The Role of Short-Chain Fatty Acids, Particularly Butyrate, in Oncological Immunotherapy with Checkpoint Inhibitors: The Effectiveness of Complementary Treatment with Clostridium butyricum 588.

The discovery of immune checkpoints (CTLA-4, PD-1, and PD-L1) and their impact on the prognosis of oncological diseases have paved the way for the development of revolutionary oncological treatments. These treatments do not combat tumors with drugs "against" cancer cells but rather support and enhance the ability of the immune system to respond directly to tumor growth by attacking the cancer cells with lymphocytes. It has now been widely demonstrated that the presence of an adequate immune response, essentially represented by the number of TILs (tumor-infiltrating lymphocytes) present in the tumor mass decisively influences the response to treatments and the prognosis of the disease. Therefore, immunotherapy is based on and cannot be carried out without the ability to increase the presence of lymphocytic cells at the tumor site, thereby limiting and nullifying certain tumor evasion mechanisms, particularly those expressed by the activity (under positive physiological conditions) of checkpoints that restrain the response against transformed cells. Immunotherapy has been in the experimental phase for decades, and its excellent results have made it a cornerstone of treatments for many oncological pathologies, especially when combined with chemotherapy and radiotherapy. Despite these successes, a significant number of patients (approximately 50%) do not respond to treatment or develop resistance early on. The microbiota, its composition, and our ability to modulate it can have a positive impact on oncological treatments, reducing side effects and increasing sensitivity and effectiveness. Numerous studies published in high-ranking journals confirm that a certain microbial balance, particularly the presence of bacteria capable of producing short-chain fatty acids (SCFAs), especially butyrate, is essential not only for reducing the side effects of chemoradiotherapy treatments but also for a better response to immune treatments and, therefore, a better prognosis. This opens up the possibility that favorable modulation of the microbiota could become an essential complementary treatment to standard oncological therapies. This brief review aims to highlight the key aspects of using precision probiotics, such as Clostridium butyricum, that produce butyrate to improve the response to immune checkpoint treatments and, thus, the prognosis of oncological diseases.

Sports-Related Gastrointestinal Disorders: From the Microbiota to the Possible Role of Nutraceuticals, a Narrative Analysis.

Intense physical exercise can be related to a significant incidence of gastrointestinal symptoms, with a prevalence documented in the literature above 80%, especially for more intense forms such as running. This is in an initial phase due to the distancing of the flow of blood from the digestive system to the skeletal muscle and thermoregulatory systems, and secondarily to sympathetic nervous activation and hormonal response with alteration of intestinal motility, transit, and nutrient absorption capacity. The sum of these effects results in a localized inflammatory process with disruption of the intestinal microbiota and, in the long term, systemic inflammation. The most frequent early symptoms include abdominal cramps, flatulence, the urge to defecate, rectal bleeding, diarrhea, nausea, vomiting, regurgitation, chest pain, heartburn, and belching. Promoting the stability of the microbiota can contribute to the maintenance of correct intestinal permeability and functionality, with better control of these symptoms. The literature documents various acute and chronic alterations of the microbiota following the practice of different types of activities. Several nutraceuticals can have functional effects on the control of inflammatory dynamics and the stability of the microbiota, exerting both nutraceutical and prebiotic effects. In particular, curcumin, green tea catechins, boswellia, berberine, and cranberry PACs can show functional characteristics in the management of these situations. This narrative review will describe its application potential.

The Potential Role of Probiotics, Especially Butyrate Producers, in the Management of Gastrointestinal Mucositis Induced by Oncologic Chemo-Radiotherapy.

Many clinical studies have now highlighted how the composition of the intestinal microbiota can regulate the effects of many oncological therapies. In particular, the modulation of microbial composition has been shown to enhance their efficacy and reduce potential side effects. Numerous adverse events induced by chemotherapy and radiotherapy appear to be strongly associated with an alteration in the intestinal microbiota caused by these treatments. This supports the hypothesis that the modulation or correction of the microbiota may decrease the toxic impact of therapies, improving patient compliance and quality of life. Among the most debilitating disorders related to oncological treatments is certainly mucositis, and recent clinical data highlight how the deficiency of short-chain fatty acids, especially butyrate, and specifically the lack of certain bacterial groups responsible for its production (butyrate producers), is strongly associated with this disorder. It is hypothesized that restoring these elements may influence the onset and severity of adverse events. Therefore, the intake of probiotics, especially butyrate producers, and specifically Clostridium butyricum (CBM588), currently the only cultivable and usable strain with a history of data proving its safety, could be a valuable ally in oncological therapies, reducing the associated discomfort and improving compliance, efficacy, and quality of life for patients.

Computational design of mRNA vaccines.

mRNA technology has emerged as a successful vaccine platform that offered a swift response to the COVID-19 pandemic. Accumulating evidence shows that vaccine efficacy, thermostability, and other important properties, are largely impacted by intrinsic properties of the mRNA molecule, such as RNA sequence and structure, both of which can be optimized. Designing mRNA sequence for vaccines presents a combinatorial problem due to an extremely large selection space. For instance, due to the degeneracy of the genetic code, there are over 10632 possible mRNA sequences that could encode the spike protein, the COVID-19 vaccines' target. Moreover, designing different elements of the mRNA sequence simultaneously against multiple objectives such as translational efficiency, reduced reactogenicity, and improved stability requires an efficient and sophisticated optimization strategy. Recently, there has been a growing interest in utilizing computational tools to redesign mRNA sequences to improve vaccine characteristics and expedite discovery timelines. In this review, we explore important biophysical features of mRNA to be considered for vaccine design and discuss how computational approaches can be applied to rapidly design mRNA sequences with desirable characteristics.

Preliminary Assessment of the Acute Effects of Far Infrared-Emitting Garments: What Are the Possible Implications for Recovery and Performance?

Technical clothing has recently been brought into the spotlight as one of the most promising tools to improve sports performance and to enhance sports recovery. Among technical clothing items, garments engineered to emit far infrared (FIR) spectrum frequencies have come to the fore as a treatment for pain, muscle fatigue, and tissue healing due to their potential antioxidative and anti-inflammatory properties, with applications not only during recovery phases but also in the active phases of exercise. These garments, composed of fibers mixed with noble metals and/or bioceramics that respond to body infrared frequencies by returning an FIR emission backwards, are thought to improve muscle oxygenation and therefore recovery. In this double-blind, randomized, placebo-controlled, crossover study, ten male trail running athletes wore a whole-body-covering suit marketed as Accapì-FIR (Bruno Chiaruttini S.r.l., Rezzato, BS, Italy), while a total body suit with the same polyester fiber without metal components was used as control for the intervention. Parameters such as weight, height, bioimpedance parameters (BIVA), lactate from capillary sampling, salivary cortisol, and average temperatures of different body areas were obtained before and after a twelve-minute incremental work run protocol on a treadmill whilst wearing the two kinds of garment. Using the intervention suit, compared to control, statistically significant reductions in BIVA parameters such as body resistance (-6.7%) and reactance (-5.4%) were observed before and after exercise while a greater, but not significant, weight reduction was observed with the intervention suit. Decrease in resistance could be the result of a different distribution of fluids and ions due to FIR influence on capillary and superficial circulation, leading ultimately to more efficient management of body heat and promoting recovery and supercompensation. Further studies on larger samples will be necessary to confirm and clarify these results.

Influence of the microbiota on the effectiveness and toxicity of oncological therapies, with a focus on chemotherapy.

Recent studies have highlighted a possible correlation between microbiota composition and the pathogenesis of various oncological diseases. Also, many bacterial groups are now directly or indirectly associated with the capability of stimulating or inhibiting carcinogenic pathways. However, little is known about the importance and impact of microbiota patterns related to the efficacy and toxicity of cancer treatments. We have recently begun to understand how oncological therapies and the microbiota are closely interconnected and could influence each other. Chemotherapy effectiveness, for example, appears to be strongly influenced by the presence of some microorganisms capable of modulating the pharmacokinetics and pharmacodynamics of the compounds used, thus varying the real response and therefore the efficacy of the oncological treatment. Similarly, chemotherapeutic agents can modulate the microbiota with variations that could facilitate or avoid the onset of important side effects. This finding has or could have considerable relevance as it is possible that our ability to modulate and modify the microbial structure before, during, and after treatment could influence all the clinical parameters related to pharmacological treatments and, eventually, the prognosis of the disease.

Ovarian Microbiota, Ovarian Cancer and the Underestimated Role of HPV.

In recent years, many studies have highlighted the possible close correlation between human diseases and definite patterns of microbial organisms colonizing various organs. Even at sites traditionally considered sterile, such as the upper female reproductive tract (FRT), it is now well-recognized as hosting a low biomass of different bacterial phyla. Additionally, the data from recent studies highlight a possible link between lower and upper FRT dysbiosis with a potential predisposition to cervical and ovarian cancer. Acinetobacter, chlamydia, increased mycoplasma, and lactobacillary scarcity in the upper FRT have all been linked to a predisposition to ovarian cancer. Additionally, a high-diversity vaginal community state type (CST) is linked to the presence and persistence of high-risk human papillomavirus (HPV), resulting in decreased cellular p53 activity and a reduction in the immune activity of T lymphocytes, resulting in cervical and ovarian cancer predisposition. While these findings are still far from being clarified in all aspects, in patients with multiple risk factors for ovarian cancer, a Lactobacillus crispatus treatment with a product with a proven ability to restore a favorable CST should be considered as an add-on therapy.

Ketogenic and Low FODMAP Diet in Therapeutic Management of a Young Autistic Patient with Epilepsy and Dysmetabolism Poorly Responsive to Therapies: Clinical Response and Effects of Intestinal Microbiota.

Autism spectrum disorder (ASD) is often associated with several intestinal and/or metabolic disorders as well as neurological manifestations such as epilepsy (ASD-E). Those presenting these neuropathological conditions share common aspects in terms of gut microbiota composition. The use of microbiota intervention strategies may be an approach to consider in the management of these cases. We describe the case of a 17-year-old girl affected by ASD, reduced growth, neurological development delay, mutations in the PGM1 and EEF1A2 genes (in the absence of clinically manifested disease) and, intestinal disorders such as abdominal pain and diarrhea associated with weight loss. As she demonstrated poor responsiveness to the therapies provided, we attempted two specific dietary patterns: a ketogenic diet, followed by a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet, with the aim of improving her neurological, metabolic, and intestinal symptoms through modulation of the gut microbiota's composition. The ketogenic diet (KD) provided a reduction in Firmicutes, Bacteroidetes, and Proteobacteria. Although her intestinal symptoms improved, KD was poorly tolerated. On the other hand, the passage to a low FODMAPs diet produced a significant improvement in all neurological, intestinal, and metabolic symptoms and was well-tolerated. The following gut microbiota analysis showed reductions in Actinobacteria, Firmicutes, Lactobacilli, and Bifidobacteria. The alpha biodiversity was consistently increased and the Firmicutes/Bacteroidetes ratio decreased, reducing the extent of fermentative dysbiosis. Gut microbiota could be a therapeutic target to improve ASD-related symptoms. Further studies are needed to better understand the correlation between gut microbiota composition and ASD, and its possible involvement in the physiopathology of ASD.

Segmental Bioimpedance Analysis as a Predictor of Injury and Performance Status in Professional Basketball Players: A New Application Potential?

Bioelectrical impedance vector analysis (BIVA) is a technique used for the assessment of body composition based on the electrical properties of biological tissues and for evaluating variations related to hydration and nutrition status changes. The present study aimed to investigate the possibility of predicting performance status and injuries using segmental BIVA analysis. Data were collected from 14 professional male athletes aged between 20 and 39 years of Caucasian and Afro-American ethnicity belonging to the US Victoria Libertas Pallacanestro Pesaro team in the Italian Serie A basketball championship. From an analysis of training injuries, the data highlight a possible positive link between the number of training injuries and upper hemisoma reactance (XCEmsSup) (t = 2.881, p = 0.007), an inverse relationship between training injury duration and higher right lower limb reactance (XCLegDx) (t = −4.213, p < 0.001), and an inverse relationship between injury duration and higher body mass index (t = −4.213, p < 0.001), highlighting how higher cellularity seems less prone to severe training injuries. Analyzing match-day injuries, right upper-limb higher reactance (XCArmdx) negatively correlates with match-day number of injuries (t = −4.469, p < 0.001), right upper limb resistance (RZArmDx) negatively correlates with lower match-day injury duration (t = −4.202, p < 0.001), and trunk resistance (RZTrunk) positive correlates with lower match-day injury duration (t = 2.803, p = 0.008), in contrast with the training data analysis. Analyzing the relationship between the BIVA parameters and performance indicators, right upper limb resistance (RzArmDx) has a positive link with plus−minus (t = 2.889, p = 0.007); however, RzArmDx negatively correlates with assist number (t = −3.362, p = 0.002), and BMI is directly proportional to assist number (t = 2.254, p = 0.032). These first data suggest a good correlation between the cellularity of different body districts and the risk of injuries in training but still leave several doubts surrounding the concrete predictive potential regarding performance and injuries during competitions while considering the numerous factors involved. Further studies on BIVA and similar applications could provide tools for managing athlete health and physical integrity preservation and potentially help us better understand the factors involved in improving performance.

A Practical Perspective on the Use of Botanicals During the COVID-19 Pandemic: From Proven to Potential Interactions.

In this review, we examined the top 10 nutraceutical products sold in Italian pharmacies and parapharmacies as well as hypermarkets and supermarkets; in the first, three product categories saw the greatest increase in sales (vitamins and minerals, immunostimulants, and sleep products) for the 12-month period between October 2019 and October 2020 (including first pandemic wave of SARS-CoV-2). We are investigating their respective formulas and isolating the botanicals that are used to make them. Many of these products have undergone preclinical and clinical studies. We performed a systematic literature search in the MEDLINE database using PubMed and Google Scholar from November 15, 2020 to December 15, 2020 (including studies carried out between 1980 and 2020). The search terms that were used included the complete name of the medicinal plant in English or Latin and the terms "cytochrome" or "drug interactions," crossing, respectively, the Latin name and English common names with "cytochrome" and "drug interactions." The search included in vitro and in vivo studies describing the effects of interaction between the plant (extract or botanical medicine) and human cytochromes. Despite their great complexity, there is decidedly limited clinical data on botanical medicine. In fact, of the 28 botanicals that were examined, only 2 (Citrus paradisi and Rhodiola rosea) show in vivo pharmacological interactions in human subjects. On the contrary, for the other botanicals, there is only weak evidence of dubious clinical significance or potential interactions shown in animal models or in vitro without clinical confirmation. This study provides a rational assessment of the most widely used products, including those used in self-medication, to simplify patient management during the COVID-19 health emergency.

Nutraceuticals and Herbal Food Supplements for Weight Loss: Is There a Prebiotic Role in the Mechanism of Action?

Numerous nutraceuticals and botanical food supplements are used with the intention of modulating body weight. A recent review examined the main food supplements used in weight loss, dividing them according to the main effects for which they were investigated. The direct or indirect effects exerted on the intestinal microbiota can also contribute to the effectiveness of these substances. The aim of this review is to evaluate whether any prebiotic effects, which could help to explain their efficacy or ineffectiveness, are documented in the recent literature for the main nutraceuticals and herbal food supplements used for weight loss management. Several prebiotic effects have been reported for various nutraceutical substances, which have shown activity on Bifidobacterium spp., Lactobacillus spp., Akkermansia muciniphila, Faecalibacterium prausnitzi, Roseburia spp., and the Firmicutes/Bacteroidetes ratio. Different prebiotics have beneficial effects on weight and the related metabolic profile, in some cases even acting on the microbiota with mechanisms that are completely independent from those nutraceuticals for which certain products are normally used. Further studies are necessary to clarify the different levels at which a nutraceutical substance can exert its action.

Atypical neutrophilic panniculitis as presentation of BCR-ABL1-negative chronic myeloid leukaemia.

We report the case of an otherwise healthy 60-year-old man presenting with fever, leucocytosis and a painful swelling of the right calf. We initially performed cultural and cytological examination of the popliteal fossa mass, but the results were disappointingly inconclusive. The subsequent development of several erythematous subcutaneous nodules, rapidly evolving to broad ulcerative lesions, prompted us to reconsider the clinical setting as a whole, which included fever, marked leucocytosis and multiple subcutaneous nodules. A biopsy of the ulcerative lesions finally led to the diagnosis of neutrophilic panniculitis, which was sustained by a hybrid myelodysplastic/myeloproliferative disorder like BCR-ABL1-negative atypical chronic myeloid leukaemia. The patient was initially treated with high-dose intravenous corticosteroids, resulting in a dramatic improvement of the skin lesions and normalisation of blood tests. Azacytidine treatment was subsequently started, and the haematological disease remained stable.

A young man with persistent dyspepsia: the unexpected virtue of proton-pump inhibitors.

A 26-year-old man was referred to our department for a 3-year history of dyspepsia responsive to oral pump-inhibitors therapy. During the last year, he underwent a gastroscopy, a colonoscopy and a computed tomography enterography that failed to reveal an underlying organic disease: a diagnosis of functional dyspepsia was made. Because of the persistence of symptoms, he came to our ambulatory where we performed an abdominal ultrasound that revealed the presence of multiple bi-lobar lesions of the liver suspected for metastases and a hypoechoic solid lesion of the pancreas body, confirmed by a contrast enhanced computed tomography. Laboratory tests showed high chromogranin A and gastrin level, and a liver biopsy was consistent with a metastatic pancreatic neuroendocrine tumor. This report aims to underlie the diffuse heterogeneous diagnostic management of some common gastrointestinal symptoms, such as dyspepsia, that are too often approached with the prescription of proton pump inhibitors.

Gut microbiota profile in systemic sclerosis patients with and without clinical evidence of gastrointestinal involvement.

Recent evidence suggests that there is a link between the gut microbial community and immune-mediated disorders. Systemic sclerosis (SSc) is an autoimmune disease characterized by immunonological abnormalities, vascular lesions, and extensive fibrosis. Since the gastrointestinal tract is one of the organs most involved, the goal of this study was to explore the composition of the intestinal microbiota in SSc patients with (SSc/GI+) and without gastrointestinal involvement (SSc/GI-) in comparison to healthy controls (HC). The fecal bacterial composition was investigated by Illumina sequencing of 16 S rRNA gene amplicons. The fecal microbiota of SSc/GI+ subjects was characterized by higher levels of Lactobacillus, Eubacterium and Acinetobacter compared with healthy controls, and lower proportions of Roseburia, Clostridium, and Ruminococcus. The gut microbiota of SSc/GI- subjects was more similar to the microbiota of HC than to that of SSc/GI+ subjects albeit Streptococcus salivarius was over-represented in SSc/GI- fecal samples compared with both SSc/GI+ subjects and controls. Our study reveals microbial signatures of dysbiosis in the gut microbiota of SSc patients that are associated with clinical evidence of gastrointestinal disease. Further studies are needed to elucidate the potential role of these perturbations in the onset and progression of systemic sclerosis, and gastrointestinal involvement in particular.

Hormonal regulation of hepatic IGF-I and IGF-II gene expression in the marine teleost Sparus aurata.

The present work aimed to determine whether GnRH potentiates the effect of growth hormone (GH) on insulin-like growth factors (IGF-I and IGF-II) hepatic gene expression in Sparus aurata liver. Since several hepatic genes were shown to underlie direct regulation via the hepatic estrogen receptor, another aim was to extend our understanding of direct estrogen effects on liver IGFs gene expression. Pre-reproductive sea bream females were treated with GH, GnRH, estradiol-17beta, GH plus GnRH, and estradiol-17beta plus GH. After 72 hr, all treatment induced an increase of plasma estradiol well correlated with the increase of plasma vitellogenin (VTG) levels. IGF-I and IGF-II expression in the liver of treated females was determined by semi-quantitative RT-PCR, using beta-actin as internal standard. The results reported here show that GH significantly stimulates hepatic transcription of IGF-I and IGF-II genes. Surprisingly, E2 and GnRH treatments decreased both IGF-I and IGF-II mRNA levels. In fishes treated with GH plus GnRH, the GnRH contrasted the GH effect: the IGF-I mRNA levels were still significantly higher than in controls, while the effect of GH on IGF-II gene expression was totally abolished. At the same time, in the combined treatment with GH plus E2, the E2 counteracted the stimulatory effect of GH on both IGF-I and IGF-II genes expression.

Peptide pheromones in newts.

This article reviews the current state of understanding of reproductive pheromones in amphibians, focusing mainly on the purification and characterization of peptide pheromones in newts of the genus Cynops, molecular cloning of cDNAs encoding the pheromone molecules, and hormonal control of secretion of these pheromones. Pheromones that attract sexually developed female Cynops pyrrhogaster and C. ensicauda newts were isolated from the male abdominal glands. The C. pyrrhogaster and C. ensicauda pheromones are peptides, designated sodefrin and silefrin, with the amino acid sequences SIPSKDALLK and SILSKDAQLK, respectively. Each pheromone attracts only conspecific females. Molecular cloning of cDNAs encoding sodefrin and silefrin revealed the presence of precursor proteins that are considered to generate these pheromone peptides. Pheromone precursor mRNA levels and radioimmunoassayable pheromone concentrations in the abdominal glands were elevated by prolactin and androgen. Sexual dimorphism and hormone dependency of the responsiveness of vomeronasal epithelium to sodefrin were noted. Significance of pheromones in the form of peptide for those performing reproductive behavior in an aquatic environment was also discussed.

Temporary impairment of reproduction in freshwater teleost exposed to nonylphenol.

New born guppies, Poecilia reticulata, were exposed to a sublethal concentration of nonylphenol (NP) for 90 days, with the aim of evaluating the influence that this pollutant has on reproductive functions. At the end of treatment, the gender balance was significantly biased towards females (sex ratio = 0.3 males per female). Treated males displayed anomalous transcription of vitellogenin in correlation with a significant reduction of the gonadosomatic index (GSI); however, an increase of vitellogenin gene transcription, correlating directly with an increase in GSI, was observed in NP treated females. The hepatosomatic index (HSI) was significantly increased in exposed males and females. Females exposed to NP showed no alteration of sexual behavior or reproduction. These findings in guppies suggest that NP has estrogenic potency sufficient to disturb reproduction. Effects were transitory in nature because three months in uncontaminated water allowed males to recover normal sexual efficiency.

Role of substrate on larval development of the freshwater teleost Pelvicachromis pulcher.

It is known that, in an aquatic environment, the mineralogical composition of the substrate can affect the structure of settled communities. In marine environments, the presence of quartz negatively influences the formation of biofilm, as well as the selection and the colonization of the substrate by benthic organisms. Direct laboratory observation revealed that the freshwater teleost Pelivicachromis pulcher selects, when available, nonquartzitic brooding substrate. To monitor the effects of substrate on larvae development, ten lots of embryos were distributed in grid nurseries; carbonatic gravel was laid in five of the nurseries, while freshly fractured quartz gravel was used in the remaining ones. All the embryos laid in the two nurseries hatched, and 90% of the carbonate developing larvae reached adulthood, while 100% of those reared on quartz grain died 120 hr post hatching. Examination was made, both in larvae developed on carbonatic substrates and in those developed on quartz substrates, of the expression of the fetal growth factor, the insulin growth factor-II (IGF-II), of the molecular chaperone, the heat shock protein 70 (HSP70), which is involved in the folding of the nascent polypeptide chain, of the key enzyme of the glycolytic pathway, the glyceraldehyde-3-phosphate dehydrogenase (GADPH), and of the housekeeping gene, the beta-actin. All the data were normalized against 18S RNA expression. In larvae reared on quartz substrate, the genes IGF-II and the beta-actin showed a lower expression, while the GADPH was totally suppressed and the expression of HSP70 increased. In conclusion, the data presented in this article demonstrated, for the first time, that the presence of quarzitic substrates is sufficient to stop larvae development through the inhibition of gene transcription in this African cichlid, leading to its death.