation results in strong BRAF kinase activation  and constitutively hyperactivation of the MAPK pathway. Approximately 19% of patients with cancer harbor RAS mutations, with KRAS responsible for 75% of that number. Furthermore, 65% of pancreatic cancers harbor an RAS mutation, 47% of colorectal, 30% of melanoma and lung cancers, and 12% of thyroid cancer. KRAS is the main isoform mutated in pancreatic and colorectal, NRAS in melanoma and thyroid carcinoma. Moreover, mutations also occur in the genes coding for the tyrosine kinase receptors  [The MAPK pathway is one of the most altered pathways in cancer. Braf is altered in 60% of thyroid cancer, 54% of melanoma, and 11% colorectal cancers ,171,172., c-KIT) ,171,172., c-KIT) ,171,172.The canonical ERK cascade, the p38 and the JNK pathways play an important role in different neurological disorders. In the brain, the MAPK pathway is involved in neurogenesis, gliogenesis, and synapse transmission, which affects cognition and memory formation. Pharmacological and genetic approaches showed that alteration of the different MAPK pathways leads to changes in behavior in terms of cognition and learning, incipient signs of neurological disorders . In human patients with AD, PD, HD, or other neurological disorders, increased levels of activated ERK, p38, and JNK have been found. Higher pMEK and pERK levels were found in AD ,175,176 In AD, MAPK pathways are linked to both amyloid and tau pathologies. In fact, in the brains of AD patients, different members of the cascade members were found to co-express in NFTs and senile plaques. Moreover, pharmacological blockade and genetic deletion of pERK, p38 and JNK ameliorate the cognitive impairments in different mouse models of AD ,184,185.ERK, p38, and JNK pathways are involved in the survival of dopaminergic cells in the striatum and the dopaminergic signaling of the brain . It has At the onset and development of HD, MAPK may also play an important role. Like humans, mouse models mimicking the effect of HD  presentep53 is a potent tumor suppressor, and it is considered the “guardian of the genome” to prevent the accumulation of oncogenic mutations that lead to malignant tumors ,192. p53p53 has been widely involved in the study of neurodegenerative diseases ,199. In Cytoplasmic p53 has been involved in both tau and amyloid pathologies in AD brains. In humans, p53 interacts with Tau and PS1. Several AD mouse models showed that Tau, APP, and PS1 expression levels modulate p53 expression. In this regard, genetic deletions of PS1 and APP decrease the expression of p53 in the mouse brain ,205. IncThe role of p53 at the onset and development of HD has been described in depth. p53 levels are high in the brains of HD patients, and its expression also positively correlates with the grade of the disorder . It has Present increased levels of p53. In these models, genetic deletions of p53, rescued neurodegeneration showed in HD and the neurodevelopmental abnormalities associated with these models ,208.In PD, p53 is an important player in dopaminergic cell loss. Specific ablation of p53 in dopaminergic neurons protects against MPTP-induced neurodegeneration and improves the motor coordination found in this pharmacological approach of PD .INK4A and p14ARF) and CDKN2B genes  are commonly deleted, or its promoter is silenced by methylation in human cancers [The cell cycle is a complex and orchestrated process that ensures duplication of the genetic material and cell division . This pa cancers ,211. Aro cancers ,171,172.Despite neurons being postmitotic cells, and hence they are in a quiescent state, dysregulations in their cell cycle have been observed in many of the most common neurodegenerative disorders ,213. NeuIn mouse models the potential involvement was also confirmed of cell cycle re-entry found in human brains with different diseases. In AD, both pharmacologic and genetic induction of Aβ accumulation in the mouse brain triggers the expression of different genes involved in the cell cycle re-entry. A recent study shows increased expression of an S/G2/M marker in the hippocampus of AD patients and mouse models . InteresSimilar to AD, SN neurons of mouse models of PD present deregulated cell cycles. MPTP treatment induces the expression and activity of CDK5 in dopaminergic neurons, and its pharmacological inhibition attenuates the MPTP-induced dopamine cell loss . α-synucThe PI3K/AKT/mTOR (phosphatidylinositol 3-kinase/protein kinase-B/mechanistic target of rapamycin) signaling pathway is one of the most signally altered in cancer . This paDysregulations in the different components of the PI3K pathway have been reported in the development of neurodegenerative diseases ,229,230.PI3K/AKT signaling has a myriad of downstream components. Among others, mTOR and GSK3β are two AKT targets involved in the control of autophagy, amyloid aggregation, and Tau phosphorylation in the progression of neurodegenerative disorders, respectively. Activated AKT induces the phosphorylation of both mTOR and GSK3β. Whereas p-mTOR is the active form, phosphorylation represses the activity of GSk3β. PI3K/AKT/mTOR pathway has been linked to disrupted autophagic processes in the human AD brain. At the onset of AD, there were increased mTOR levels  and corrThe PiI3K/AKT/GSK3β pathway has an important role in the hyperphosphorylation of Tau. GS3Kβ has been pinpointed as one of the most important players in Tau phosphorylation, and the consequent accumulation of NFTs reports linking AKT with GS3Kβ might also be confusing ,240. IncIn this review we describe the individual role and genetic alterations of the significant components of the canonical molecular cancer pathway in the context of progression of different neurodegenerative diseases . EffectoDespite this review focusing on the most altered signaling pathways in the different neurodegenerative diseases, other factors are also involved in the appearance of their pathologies. For example, the role of metabolism in the control of cognitive functions has gained relevance in the last few years . It is k


Et). The IPDT and Et values of the DGEBA/PEI blends containing 2 wt% of PEI increased by 2% and 22%, respectively, compared to those of neat DGEBA. Moreover, the critical stress intensity factor and critical strain energy release rate for the DGEBA/PEI blends containing 2 wt% of PEI increased by 83% and 194%, respectively, compared to those of neat DGEBA. These results demonstrate that PEI plays a key role in enhancing the flexural strength and fracture toughness of epoxy blends. This can be attributed to the newly formed semi-interpenetrating polymer networks (semi-IPNs) composed of the epoxy network and linear PEI.Bisphenol A diglycidyl ether (DGEBA) was blended with polyetherimide (PEI) as a thermoplastic toughener for thermal stability and mechanical properties as a function of PEI contents. The thermal stability and mechanical properties were investigated using a thermogravimetric analyzer (TGA) and a universal test machine, respectively. The TGA results indicate that PEI addition enhanced the thermal stability of the epoxy resins in terms of the integral procedural decomposition temperature (IPDT) and pyrolysis activation energy ( Epoxy is extensively used as a typical thermosetting resin. Epoxy resin is widely used as adhesives, high-performance coatings, packaging, and lamination materials because it exhibits excellent chemical stability, low shrinkage, good adhesion to various metals, good thermal stability, and good mechanical properties ,3,4,5,6.Since the term of “IPN” was first introduced by John Millar in 1960, various studies have reported about IPN-based epoxy systems incorporating thermoplastic polymers, such as polysurfone (PSF), polyethersulfone (PES), polycarbonate (PC), polyetheretherketone (PEEK), and polyetherimide (PEI), and have demonstrated the enhancement in mechanical properties  of epoxy resins ,9,10.−2, flexural strength of 156–172 MPa, and tensile strength of 78–85 MPa.Lee et al.  reportedTg) of ≈215 °C, higher strength and rigidity at elevated temperatures, higher moisture resistance, lower shrinkage, etc., thereby showing a wider range of processing capabilities. Recently, PEI has emerged as a promising candidate for enhancing the mechanical properties of epoxy systems for engineering applications due to its good compatibility and miscibility with epoxy resins. PEI has been reported to enhance the interfacial adhesion between the two phases by forming a strong network, i.e., semi-IPN structures, which increases the thermal and mechanical properties of the resultant epoxy system. These improve the stress transfers at the interfaces between PEI and epoxy without significantly decreasing the modulus or Tg and resistance to solvents and radiation  vs. θ. The Et value was calculated from the slope of the straight lines using Equation (4).For detailed investigation of the polymer blends’ decomposition and activation energy of thermal degradation, the ( follows :(4)lnlnTmax, and Et values of the neat DGEBA and DGEBA/PEI blends. The PDT and IPDT values of the blends slightly increased due to PEI addition. The Tmax value of the DGEBA/PEI blends was similar to that of neat DGEBA. The Et value of neat DGEBA was 256.3 kJ·mol−1, whereas that of the blends was significantly higher (294.1–312.8 kJ·mol−1). This confirms that more activation energy was needed for pyrolysis, as the DGEBA/PEI blend was more stable and more difficult to decompose [ecompose ,29,30.Flexural strength , a (mm), W, and B are the critical load, crack length, width, and thickness of the specimen, respectively. Moreover, f (a/W) is the geometric element obtained from Equation (7).υ is the Poisson’s ratio (0.3), and E is the tensile modulus obtained from the fracture testing [Fracture toughness is a fundamental property of polymeric materials indicating the strain energy and absorbing ability of pre-fracture materials. A higher fracture toughness indicates higher resistance to crack propagation. The fracture toughness of the DGEBA/PEI blends was investigated using the C values . The KIC follows ,38,39:( testing .KIC and GIC values of the blends increased with the PEI content up to 2 wt%. The KIC values of the blends containing the blends containing 2 wt% of PEI were 4.9 MPa·m1/2, which were 83% higher than those of neat DGEBA (GIC values of the blends containing 2 wt% of PEI were 58.5 kJ·m−2, which were 194% higher than those of neat DGEBA (KIC and GIC, of the DGEBA/PEI blends are indicated in KIC and the GIC. Thus, we confirmed that the PEI particles in the epoxy matrix act as stress concentrators to absorb the external energy and mitigate the crack growth [at DGEBA b. Moreovat DGEBA c. This ck growth ,44,45,46Et value of the blends significantly increased by 22% from 256.3 to 312.8 kJ·mol−1 after the addition of 2 wt% of PEI. The KIC and GIC values of the blends containing 2 wt% of PEI were 83% and 194%, respectively, higher than those of neat DGEBA, which is associated with the increase in the activation energy of decomposition in thermal stability studies. The SEM images indicated that the surfaces of the DGEBA/PEI blends were rougher than those of neat DGEBA, accounting for their excellent fracture toughness. In summary, the addition of PEI to DGEBA significantly improved the fracture toughness due to the newly formed semi-IPN structures, which resulted from the combination of two noncompatible polymers. Thus, PEI plays an important role in enhancing the interfacial adhesion of epoxy. Therefore, the applications of the obtained DGEBA/PEI blends should be extended, such as heat resistant adhesive, surface coating, high performance blends, and electrical and electronic encapsulation.In this study, we observed the thermal stability and fracture toughness of neat DGEBA and DGEBA/PEI blends. The PDT and IPDT values of the blends slightly increased with the PEI content. The


Phlebopus portentosus, provides various nutritional benefits and natural antioxidants to humans. In this study, the chemical composition, phenolic compounds, and antioxidant and antimicrobial activities of fresh mushroom samples and samples stored for a period of one year using different preservation methods  were investigated. The results indicated that the brining method significantly reduced the protein and fat contents of the mushrooms. The polyphenol and flavonoid contents of the frozen sample were not significantly different from that of the fresh sample. The results revealed that an inhibition value of 50% (IC50) for the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay of the extract of the dried and frozen samples was not statistically different from that of the fresh sample. The IC50 value of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assay and ferric reducing antioxidant power (FRAP) value in the extract of the frozen sample were not found to be significantly different from those of the fresh sample. Furthermore, the lowest degree of antioxidant activity was found in the extract of the brined sample. Additionally, the antimicrobial activities of the extracts of the fresh and frozen samples were not significantly different and both extracts could have inhibited the growth of all tested Gram-positive bacteria and Pseudomonas aeruginosa.Tropical black bolete,  Agaricus, Auricularia, Lentinus, Lentinula, Pleurotus, Tramella, and Volvariella, account for the majority of the mushrooms traditionally consume by humans [Cantharellus spp.), king boletes (Botetus edulis), matsutakes (Tricholoma matsutake), morels (Morchella spp.), and truffles (Tuber spp.), are among the world’s most expensive foods [Cantharellus spp.), king boletes (B. edulis), morels (Morchella spp.), and truffles (Tuber spp.), are commonly preserved through the different processes [Varieties of certain cultivated edible mushroom genera, such as y humans ,2,3. Howy humans ,5,6. Ecty humans ,8. ECM my humans ,10,11. Ay humans ,13,14,15ve foods ,8,16,17.ve foods ,19. Fresve foods ,21. For rocesses ,23,24.Amanita, Astraeus, Boletus, Cantharellus, Lactarius, Phlebopus, and Russula [Phlebopus portentous, is a wild edible ECM mushroom that is known to be distributed throughout Asia, Australasia, and Mexico [Thailand is home to a great diversity of wild edible mushroom species that are most abundant during the wet season (mid-May to October) of each year ,25. Norm Russula ,16,26,27d Mexico ,29,30,31d Mexico . This mud Mexico . The stud Mexico ,19,20,21Fresh fruiting bodies of TBB were bought from local markets at Mae Ta District, Lamphun Province, northern Thailand in 2018 . The fruBriefly, the sliced fresh mushroom samples were loaded onto trays and placed in a commercial food dryer at a temperature of 45 °C for 72 h (completely dried). The moisture content was then recorded. The samples were placed in zip-lock plastic bags and kept at room temperature (28 ± 2 °C) in the darkness.Sliced fresh mushroom samples were boiled in hot water (95 to 99 °C) for 5 min for the purposes of blanching, according to the method described by Lungu et al. . They weThe sliced fresh mushroom samples (20 pieces) were placed in each commercial zip-lock plastic bag (25 × 35 cm) and frozen at −20 °C in a freezer.The proximate composition of each mushroom sample was identified as carbohydrate, protein, fat, ash, and fiber according to the Association of Official Analytical Chemists (AOAC) method  at CentrFresh samples were oven-dried in an oven at 45 °C for 72 h before being used. Additionally, all one-year storage samples, except the dried sample, were also oven-dried at 45 °C for 72 h. Each dried sample was ground using a Waring blender . Ground mushroom samples (20 g) were extracted with 200 mL of methanol at 25 °C and at 150 rpm for 24 h following the method described by Kaewnarin et al. . The ext2CO3 (20% w/v) was added. The reaction mixture was then incubated at room temperature for one hour. Analysis of total polyphenol content was carried out by measurement of the absorbance at 760 nm. The standard curve of gallic acid was used to calculate the total polyphenol content of the samples . The results were expressed as milligrams of gallic acid equivalent per gram of dry weight (mg GAE/g dw). Five replications were performed for the samples of each treatment.The total polyphenol content was estimated using the protocol previously described by Thitilertdecha et al.  with som2 (50 g/L) was added. After 5 min, 0.15 mL of AlCl3 (100 g/L) was added. The reaction was mixed and incubated at room temperature for 15 min. Absorbance was measured at 415 nm. The standard curve of quercetin was then used to calculate the total flavonoid content in the samples . The total flavonoid contents were expressed as milligrams quercetin equivalent per gram of dry weight (mg QE/g dw). The data were presented as the average of five replications of each treatment.Total flavonoid content was determined according the protocol established by Kaewnarin et al. , and queo − As/Ao) × 100, where Ao represents the absorbance of the control and As represents the absorbance of the mixture containing the extract sample. An inhibition concentration of 50% (IC50) was expressed as a calculation from the plot of percentage inhibition against the extract concentration. Samples of each treatment were analyzed in five replications.The DPPH  scavenging ability was determined according to the method described by Gülçin et al. . Initial2S2O8. The solution was kept in darkness at 25 °C for 16 h. The ABTS solution was adjusted to an absorbance value of 0.70 ± 0.2 at 734 nm by dilution with the phosphate buffer  before being used. Next, 2.9 mL of the ABTS solution was mixed with 0.1 mL of different concentrations of each extract sample. A mixture composed of the ABTS solution and methanol was used as the control. The mixtures were incubated at room temperature for 30 min in the dark. The absorbance value of the mixture was measured at 734 nm. The percentage of discoloration of the ABTS radical was calculated according to the formula previously described in the DPPH assay, as has been described above. The IC50 value was then calculated, and five replications were completed for the samples of each treatment.ABTS  scavenging activity was determined according to the method described by Re et al.  with som2 = 0.995), and the FRAP value was calculated as mg GAE/g dw. The data were presented as the average of five replications of each treatment.FRAP (ferric reducing antioxidant power) assay was performed according to the protocol described by Li et al. . The FRABacillus cereus, B. subtilis, Enterococcus faecalis ATCC29212, Listeria monocytogenes, Micrococcus luteus, Methicillin-resistant Staphylococcus aureus, Sta. aureus ATCC29213, and Streptococcus pneumoniae ATCC49699), 10 strains of Gram-negative bacteria , and 2 yeast strains . All tested microorganisms were obtained from the Sustainable Development of Biological Resources Laboratory, Department of Biology, Faculty of Science and the Central and Diagnostic Laboratory, Maharaj Nakorn Chiang Mai Hospital, Faculty of Medicine Chiang Mai University, Thailand. Bacteria and yeast samples were grown and maintained on nutrient agar (NA) and yeast extract peptone dextrose agar (YPDA) slants, respectively. The inoculated slants were incubated at 37 °C.The microorganisms used in this study consisted of 8 strains of Gram-positive bacteria (8 CFU/mL that corresponded to the 0.5 McFarland standard. All prepared suspensions of the test microorganisms were swabbed on their respective agar media including NA (for the bacteria test) and YPDA (for the yeast test). Sterile paper discs (8 mm in diameter) were impregnated with 40 μL of each mushroom extract at a concentration of 100 mg/mL. The discs were allowed to dry and then placed on the agar surface of the tested plate. Discs with the methanol were used as the negative control, while standard antibiotics such as ampicillin, streptomycin, and nystatin at concentrations of 10 mg/mL were used as positive controls. The plates were incubated at 37 °C for 24 h. After incubation, the zone of inhibition appeared around the discs and was measured and recorded. Five replications were made for each sample extract obtained from each treatment.The antimicrobial activity of the mushroom extracts was determined by paper disc diffusion assay ,42. Bactp < 0.05) between the mean values.The data collected were subjected to one-way analysis of variance (ANOVA) by SPSS program version 16.0 for Windows. Tukey’s test was used to determine significant differences  after storage at room temperature for four weeks. Previous studies have reported that lower protein and fat contents in the brined samples can be explained by the much greater amounts of fat, protein, and amino acid solubilizations that exist as a result of employing the brining method [The amounts of ash, carbohydrate, protein, fat, and fiber of the different mushroom samples are shown in g method ,48,53,54Agaricus bisporus) and boletes (B. edulis and Sui. luteus) were due to the blanching and brining processes, respectively. Nevertheless, the total polyphenol and flavonoid contents in the frozen samples examined in this study were not found to be significantly different when compared with the fresh sample. This result was in full agreement with that the findings presented in previous studies that reported that the freezing process can cause minimal amounts of destruction of the polyphenol and flavonoid compounds in fruits, some vegetables, and mushrooms [Total polyphenol and flavonoid contents of all methanol extracts of TBB samples are shown in ushrooms ,59. In aAmanita, Astraeus, Boletus, Cantharellus, Lactarius, Leccinum, Phlebopus, Russula, Tricholoma, Suillus, and Xerocomus, have been reported to contain higher amounts of secondary metabolites, which are indicative of multiple biological effects, including the antioxidant activity that can act according to different mechanisms of action for each mushroom species [3+) to the ferrous form (Fe2+). Results are shown in Several edible ECM mushroom genera, namely,  species ,47,56,60In the DPPH and ABTS radical scavenging systems, the extract concentrations providing IC50 values were of particular interest. The IC50 value is a comparable parameter widely used to measure the potency of antioxidant activity of test samples. Thus, the lower IC50 value indicated the higher antioxidant activity. In the DPPH scavenging system, the results indicated that the IC50 values of the DPPH assay varied for each sample. The lowest IC50 value of the DPPH activity was observed in the extract of the fresh sample (2.11 ± 0.08 mg/mL), which was not found to be statistically different from that of the dried (2.20 ± 0.60 mg/mL) and frozen samples (2.14 ± 0.72 mg/mL). However, they were significantly lower than that of the brined sample (3.65 ± 0.48 mg/mL). In the ABTS scavenging system, all extracts showed positive results in terms of the ABTS assay and the IC50 values, which varied from 1.30 to 2.85 mg/mL. The lowest IC50 value of ABTS activity was observed in the extract of the fresh sample, followed by the frozen sample and the dried sample.50 values, which varied from 1.30 to 2.85 mg/mL. The lowest IC50 value of ABTS activity was observed in the extract of the fresh sample, followed by the frozen sample and the dried sample. However, the highest IC50 value of ABTS activity was found in the extract of the brined sample. In the FRAP system, the FRAP values of the extract of the fresh sample (7.86 ± 0.11 mg GAE/g dw) and frozen sample (7.52 ± 0.38 mg GAE/g dw) were significantly higher than those of the extracts obtained from the other samples. Moreover, the lowest FRAP value was observed from the extract of the brined sample (3.81 ± 0.46 mg GAE/g dw).In the ABTS scavenging system, all extracts showed positive results in terms of the ABTS assay and the ICPleurotus cystidiosus) revealed the strongest degrees of antioxidant activity when compared to the brined mushrooms. Moreover, Pagoń et al. [B. edulis and Sui. luteus after four weeks of storage were lower than in the fresh samples. In this study, the freezing process maintained the antioxidant activity in the TBB sample during storage. This result was supported by the findings of previous studies that indicated that the act of freezing did not induce or even slightly change the degree of antioxidant activity in certain mushrooms  [Our results are similar to those of previous studies that reported that the methanolic extract of ECM mushrooms, including boletes, revealed notable DPPH, ABTS, and FRAP activities ,47,60,61ń et al.  reportedshrooms)  and vegeshrooms) ,64,65,66B. subtilis and L. monocytogenes. The growth of B. cereus and M. luteus could not be inhibited by the extract of the brined sample. The extract of the fresh sample displayed the largest diameter of the inhibition zone over the other extracts. Most of the extracts showed no antimicrobial activity against all Gram-negative bacteria, except for the extract of the fresh and frozen samples that could inhibit the growth of Ps. fluorescens. However, all extracts displayed no antimicrobial activity against all the yeast samples at the concentration values used. Similarly, antimicrobial potential has been observed in the extracts of the other edible ECM mushrooms in that they displayed greater activity against Gram-positive bacteria than against Gram-negative bacteria and yeast specimens [Antimicrobial activity of the crude extracts of the fresh and preserved samples after one year of storage was investigated in terms of the inhibition zone against eighteen strains of pathogenic bacteria and yeast. The diameter of the inhibition zone is shown in pecimens ,14,42,55pecimens  and Smolpecimens  reportedAdditionally, it was found that freezing serves as a suitable preservation method in maintaining the antimicrobial activity in the TBB sample during storage. These results were supported by the findings of previous studies that found that the perseveration process does play a significant role in reducing the antimicrobial activity of mushrooms. Additionally, it was found that the high temperatures reached during the preservation process, for exampl, drying, boiling, and blanching, could partially degrade the antimicrobial active compounds in mushrooms ,68,69. FTBB is considered a nutritional mushroom with a number of health benefits. Therefore, the ability to extend the shelf-life of this mushroom is crucial to gaining an understanding of how different preservation methods could affect the mushroom’s nutrient composition and antioxidant and antimicrobial properties. In this study, three preservation methods were used, namely, brining, drying, and freezing, in order to determine the effect on nutrient composition, phenolic compound content, and antioxidant and antimicrobial properties in TBB. After one year of storage, the brined sample showed significant reductions in crude protein, fat, polyphenol and flavonoid contents, as well as antioxidant and antimicrobial properties, when compared with the dried, frozen, and fresh samples. The outcomes of this study demonstrate that freezing could serve as a suitable preservation process by resulting in little or no change to the nutrient composition, phenolic compound content, and antioxidant and antimicrobial properties in samples after one year of storage. However, differences in phenolic profiles in terms of the amount of individual phenolic compounds present in the samples during storage should be determined in future studies. Moreover, mineral analysis, sensory evaluation, microbial contamination, and long-term storage of the preserved mushroom samples would be necessary, and to identify a suitable preservation method for potential commercial development.


Data were obtained from the electronic health records of the Milan Agency for Health Protection, Italy. Two-year risks for overall mortality, myocardial infarction, stroke and bleeding were computed using Cox models. Age, sex, number of comorbidities, use of platelet aggregation inhibitors and Proton pump inhibitors and area of residence were used as confounding factors. We also controlled by indication bias-weighting NOACs and warfarin users based on the weights computed by a Kernel propensity score. Results: For all NOACs, we found a decrease in the risks compared with warfarin for mortality (from −25% to −49%), hospitalization for myocardial infarction  and ischemic stroke . The risk of bleeding was decreased for rivaroxaban (−33%) and numerically but not significantly for the other NOACs. Conclusions: After two years of follow-up, in comparison with warfarin, NOACs users showed a significant reduction of overall mortality , hospital admission for myocardial infarction (apixaban and edoxaban), ischemic stroke (dabigatran) and bleeding (rivaroxaban).Background: New oral anticoagulant agents (NOACs) are valid alternatives for vitamin K antagonists (VKA) in patients with non-valvular atrial fibrillation (NVAF) for stroke prevention. In clinical practice, NOACs users may differ from patients enrolled in clinical trials in age or comorbidities, and thus it is a critical issue to evaluate the effectiveness and safety of NOACs in the real-world. Accordingly, we assessed two-year overall mortality and hospital admissions for myocardial infarction, stroke or bleeding in patients with NVAF users of NOACs compared to warfarin-treated patients. Methods: This is a population-based retrospective new user active comparator study. All atrial fibrillation patients who were naïve and not switcher users of oral anticoagulants from January 2017 to December 2019 were included ( New oral anticoagulant agents (NOACs: dabigatran (Pradaxa©: Boehringer Ingelheim am Rhein Germany), rivaroxaban (Xarelto©: Bayer AG Kaiser), apixaban  and edoxaban (Lixiana©: Daiichi Sankyo Germany)) are all authorized in Europe as valid alternatives for vitamin K antagonists (VKA) in patients with non-valvular atrial fibrillation (NVAF) for stroke prevention ,2,3,4. IAll NOACs have been shown to be at least as effective and safe as warfarin . FurtherTherefore, their use has speedily increased ,8,9. In In clinical practice, NOACs users may differ from patients enrolled in clinical trials in age or comorbidity  and in tHowever, NOACs have not been placed on the market at the same time, so real-world evidence is lower for those which have entered more recently . In ItalAccordingly, in the present manuscript, we sought to assess two-year risk of overall mortality and hospital admissions for myocardial infarction, stroke or bleeding in a large cohort of NVAF patients who were naïve users of each NOAC in the Italian universal healthcare setting, compared to patients treated with warfarin.This is a population-based retrospective cohort study conducted on residents in the area of the Milan Health Protection Agency , Italy, who used anticoagulant agents.In particular, this is a new user active comparator study  that incAnticoagulant users were identified among the residents in the AHP area, enrolled in the regional universal coverage healthcare system. Anticoagulant users were identified among the permanent residents in the AHP area registered in the regional universal coverage healthcare system.n = 103,115 patients). We defined new users as those who had no prescriptions for any such drugs in the year prior to the first specific prescription .We selected citizens who had an anticoagulant prescription in 2017–2019 of warfarin, rivaroxaban, dabigatran, apixaban or edoxaban . We also considered patients who had a time interval of less than 180 days between two following prescriptions. Therefore, we selected 33,674 NOACs or warfarin users.In addition, we included only patients who did not switch from one anticoagulant to another during the study period  and the “General Authorisation to Process Personal Data for Scientific Research Purposes” . Administrative permission to perform the study was granted by the General Direction of the Agency for Health Protection (ATS) of Milan, resolution No. 36 16 January 2018).This study is ethically compliant with the National Law : B01AA03 (warfarin), B01AE07 (dabigatran), B01AF01 (rivaroxaban), B01AF02 (apixaban) and B01AF03 (edoxaban).Anticoagulant treatment was determined using the drug prescription database and selecting the following codes of the Anatomical Therapeutic Chemical (ATC) classification system ) and A02BC (proton pump inhibitors (PPI)).We also considered six sub-areas of residence (ASST) within the AHP: Milan (the main city), Rhodese, North Milan, West Milan, Melegnano and Lodi, in order to take into account drug prescription attitudes of the primary care groups of general practitioners and the interaction with the hospital and healthcare facilities of the territory.NVAF patients were followed up until 31 December 2019, for the status of life. In addition, we checked the admissions database for the first admission after the index date and before 1 January 2020, for myocardial infarction, stroke or bleeding. Myocardial infarction and stroke were defined with the algorithms established by the Lombardy region ,23. BleePeople were followed from the index date to the date of each of all possible events or until the end of follow-up (31 December 2019). To reduce the possible bias due to the different time of availability on the market of NOACs in the analysis, the maximum follow-up was truncated to 2 years.t-test, or chi-squared test when appropriate.For each NOAC, the characteristics of the analyzed population were presented as frequencies or means, and compared with warfarin by To adjust for potential confounding due to indication bias, for each comparison between any different type of NOAC and warfarin, we applied a propensity score Kernel weighting. The propensity score approach has been applied to make the sample distribution of the observed covariates very similar in treated (any single NOAC) and untreated (warfarin) groups, assuring that any difference is mainly attributed to the treatment itself and that the covariates  and treatment become unrelated in both groups. This technique may have the potential to estimate the casual effect of the treatment . The appRubin recommends that B should be less than 25 and that R be between 0.5 and 2 for the samples to be considered sufficiently balanced [p-value of less than 0.05 was considered significant for all tests. All statistical analyses were conducted using Stata Statistical Software: Release 12. College Station, TX: StataCorp LP.For each NOAC, multivariate hazard ratios (HR) and 95% confidence intervals (CIs) for overall mortality, hospitalization for myocardial infarction, stroke or bleeding were calculated using Cox models, in comparison with warfarin. All the variables used for propensity score computation were included in each multivariate model. Moreover, we also included the Kernel weights as the weighting variable in the full models. A two-tailed The characteristics of the 8543 NVAF patients included in the analysis are shown in p < 0.001), and higher for both edoxaban  and apixaban . The proportion of women was higher among patients treated with apixaban  and edoxaban  than patients prescribed warfarin (44.2%).The mean age at the start of treatment was lower for patients prescribed rivaroxaban than warfarin . The proportion of patients using platelet inhibitors did not differ among groups (mean 4.2%). The use of PPI was lower for all the NOACs users (from 55.0% to 62.5%) than for warfarin users .Patients using NOACs had a significantly lower average number of comorbidities (from 2.0 to 2.1) than those using warfarin , edoxaban  and apixaban  than for warfarin users (35.5%).Concerning residence area, the proportion of those residing in Milan was greater for those prescribed rivaroxaban  and rivaroxaban  than warfarin users (1.16).The mean follow-up  was longer for dabigatran, apixaban , 114.6 (100.4–130.8) for edoxaban (n = 220), 111.1 (100.3–123.2) for apixaban (n = 364), 68.6 (57.4–82.0) for rivaroxaban (n = 121) and 68.1 (57.6–80.6) for dabigatran users (n = 136). The crude rate of hospitalizations for acute myocardial infarction was 93.0 per 1000 person-years for warfarin , 68.4 (57.6–81.3) for dabigatran, 59.6 (43.6–65.9) for rivaroxaban, 58.6 (48.6–70.8) for edoxaban and 53.6 (43.6–65.9) for apixaban users.During the first two years after the index date, the crude mortality rate was 150.3 (95% CI 130.4–173.1) per 1000 person-years for warfarin users  among patients using warfarin, and crude rates were 27.2 (22.1–33.6), 25.4 (19.1–33.7) and 24.7 (18.3–33.3) for apixaban, edoxaban and rivaroxaban users, respectively.Moreover, there were 60 hospitalizations for bleeding among warfarin users , 135 among those prescribed apixaban , 73 for edoxaban , 72 for dabigatran  and 52 for rivaroxaban .Regarding hospitalization for myocardial infarction during the first two years of follow-up, all NOACs showed adjusted HR lower than unity in comparison with warfarin   and by 26% for apixaban users  in comparison with warfarin users. The risk was numerically but not significantly reduced for edoxaban  and rivaroxaban  users.Finally, the risk of hospitalization for bleeding during the first two years of NOAC exposure was reduced for rivaroxaban users  and numerically but not significantly lower than that for warfarin for the other NOACs users, from −22% to −19% .In this large cohort of Italian NVAF patients based on the real-world population, we compared the short-term comparative performance of warfarin vs. four NOACs currently on the Italian market: dabigatran, rivaroxaban, apixaban and edoxaban. The purpose of the study was to provide evidence from clinical practice on both the effectiveness and the safety of NOACs compared to traditional warfarin. NOACs have shown efficacy and safety equal to or greater than warfarin in randomized clinical trials ,27,28,29A recent meta-analysis, including 28 real-word studies, confirmed the experimental results for dabigatran, rivaroxaban and apixaban . NotablyEdoxaban was authorized in the European Union in June 2015, and in Member States thereafter. In Italy, edoxaban entered into the market in late 2016, more than 2 years after dabigatran, 2 years after rivaroxaban and 18 months after apixaban . TherefoWe showed that all the four analyzed NOACs were more effective than warfarin in reducing two-year overall mortality, whereas apixaban, edoxaban and rivaroxaban also significantly decreased hospitalizations for myocardial infarction.Additionally, dabigatran and apixaban were associated with a decreased risk of hospitalization for stroke. Furthermore, the hazard ratio of hospitalization for bleeding was below unity for all NOACs, although only rivaroxaban reached statistical significance .Our data show that edoxaban was as effective as the other NOACs in significantly reducing mortality, as compared to warfarin. Moreover, edoxaban use was associated with numerically lower rates of hospitalizations for bleeding, confirming the results of a European observational study carried out on high-risk patients with NVAF routinely treated with edoxaban from 10 countries, that recently documented low rates of stroke, systemic embolism and major bleeding . FurtherThe real-world picture of NOACs is changing rapidly, based on the availability of new drugs . A recenThe present study has several limitations, which mainly relate to the observational nature of the data. Some unmeasured and residual confounding is likely to persist. However, this limitation is typical of all real-world studies. Moreover, we sought to address indication bias—for each NOAC or warfarin prescription—by a Kernel weighting, which adjusted each NOAC and warfarin patient based on a specific propensity score computed on the basis of many demographic and clinical covariates. We also included the number of comorbidities as a general measure of the health status. The check of bias changed before and after weighting measures based on the efficacy of such an approach.Another limitation of this study, typical of all real-world studies based on administrative data, is represented by the exclusion of non-resident subjects who consume drugs, since it is not possible to identify the outcomes.These exclusions are more theoretical than realistic .As in all real-world studies, we do not have data on the quality of anticoagulation control among warfarin users, as reflected by time in the therapeutic range, which is important given its relationship with the efficacy and safety of VKA therapy. Moreover, the clinical outcomes of the study are based on specific hospitalization codes. Therefore, some errors cannot be excluded. Furthermore, the risks for clinical outcomes should also be considered, limited to those complications (including bleeding) so severe that they required hospitalization. Therefore, results may not be representative of the average real-world population. Moreover, no clues for the appropriateness of anticoagulant prescriptions may come from this study .http://dati.istat.it, accessed on 30 July 2021). Furthermore, in the Framingham study, the risk of incident NVAF increased for BMI ≥ 30 kg/m2 [The prevalence of NVAF is strongly influenced by the age of patients . As of 130 kg/m2 . The proFinally, the short-term follow-up, chosen for a fair comparison among the NOACs, did not allow for any prediction of late efficacy and safety.Our results showed that in the real world, the NOACs are, in the first two years from starting treatment, more effective and safer than warfarin, at least for the analyzed outcomes. Their use is associated—in multivariate models—with a reduced risk of dying , of hospitalization for myocardial infarction , of stroke (dabigatran and apixaban) and of hospitalizations for bleeding (rivaroxaban).


The present review and meta-analysis identified meaningful benefits of exercise on QoL of HNC survivors; this has been confirmed in a meta-analysis. This review adds evidence supporting exercise interventions on Head and Neck Cancer population whose opportunities for successful recovery after medical treatment are more limited.The objective was to describe the effectiveness of different physical therapy modalities to improve Quality of Life (QoL) in Head and Neck Cancer (HNC) survivors. PubMed, Scopus, Web of Science, CINAHL and Cochrane Library were searched for randomized clinical controlled trials published until 30 April 2020. Risk of bias assessment and meta-analysis were conducted using the Cochrane tools. A total of 251 records were retrieved, and 10 met the inclusion criteria. Interventions whose parameters focus on a 12-week exercise programs of aerobic activity  or Progressive Resistance Training (PRT) for the whole body are effective and safe modalities improving QoL in HNC survivors. Electrophysical agents did not show significant results between groups. As for the assessment of methodological quality, 4 of the 10 articles included had a high risk of overall bias. Only five articles provided sufficient information to conduct a meta-analysis for exercise program intervention on QoL, showing a tendency in favor of intervention group, even when the global results did not show statistically significant improvements (pooled Cohen’s d 0.11; 95% CI: −0.27 to 0.50; I Head and Neck Cancer (HNC) covers sites located on the lips (mucosa surface), oral cavity, pharynx, larynx, cervical esophagus, nose, paranasal sinuses, salivary glands, thyroid gland and parathyroid glands . Both eaA large proportion of these patients receive surgery 32–75%) [% [5], ra“Cancer survivor” has been defined in different ways; one of them is as follows: patients living beyond the end of treatment or 3–5 years from diagnosis in complete remission ,16.The survival rate in HNC is one of the most complex owing to the anatomical difficulty of this region  and the Physical therapists, who are responsible for examining and managing the side effects derived from cancer and its treatment, have become an indispensable part of the continuum of cancer care ,25,26. DBetween both published reviews and meta-analyses, there is a tendency to evaluate the effects of exercise ,34,35,36A systematic review protocol that defined inclusion criteria, search strategy and outcomes of interest was developed and registered with PROSPERO . Reporting of this systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . AccordiDetailed search strategies were developed for each database used in the review: Medline (via PubMed searcher), Scopus, Web of Science, Cumulative Index for Nursing and Allied Health Literature (CINAHL) and Cochrane Library. The literature search was conducted between 1 March and 30 April 2020. The following keywords were used for the search: “head and neck cancer”, “survivor”, “physical therapy modalities”, “quality of life” . Keywords were combined using the Boolean operators “AND” and “OR”. No restrictions were placed on the year of publication, but only published studies in Spanish and English from inception to 30 April 2020 were considered. Studies were included if they met the following criteria: (1) design: randomized controlled trials (RCTs); (2) population: adults (over 18 years old) considered to be HNC survivors; (3) intervention: physical therapy modalities such as electric stimulation therapy , exercise therapy, hydrotherapy, musculoskeletal manipulations , myofunctional therapy and laser therapy (low-level light therapy); (4) control group: placebo, usual care or no intervention; and (5) outcome: QoL. Furthermore, an automatic alert notification for new publications relevant to search term combination was created in all databases from the initial search date. Two independent researchers (B.B.M. and M.L.L.) performed the selection of the studies through Covidence systematic review software  ; then, tp-values. The outcome measures, such as the European Organization for Research and Treatment of Cancer Questionnaire (EORTC QLQ-C30) [This process was performed independently by two review authors (B.B.M. and M.L.L.) using an Excel spreadsheet applying a predesigned criterion data collection form. The data collected were study characteristics such as authors, country of origin, study design and sample size and participant characteristics such as sex, mean age, stage of cancer , location of HNC  and type of oncological treatment  were included in the data. Additionally, data on the characteristics of the interventions included frequency, duration, comparison, outcome measures, adverse events, measured time points, intervention group (IG), control group (CG), mean change, group differences in mean change and QLQ-C30) , FunctioQLQ-C30)  and HeadQLQ-C30)  were recQLQ-C30) .2  [After the data extraction, the reviewers determined the possibility of performing a meta-analysis by considering if the heterogeneity was moderate or strong as assessed by Igeneity) . For theThe literature search identified 251 articles, with 77 duplicates, and automatic alert notification provided information on approximately 1 new article, which was also included. A total of 148 articles were excluded after screening the titles and abstracts. After that, 27 studies were then retrieved for full-text review, and 17 records were excluded for the following reasons: 3 had incorrect patient populations, 9 were not RCTs, 2 had people undergoing active treatment, 1 included patients with metastasis, 1 included other treatments (nonsteroid anti-inflammatory drugs—NSAIDs) and 1 did not include QoL as a relevant outcome measure. Finally, 10 records were included in this systematic review. Interrater agreement in the selection of studies was 51.4% . After dn = 4) [n = 2) [The 10 studies included in this review were conducted across six countries, most commonly in Canada (n = 4) ,59,60,61 [n = 2) ,63. A toRegarding physical therapy modalities, 60% of the studies focused on exercise programs ,63,64,652 power density, 71 J/cm2 dose per point and application time 20 s on major salivary glands, parotid glands, submandibular glands and sublingual glands (0.028 cm2). Patients underwent two weekly sessions for 6 weeks. Of the included studies, only three considered follow-up periods [Considering the electrophysical agents, electrostimulation was the main agent performed ,61,67. I periods ,65, incl periods , another periods ,63,64,65 periods ,59,60,63 periods ,64,65 an periods , H&N CanOnly one study  (10%) rep < 0.05) from baseline to week 12. Both studies used the same instrument (EORTC QLQ-C30). However, O’Neill et al. [p = 0.433). McNeely et al. [p > 0.05). Additionally, McNeely et al. [p < 0.001) and CG (p < 0.05) postintervention. Considering studies that tested electrophysical agents, no intergroup differences were found (p > 0.05) [p < 0.05), although different instruments were used as outcomes . Regarding follow up, only three studies assessed cumulative effects [The analysis was performed by subgroups considering each physical therapy modality. Chang et al.  and Lønbl et al.  did not y et al.  and Su ey et al.  measuredy et al.  did not y et al.  and Lønby et al.  had favo > 0.05) ,61,66,67 > 0.05) ,66,67 sh effects ,65 as itThe results of the methodological quality assessment of the 10 included RCTs are shown in The major methodological quality issues were deviations from intended interventions (30%) and missing outcome data (30%) with “high risk”. In contrast, “low risk” percentages were reported for the randomization process (70%) and measurement of the outcome (70%). Of the ten studies included in the systematic review that measured QoL, it was only possible to include five in the meta-analysis ,63,64,65The meta-analysis included a total of 182 participants, 93 (IG) and 89 (CG). Regarding the assessment instruments used to measure QoL, two studies used the EORTC QLQ-C30 ,65, two 2 42.68%; p heterogeneity = 0.12). Pooled results are presented in Regarding the data presented, there seems to be a tendency in favor of IG in terms of improvement in QoL after exercise program intervention  or PRT for the whole body seem to be the modalities with more benefits to ameliorate QoL perception in HNC survivors. Neither electrophysical agent  showed significant results between groups, although almost every group improved their results. The meta-analysis supports the results in favor of exercise programs.HNC survivors are recognized as a heterogeneous population in regard to the location of the tumor , and as On the one hand, there are reports that involved only upper limb and scapular muscles ,59,63, aAnother detail that could have been crucial would be the use of an informatics component . MonitorFinally, all reports were performed over 12 weeks (with or without significance), so it seems to be an adequate point to observe benefits in terms of QoL. Both modalities (aerobic and/or resistance exercises) should be considered in the rehabilitation of HNC survivors. Research within breast and colon cancer populations has already demonstrated relevant effects of different exercise interventions on global health status, pain, QoL and fatigue through clinical trials ,82,83,84Regarding electrophysical agent studies, there was no benefit between groups, even when the intervention and comparison groups were successfully separated ,66,67. SMeta-analysis suggests that patients in the exercise group improved their QoL compared to the CG. Regarding the results and the aim of systematic review, the possibility of carrying out a network meta-analysis was raised to determine the mediation effect between the different physical therapy interventions proposed in the global effect on QoL and to establish the best possible treatment. However, although it would have been interesting to know a global estimator of the efficacy of these interventions in improving the QoL of HNC, the heterogeneity of these interventions, added to the small number of studies collected, made it impossible to combine them quantitatively. However, this same reasoning supports the results of the meta-analysis in favor of exercise: the inconclusive results of the other techniques and the low number of studies, together with the significant tendency shown in the meta-analysis, seem to postulate exercise as the gold standard in improving the QoL of these patients. The results are in line with several meta-analyses ,91,92,93To our knowledge, this is the first review evaluating the effect of different physical therapy modalities on improving QoL in HNC survivors. The strengths of this review are reporting according to the PRISMA guidelines, inclusion of risk of bias assessment and meta-analysis with the low statistical heterogeneity obtained.Limitations in published reports restricted the ability to determine those parameters of the interventions that were effective; further limitations include that the meta-analysis comprises only five studies and none of studies achieved a low overall risk of bias assessment, and it was not possible to combine the data from the studies that used electrophysical agents due to lack of methodological similarity between them.In summary, this systematic review identified meaningful benefits of exercise with regard to QoL. This has been confirmed in a meta-analysis that comprises five out of ten studies involved. However, reports based on electrophysical agents such as electrostimulation and laser therapy were not able to find results between groups despite groups improving separately. The maintenance of effects in both modalities was also inconclusive. The potential of exercise and partly electrophysical agents to enhance QoL in HNC survivors seems to be clear, although it has not been possible to reach a reliable consensus in terms of the parameters analyzed due to the disparity in the data retrieved. This systematic review has brought to light the gaps in physical therapy strategies that affect this oncology population. This issue can be a starting point for future lines of research. To reinforce the emerging findings, it has found that all methods evaluated seem to be safe. This review adds to the growing evidence supporting exercise interventions to improve QoL in a cancer population such as HNC survivors, whose opportunities for successful recovery after medical treatment are more limited.


In rabbit farms, the main production costs come directly from food supplies. Although the reproductive outcomes in this species are acceptable, the results are worse when it comes to primiparous rabbits, so it is recommended that insemination be carried out post-weaning. By avoiding the overlap of the second gestation and the first lactation, better fertility results are expected. Still, despite this, the rabbits garner more adipose tissue than desired, and the productive efficiency deteriorates in the long term. The purpose of this study was to evaluate the influence of different periods of moderate feed restriction  applied during the second pregnancy of primiparous does. We studied fetoplacental development, productive parameters, metabolism and possible stress indicators. Results showed that the voluntary feed intake of dams increased right after feed restriction. No permanent alterations were found in reproductive outcome, metabolism or welfare of does, meaning that this feeding strategy could be successfully applied in rabbit farms.In this study, a maternal feed restriction  in primiparous rabbit does was applied from day 0 to 7 post artificial insemination (AI) , from day 7 to 21 post AI , from day 0 to 21 post AI  or fed ad libitum during whole pregnancy . Feed intake (FI) was measured after MFR was over. On day 28 of gestation, fetoplacental development was evaluated (n = 11/group) and the productive parameters of the remaining dams were analyzed. Plasma free tri-iodothyronine (T3) and thyroxine, glucose, insulin, non-esterified fatty acids (NEFA), and corticosterone were analyzed during gestation and lactation (n = 5/group). After MFR, all groups significantly increased their voluntary FI. The longer MFR was, the lower the weight and length of the fetuses, but no long-term effects over litter performance were observed. R021 groups had the lowest T3 and the highest NEFA concentrations during pregnancy and showed insulin resistance at the end of gestation, but during lactation, energy homeostasis was balanced in all groups. MFR did not affect corticosterone concentrations. In conclusion, the ration setting applied slightly involved the energy homeostasis and metabolism of the animals, but their overall metabolic condition, productive performance and welfare were not compromised. In rabbit farms, dam feeding represents roughly a third of the total feed costs  . AlternaMFR has had diverse targets to avoid fattening and high mortality around parturition , to deteWhat we can introduce about the application of MFR is largely based upon our previous experimental studies ,15, in wThus, in order to gain further understanding of the metabolic changes and energetic modulations of primiparous does subjected to MFR, the novelty of this study has been to apply shorter and more specific periods of restriction during gestation studying the long-term consequences on additional hormones and metabolites. Among others, thyroid hormones are key to the regulation of metabolism and adaptation to fasting. They contribute to both mandatory and adaptive thermogenesis, regulating appetite and energy expenditure . On the Therefore, the main goal of this study was to determine in primiparous lactating does the comparative effect of MFR applied during one, two or three weeks of pregnancy followed by ad libitum refeeding on the feed intake of the dams, feto-placental development on day 28 of pregnancy, productive performance, the weekly plasma concentrations of thyroid hormones and corticosterone, and the glucose and lipid metabolism during pregnancy and consequent lactation.The animals were housed at the animal facilities of the Technical University of Madrid (Spain), which meet the local, national and European requirements for Scientific Procedure Establishments . The experimental design is displayed in -Control group (n = 92) always fed ad libitum.-R07 (n = 96) with MFR applied from day 0 to day 7 post-AI.-R721 (n = 92) with MFR applied from day 7 to day 21 post-AI.-R021 (n = 94) with MFR applied from day 0 to day 21 post-AI.After parturition and weaning (day 30 post-partum) these does started a second cycle and were artificially inseminated (AI) with fresh diluted semen . Each dose contained at least 20 million spermatozoa in 0.5 mL of semen diluent. Ovulation was induced with gonadoreline at the time of AI . At this time (day 0), a total of 374 does were randomly allocated into four groups:MFR was set at 60% of the measured voluntary feed intake of the first pregnancy (105 g/day), in order to maintain their basal metabolic needs. In the fourth week of pregnancy, all animals were fed ad libitum until the end of the study. Pregnancy was diagnosed at day 11 post-AI by means of abdominal palpation and fertility ([no. of does pregnant at day 11 after AI/no. of does inseminated] × 100) was calculated. Feed intake was weekly calculated exclusively in the pregnant does from day 0 until the day of parturition.On day 28 of gestation, 44 pregnant does (n = 11 from each group) were weighed and euthanized with an overdose barbiturate  to study fetoplacental development. A ventral laparotomy was performed to count the corpora lutea present in the ovaries and calculate the ovulation rate per animal. Both uterine horns were opened to extract the fetuses and placentas, calculating the rate of viable structures [ × 100]. In morphologically viable fetuses, crown–rump length (CRL), biparietal (BPD), occipito-nasal (OND), and thoracic (TD) diameters were measured. Whole fetuses were weighed, and after decapitation, heads and trunks were weighed separately. Fetal organs’  weights and their ratios (organ weight/fetus weight) were calculated to assess fetal growth patterns. Placentas were weighed both as a whole and separately for the maternal (decidua) from the fetal (labyrinth) part. The length, width and thickness of each of the pieces were recorded. Placental efficiency was calculated by dividing the weight of the fetus between the weight of the whole placenta.The gestation of the remaining rabbit does was carried out, and prolificacy  and litter weights at birth were recorded. Litter size was subsequently standardized to 8–12 kits by removing or adding kits within each experimental group.During lactation, a total number of 50 litters from each experimental group were weighed at day 7, 14 and 21 post-partum. Milk production was estimated using the regression equation developed by Helfenstein et al.  as folloIn addition, the evaluation of metabolic and hormonal parameters was carried out on blood samples obtained from the marginal ear vein of randomly chosen females. An initial blood sample was taken at the moment of AI (day 0 of pregnancy) from 10 dams before being allocated into the experimental groups. After pregnancy diagnosis, five pregnant animals per group were sampled at three different moments of gestation: day 14 (n = 20), day 21 (n = 20) and day 28 (n = 20) of gestation. Following parturition, samples were taken from lactating females (five per group) at three moments of lactation: day 7 (n = 20) and day 14 (n = 20). On day 14 post-partum, all does were re-inseminated as previously described. Then, on day 30 post-partum, weaning was performed and blood samples were taken from pregnant (n = 20) and non-pregnant (n = 20) does from the third AI. Blood samples were placed in tubes with EDTA as an anticoagulant and centrifuged for 15 min at 1200 g to obtain plasma.Moreover, the evaluation of energetic homeostasis was performed by measuring free triiodothyronine (T3) and thyroxine (T4) in plasma samples using commercial immunoassays . The assay sensibility was 0.05 pg/mL for both T3 and T4, and the inter-assay and intra-assay variation coefficients were 9.8% and 3.6% for T3 and 4.9% and 3.3% for T4. Glycemic metabolism was assessed by the determination of insulin and glucose levels. Insulin was determined using a commercial immunoassay  with an assay sensitivity of 0.071 mU/L and inter-assay and intra-assay variation coefficients of 6.2% and 4.2%, respectively. Insulin sensitivity was calculated by glucose-to-insulin ratio and the homeostasis model assessment for insulin resistance (HOMA-IR) using the following equation: [insulin (mU/L) × (glucose (mg/dL)/18)]/22.5 . Low HOMp value of less than 0.05. All data are presented as least squares means.SAS software  was used for the statistical analysis of the data. In all analyses, the doe was considered the experimental unit. Differences between groups in the total feed intake were analyzed by a one-way ANOVA (Proc GLM) with the feed regime as the main effect. The effect of MFR on weekly feed intake during gestation was analyzed by repeated measure analysis (MIXED), with feed regime , time , and their interaction as main effects. Ovulation rate, live body weight of does, number, weights and measurements of fetuses and placentas, and placental efficiency on day 28 of pregnancy were analyzed (Proc GLM) with feed regime as main effect and considering the litter size as a covariate. With the same procedure, prolificacy and milk production were analyzed with feed regime as the main effect. A chi squared test (Proc CATMOD) was used to evaluate the effect of MFR on fertility and percentage of culled does. Litter weights during the lactation period were analyzed by repeated measure analysis (Proc MIXED), considering the MFR, the time  and their interaction in the model. For hormonal and metabolic parameters, due to the blood sampling being carried out in independent randomly chosen rabbit does, a GLM procedure was performed, considering as main effects the treatment (MFR), the time , and the interaction between both. If significant main effects were detected, a Tukey test (for parametric variables) or Kruskal–Wallis (non-parametric variables) were used to compare means among groups, considering the existence of significant differences for a p < 0.0001). The Control and R07 groups consumed 5854 ± 124.3 g and 5529 ± 109 g, respectively, followed by R721 does (4518 ± 112 g) and the R021 group (4007 ± 106.3 g). The weekly evolution of daily feed intake is shown in As expected, whole feed intake during pregnancy was different between groups (p = 0.0254), whereas does restricted for three weeks (R021) had an intermediate body weight.Results obtained on day 28 of pregnancy are shown in From a reproductive point of view, the number of corpora lutea, total fetuses per doe, implantation rate and fetal viability were high and similar in all groups. In R07 does, there is a tendency (p = 0.0824) to have more fetuses but with lower viability.p < 0.01) the total, head and trunk weights and CRL of fetuses, being lower in those from R721 and R021 does than in the control group, and intermediate in R07 females. Regarding fetal cephalic diameters, BPD was similar in all groups (p > 0.05), however OND was higher in Control and R07 does than in R021, being intermediate in R721 (p = 0.0032). Fetal thoracic diameter was greater in R07 compared to the other three groups (p = 0.0034). Regarding fetal organs, only liver, lung and kidney weights were different between groups , with those of the Control group being heavier except for the liver.Feed restriction significantly affected (p < 0.0001). Furthermore, the labyrinth of R07 does tended to be the heaviest (p = 0.0809), whilst that of R021 does was the shortest (p < 0.0001) and that from R721 the thinnest (p < 0.0053). In does subjected to MFR for two weeks (R721), decidua had lower weight (p < 0.0001) than the other three groups. The longest decidua was observed in Control does (p < 0.0001) and the thinnest was observed in R721 (p = 0.0069). Finally, the lowest placental efficiency was observed in R07 does, the highest in R721, and intermediate in Control and R021 does (p = 0.0162).Weights and dimensions of labyrinth and decidua from euthanized does at day 28 of pregnancy are shown in Productive outcome is shown in p > 0.05). However, after litter adjustment, the effect of MFR on the number of weaned kits and mortality of kits during lactation was significantly different between groups . Control and R07 does weaned more kits than R721 does, whereas R021 does had an intermediate result. The highest and lowest mortalities during lactation were observed in R021 and R07 litters, respectively.Fertility, kits born alive and stillborn, and litter weight at birth and during lactation were similar between groups (p > 0.05).At the end of the study, the percentage of culled does was 7.6, 4.2, 5.4 and 6.4% in Control, R07, R721 and R021 groups, respectively  but similar to R721 ones. Plasma T3 concentrations decreased significantly on days 14 and 21 of pregnancy in relation to day 0 and returned to intermediate values on day 28 (p = 0.0026). Plasma T4 concentrations on Days 14 and 21 of pregnancy were also significantly lower than on day 28 (p = 0.0001) but similar to that on day 0. MFR did not affect T4 concentrations, T3 to T4 ratio, plasma glucose and HOMA-IR (p > 0.05).Regarding thyroid hormones, the animals subjected to the most extended restriction treatment (R021) had lower plasma T3 concentrations than Control and R07 does . In addition, plasmatic glucose increased dramatically at the end of pregnancy in all groups (p < 0.0001).However, insulinemia was lower, and glucose-to-insulin ratio was higher in R721 does than in Control and R07 does, but similar to R021 ones (p = 0.0158). No significant differences in NEFA levels throughout the pregnancy period were observed (p > 0.05).The highest and lowest NEFA concentrations were obtained in R721 and R07 does, respectively, and Control and R021 does showed intermediate values (p < 0.0001).Finally, plasma corticosterone concentration was only affected by time. The lowest concentrations of this stress indicator were observed at 21 and 28 days of pregnancy (p = 0.0353), insulin (p = 0.0055), NEFA (p = 0.0100) and HOMA index (p = 0.0049) (MFR and time had significant effects on plasma concentrations of T3 (p > 0.05). As the lactation period progressed, T3 and glucose concentrations remained at similar values during the first two weeks of lactation, but insulin and HOMA-IR decreased on day 14 (p = 0.0006) compared to day 7. On weaning day, non-pregnant does had lower T3 concentrations than pregnant ones (p < 0.0056), but HOMA-IR, glucose and insulin concentrations were similar in both (p > 0.05).As shown in Energy mobilization measured by means of plasma NEFA concentrations was similar in all groups and during all lactation. Plasma corticosterone concentrations as welfare indicators were not affected by MFR. However, significant increases in this hormone were observed as lactation progressed. No significant interactions between MFR and time in any of the studied variables were detected in this period.This work deals with the potential consequences of moderate MFR in different periods  throughout gestation on reproductive outcome, including fetoplacental development and post-natal growth and survival of litters from primiparous rabbit does, and introduces further insight involving endocrine and metabolic parameters during pregnancy and the following lactation.After different MFR periods, when fed ad libitum, all pregnant does significantly increased their feed intake. These results match with those observed in our previous studies ,14,15. DAs expected, the number of corpora lutea assessed in the rabbits on day 28 of gestation was similar in all groups, as MFR was applied right after AI, with no impact on the ovulation rate. Similar results have been described in our previous studies where only Control and R021 treatments were compared ,15. NoneThe dimensions of the fetuses were affected by the restriction, so that the longer it was, the more weight and length of the fetuses decreased, although the TD and the OND did not seem to have the same response. MFR usually causes vital organs, such as the brain or the liver, to increase their relative weight to the detriment of other organs ,26. ThisIn addition, MFR for 1, 2 or 3 weeks affected the growth of the placental structures. The largest placentas were those of R07 does, but this group was one of the least efficient, meaning that even though fetal growth directly depends on the placenta , in thisFurthermore, during lactation and in the juvenile stage, our previous studies ,15 that Regarding the effects of MFR on fertility and prolificacy of does, there were no adverse consequences. Although litter weight and milk production were similar between groups during lactation, a significant increase in kit mortality was observed in both the Control and R021 groups. It may be that litter adjustment performed after birth affected these results, but it is difficult to explain. Interestingly, does in group R07, despite previous lower fetal viability detected during pregnancy, had a better weaning outcome and lower kit mortality, outpacing the results of the other groups.Concerning the mortality rate of the dams during the study , the data collected did not show significant differences between groups. They were consistent with the experimental farm’s historical data, so these casualties can be considered incidental rather than related to the experimental conditions.As to the effects of MFR on energy metabolism, thyroid hormones were determined to evaluate metabolic adaptation to energy intake deprivation. In the current study, the mothers that underwent a longer MFR presented lower T3 plasma concentrations. During the first three weeks of gestation, a decrease in T3 and T4 was also noted, along with an increase at the end when the females were fed ad libitum. The significant treatment × time interaction observed in T3 concentrations was due to the R021 group having the lowest T3 values on day 21 of pregnancy (after three continuous weeks of moderate restriction), but by the end of gestation all groups had similar concentrations. The decrease in free T3 during periods of feed restriction usually reduces the basal metabolic rate, resulting in energy savings for the animal , but of The studied relation between insulin and glucose profiles suggests that females in the first half of pregnancy, being subjected to MFR, manage the diet’s energy and body reserves. Insulin is an intermediate metabolic hormone, involved in many metabolic pathways to maintain energy homeostasis by coordinating the different axes and systems ,35. FurtMoreover, HOMA-IR results showed significant differences between groups by the end of gestation (day 28). Particularly, R021 does displayed a critical rise in HOMA-IR values, while other groups still did not exceed the limit to be considered insulin resistant (R07 and R721). This could be due to the continuous consumption of glucose by the fetuses that forces an increase in the mother’s hepatic production of glucose by the liver during fasting to maintain plasmatic glucose sufficient to meet the needs of glucose-dependent tissues , which wIn humans and other species, the second half of pregnancy is defined by a progressive increase in resistance to the action of insulin, so that in the third-trimester insulin sensitivity is about a third of normal and insulin levels are increased by about four times ,40, whicAs shown by the data, MFR during gestation affected the overall energetic balance of the does and high NEFA plasma concentrations are a manifestation of body reserves mobilization. In this study, MFR affected plasma NEFA concentrations, and the highest values were observed on day 14 in the mothers with a more prolonged period of restriction at this time. This is in accordance with other studies where authors determined higher NEFA plasma concentrations in does undergoing slight to moderate MFR during similar gestation periods ,42. AddiConductive to the lactation period, the main difference between groups occurred with T3 concentrations in pregnant and non-pregnant females, with lower levels in the latter. Since the third AI was performed on day 14 after parturition, increased T3 in lactating-pregnant dams may be explained by its role in tissue synthesis, particularly in the first half of pregnancy . MoreoveSurprisingly, no differences due to MFR between experimental groups were observed during pregnancy and lactation, something unexpected since corticosterone was assessed as a hormonal measure of stress in the animals. Some authors contend that plasma corticosterone concentrations correspond more with metabolic stress than with behavioral stress , which wHowever, it is interesting to note that at the end of lactation, corticosterone levels are higher than those on day 7 of lactation. This could be explained due to the size of the kits towards the end of lactation. Kits begin to leave the nest at 14–16 days of age , and othThe present study states that a moderate MFR (60% of the estimated voluntary feed intake) applied during 1, 2 or 3 weeks of gestation followed by ad libitum refeeding confirms previous results regarding compensatory food intake by mothers, which helps to preserve maternal energy homeostasis  and lipid metabolism (NEFA). This allowed the necessary energy supply to be delivered to the fetuses to conduct fetal growth and development satisfactorily, confirming previously obtained results as no major long-term effects in the early life development of the offspring were observed. Moreover, the compensatory feed intake granted the maintenance of an adequate productive performance in the current pregnancy and showed no effect whatsoever in the amount of milk produced, the viability of litters or the mortality rate of the dams. In addition, the corticosterone concentrations observed throughout pregnancy and lactation seem to indicate that, in our experimental conditions, the moderate MFR applied seems not to induce additional stress in dams along the gestation and lactation periods studied. Moreover, it has proven that this strategy can be profitable for the farmer as overall feed intake was lower in all experimental groups compared to the Control group. In summary, these results reveal that as long as the feed supply covers maintenance needs, moderate MFR is a suitable strategy to reduce production costs, since it implies no adverse effects on the metabolic, energetic and welfare status of the dams, and on pre- and post-natal growth of fetuses and litters, respectively.