Effects of combined ciprofloxacin and Neulasta therapy on intestinal pathology and gut microbiota after high-dose irradiation in mice.

Introduction: Treatments that currently exist in the strategic national stockpile for acute radiation syndrome (ARS) focus on the hematopoietic subsyndrome, with no treatments on gastrointestinal (GI)-ARS. While the gut microbiota helps maintain host homeostasis by mediating GI epithelial and mucosal integrity, radiation exposure can alter gut commensal microbiota which may leave the host susceptible to opportunistic pathogens and serious sequelae such as sepsis. To mitigate the effects of hematopoietic ARS irradiation, currently approved treatments exist in the form of colony stimulating factors and antibiotics: however, there are few studies examining how these therapeutics affect GI-ARS and the gut microbiota. The aim of our study was to examine the longitudinal effects of Neulasta and/or ciprofloxacin treatment on the gut microbiota after exposure to 9.5 Gy 60Co gamma-radiation in mice. Methods: The gut microbiota of vehicle and drug-treated mice exposed to sham or gamma-radiation was characterized by shotgun sequencing with alpha diversity, beta diversity, and taxonomy analyzed on days 2, 4, 9, and 15 post-irradiation. Results: No significant alpha diversity differences were observed following radiation, while beta diversity shifts and taxonomic profiles revealed significant alterations in Akkermansia, Bacteroides, and Lactobacillus. Ciprofloxacin generally led to lower Shannon diversity and Bacteroides prevalence with increases in Akkermansia and Lactobacillus compared to vehicle treated and irradiated mice. While Neulasta increased Shannon diversity and by day 9 had more similar taxonomic profiles to sham than ciprofloxacin-or vehicle-treated irradiated animals. Combined therapy of Neulasta and ciprofloxacin induced a decrease in Shannon diversity and resulted in unique taxonomic profiles early post-irradiation, returning closer to vehicle-treated levels over time, but persistent increases in Akkermansia and Bacteroides compared to Neulasta alone. Discussion: This study provides a framework for the identification of microbial elements that may influence radiosensitivity, biodosimetry and the efficacy of potential therapeutics. Moreover, increased survival from H-ARS using these therapeutics may affect the symptoms and appearance of what may have been subclinical GI-ARS.

Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome.

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril's effects on the GI following TBI (60Co 1.79 or 1.80 Gy, 0.42-0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

First do no harm: A patient-reported survey of split skin graft donor site morbidities following thin and super-thin graft harvest.

The split-thickness skin graft (STSG) donor site is the commonest used during burn surgery which has its own complications and as such the focus should be on minimizing it. Modifications to practice in our unit which we believe aid this include limiting the amount of STSG taken and the harvest of super-thin STSGs, with 0.003-0.005 in. (0.08-0.13 mm) being the commonest dermatome settings used. A patient-reported survey via a mobile phone link to a questionnaire was sent to 250 patients who had a STSG for an acute burn between 1st August 2020 and 31st July 2021. Patient demographics were collected from electronic records including the thickness of the FTSG taken when recorded. Patient responses were statistically analyzed and logistic regression with backwards elimination was performed to explore which contributing factors led to an improved experience of the donor site. Questionnaire responses were obtained from 107 patients (43%). These were between one and two and a half years after the injury. Concerning early donor site issues, itch was a problem for 52% of patients, pain was a problem for 48% of patients. Less common problems (fewer than 25% of patients) were leaking donor sites, wound breakdown, and over-granulation. Regarding long-term outcomes, increased, decreased or mixed pigmentation at the donor site was reported by 32% patients at the time of the survey. Hyper-vascular donor sites were reported by 24% patients. Raised or uneven feeling donor sites were reported by 19% patients, firm or stiff donor sites by 13% patients, and altered sensation by 10% patients. At the time of the survey, 70% responders reported their donor site looked "the same or about the same as my normal skin". Of these, 62 reported how long it took for this to happen, and it equates to a third looking normal at 6 months and half looking normal at a year. For the 32 patients who reported their donor site looking abnormal, 72% were "not bothered" by it. Patients with super-thin grafts (0.003-0.005 in.) were significantly more likely to have normal sensation, normal stiffness, and be less raised at their donor sites than those who had thin grafts (0.006-0.008 in.). This survey gives important information on patients' experiences of donor site morbidity that may form part of an informed consent process and allow tailored advice. Furthermore, it suggests that super-thin grafts may provide a superior donor site experience for patients.

SOS1 inhibition enhances the efficacy of and delays resistance to G12C inhibitors in lung adenocarcinoma.

Clinical effectiveness of KRAS G12C inhibitors (G12Cis) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. We found that targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 both enhanced the potency of and delayed resistance to G12Ci treatment, but the extent of SOS1i effectiveness was modulated by both SOS2 expression and the specific mutational landscape. SOS1i enhanced the efficacy of G12Ci and limited rebound RTK/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. Survival of drug-tolerant persister (DTP) cells within the heterogeneous tumor population and/or acquired mutations that reactivate RTK/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) that drive therapeutic resistance. G12Ci drug tolerant persister cells showed a 2-3-fold enrichment of TICs, suggesting that these could be a sanctuary population of G12Ci resistant cells. SOS1i re-sensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tumor suppressor KEAP1 limits the clinical effectiveness of G12Cis, and KEAP1 and STK11 deletion increased TIC frequency and accelerated the development of acquired resistance to G12Ci in situ. SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. These data suggest that SOS1i could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations.

What is the future of Periodontal Medicine?

In the last five decades, considerable progress has been made towards understanding the etiology and pathogenesis of periodontal diseases and their interactions with the host. The impact of an individual periodontal condition on systemic homeostasis became more evident because of this knowledge and prompted advances in studies that associate periodontitis with systemic diseases and conditions. The term Periodontal Medicine describes how periodontal infection/inflammation can affect extraoral health. This review presents the current scientific evidence on the most investigated associations between periodontitis and systemic diseases and conditions, such as cardiovascular diseases, diabetes, preterm birth and low birth weight, and pneumonia. Additionally, other associations between periodontitis and chronic inflammatory bowel disease, colorectal cancer, and Alzheimer's disease that were recently published and are still poorly studied were described. Thus, the aim of this review was to answer the following question: What is the future of Periodontal Medicine? Epidemiological evidence and the evidence of biological plausibility between periodontitis and general health reinforce the rationale that the study of Periodontal Medicine should continue to advance, along with improvements in the epidemiological method, highlighting the statistical power of the studies, the method for data analysis, the case definition of periodontitis, and the type of periodontal therapy to be applied in intervention studies.

What is the future of Periodontal Medicine?

Abstract In the last five decades, considerable progress has been made towards understanding the etiology and pathogenesis of periodontal diseases and their interactions with the host. The impact of an individual periodontal condition on systemic homeostasis became more evident because of this knowledge and prompted advances in studies that associate periodontitis with systemic diseases and conditions. The term Periodontal Medicine describes how periodontal infection/inflammation can affect extraoral health. This review presents the current scientific evidence on the most investigated associations between periodontitis and systemic diseases and conditions, such as cardiovascular diseases, diabetes, preterm birth and low birth weight, and pneumonia. Additionally, other associations between periodontitis and chronic inflammatory bowel disease, colorectal cancer, and Alzheimer's disease that were recently published and are still poorly studied were described. Thus, the aim of this review was to answer the following question: What is the future of Periodontal Medicine? Epidemiological evidence and the evidence of biological plausibility between periodontitis and general health reinforce the rationale that the study of Periodontal Medicine should continue to advance, along with improvements in the epidemiological method, highlighting the statistical power of the studies, the method for data analysis, the case definition of periodontitis, and the type of periodontal therapy to be applied in intervention studies.

The Dentist's Role in Southern Brazilian Teaching Hospitals: A Grounded Theory Study.

The aim of this study was to develop a theoretical model to describe the role that the dentist plays in Brazilian hospital settings. This qualitative study was based on the grounded theory research method. Participants were a total of 27 individuals in three groups: dentists and general practice and oral and maxillofacial surgery residents; faculty; and other health professionals who interacted with dental patients in the hospital setting during the 2012-13 year. Data were collected in three teaching hospitals in the state of Santa Catarina, Brazil, through scripted interviews using open-ended questions. The stages of collection, codification, ordination, and integration of data were guided by constant comparative techniques to formulate a theoretical model. The codes generated were organized into seven categories: identifying the hospital as a working and teaching environment; recalling the dentists' professional pathways; reflecting on the dentist's work in the hospital; considering the political and organizational dimension of the role of the dentist in the hospital; understanding patients' life and health contexts; education and professional practice; and moving on towards interdisciplinary practices in the hospital setting. Integrating the categories led to a theoretical model called "The Dentist's Role in the Hospital Setting: An Interdisciplinary Construction." This theoretical model provides a framework to understand how dentists perform in the hospital setting, with a focus on interdisciplinary practice, which in this study was shown to be incipient and heterogeneous.

Medical condition is related to treatment preference in cancer patients: implications for quality assessment.

Ongoing communication with cancer patients about their treatment preferences is important. A survey assessing treatment preferences was distributed to 100 cancer patients who were newly diagnosed, 100 in remission after therapy, and 60 who had failed therapy/ relapsed; 100 cancer caregivers, and 100 noncancer patients attending the cancer center for benign hematologic problems. Almost 59% of respondents preferred treatment even if the chance of cure was less than 10%. Among subjects who did not have cancer, less than 50% wanted treatment under these circumstances, whereas over 70% of cancer patients who had failed treatment or relapsed wanted treatment (P=.0994). Multiple logistic regression analysis revealed that the adjusted odds of preferring aggressive treatment were less for those without cancer and those with newly diagnosed cancer than for respondents who had failed treatment or were in relapse. The preference for aggressive cancer treatment is related to medical condition.