-
BioRxiv : the Preprint Server For... Apr 2024The major gram-positive pathogen group A (GAS) is a model organism for studying microbial epidemics as it causes waves of infections. Since 1980, several GAS epidemics...
The major gram-positive pathogen group A (GAS) is a model organism for studying microbial epidemics as it causes waves of infections. Since 1980, several GAS epidemics have been ascribed to the emergence of clones producing increased amounts of key virulence factors such as streptolysin O (SLO). Herein, we sought to identify mechanisms underlying our recently identified temporal clonal emergence amongst GAS, given that emergent strains did not produce augmented levels of virulence factors relative to historic isolates. Through the creation and analysis of isoallelic strains, we determined that a conserved mutation in a previously undescribed gene encoding a putative carbonic anhydrase was responsible for the defective growth observed in the emergent strains. We also identified that the emergent strains survived better inside macrophages and killed macrophages at lower rates relative to the historic strains. Via creation of isogenic mutant strains, we linked the emergent strain "survival" phenotype to the downregulation of the SLO encoding gene and upregulation of the operon which encodes proteins involved in defense against extracellular oxidative stress. Our findings are in accord with recent surveillance studies which found high ratio of mucosal (i.e., pharyngeal) relative to invasive infections amongst GAS. Inasmuch as ever-increasing virulence is unlikely to be evolutionary advantageous for a microbial pathogen, our data furthers understanding of the well described oscillating patterns of virulent GAS infections by demonstrating mechanisms by which emergent strains adapt a "survival" strategy to outcompete previously circulating isolates.
PubMed: 38645060
DOI: 10.1101/2024.04.09.588776 -
JAMA Otolaryngology-- Head & Neck... Jun 2024Closure technique for optimization of postoperative and functional outcomes following salvage laryngectomy remains an area of debate among head and neck surgeons.
IMPORTANCE
Closure technique for optimization of postoperative and functional outcomes following salvage laryngectomy remains an area of debate among head and neck surgeons.
OBJECTIVE
To investigate the association of salvage laryngectomy closure technique with early postoperative and functional outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included patients from 17 academic, tertiary care centers who underwent total laryngectomy with no or limited pharyngectomy after completing a course of definitive radiotherapy or chemoradiotherapy with curative intent between January 2011 and December 2016. Patients with defects not amenable to primary closure were excluded. Data were analyzed from February 14, 2021, to January 29, 2024.
EXPOSURES
Total laryngectomy with and without limited pharyngectomy, reconstructed by primary mucosal closure (PC), regional closure (RC), or free tissue transfer (FTT).
MAIN OUTCOMES AND MEASURES
Patients were stratified on the basis of the pharyngeal closure technique. Perioperative and long-term functional outcomes were evaluated with bivariate analyses. A multivariable regression model adjusted for historical risk factors for pharyngocutaneous fistula (PCF) was used to assess risk associated with closure technique. Relative risks (RRs) with 95% CIs were determined.
RESULTS
The study included 309 patients (256 [82.8%] male; mean age, 64.7 [range, 58.0-72.0] years). Defects were reconstructed as follows: FTT (161 patients [52.1%]), RC (64 [20.7%]), and PC (84 [27.2%]). A PCF was noted in 36 of 161 patients in the FTT group (22.4%), 25 of 64 in the RC group (39.1%), and 29 of 84 in the PC group (34.5%). On multivariable analysis, patients undergoing PC or RC had a higher risk of PCF compared with those undergoing FTT (PC: RR, 2.2 [95% CI, 1.1-4.4]; RC: RR, 2.5 [95% CI, 1.3-4.8]). Undergoing FTT was associated with a clinically meaningful reduction in risk of PCF (RR, 0.6; 95% CI, 0.4-0.9; number needed to treat, 7). Subgroup analysis comparing inset techniques for the RC group showed a higher risk of PCF associated with PC (RR, 1.8; 95% CI, 1.1-3.0) and predominately pectoralis myofascial flap with onlay technique (RR, 1.9; 95% CI, 1.2-3.2), but there was no association of pectoralis myocutaneous flap with cutaneous paddle interposition with PCF (RR, 1.2; 95% CI, 0.5-2.8) compared with FTT with cutaneous inset. There were no clinically significant differences in functional outcomes between the groups.
CONCLUSION AND RELEVANCE
In this study of patients with limited pharyngeal defects, interpositional fasciocutaneous closure technique was associated with reduced risk of PCF in the salvage setting, which is most commonly achieved by FTT in academic practices. Closure technique was not associated with functional outcomes at 1 and 2 years postoperatively.
Topics: Humans; Laryngectomy; Male; Female; Retrospective Studies; Salvage Therapy; Middle Aged; Laryngeal Neoplasms; Aged; Pharyngectomy; Plastic Surgery Procedures; Postoperative Complications; Pharyngeal Diseases; Cutaneous Fistula
PubMed: 38635282
DOI: 10.1001/jamaoto.2024.0103 -
Infection and Immunity May 2024, a common colonizer of the upper respiratory tract, invades nasopharyngeal epithelial cells without causing disease in healthy participants of controlled human...
, a common colonizer of the upper respiratory tract, invades nasopharyngeal epithelial cells without causing disease in healthy participants of controlled human infection studies. We hypothesized that surface expression of pneumococcal lipoproteins, recognized by the innate immune receptor TLR2, mediates epithelial microinvasion. Mutation of in serotype 4 (TIGR4) and serotype 6B (BHN418) pneumococcal strains abolishes the ability of the mutants to activate TLR2 signaling. Loss of also led to the concomitant decrease in interferon signaling triggered by the bacterium. However, only BHN418 but not TIGR4 was significantly attenuated in epithelial adherence and microinvasion compared to their respective wild-type strains. To test the hypothesis that differential lipoprotein repertoires in TIGR4 and BHN418 lead to the intraspecies variation in epithelial microinvasion, we employed a motif-based genome analysis and identified an additional 525 a.a. lipoprotein (neumococcal ccessory ipoprotein ; ) encoded by BHN418 that is absent in TIGR4. The gene encoding sits within a putative genetic island present in ~10% of global pneumococcal isolates. While was enriched in the carriage and otitis media pneumococcal strains, neither mutation nor overexpression of the gene encoding this lipoprotein significantly changed microinvasion patterns. In conclusion, mutation of attenuates epithelial inflammatory responses during pneumococcal-epithelial interactions, with intraspecies variation in the effect on microinvasion. Differential lipoprotein repertoires encoded by the different strains do not explain these differences in microinvasion. Rather, we postulate that post-translational modifications of lipoproteins may account for the differences in microinvasion.IMPORTANCE (pneumococcus) is an important mucosal pathogen, estimated to cause over 500,000 deaths annually. Nasopharyngeal colonization is considered a necessary prerequisite for disease, yet many people are transiently and asymptomatically colonized by pneumococci without becoming unwell. It is therefore important to better understand how the colonization process is controlled at the epithelial surface. Controlled human infection studies revealed the presence of pneumococci within the epithelium of healthy volunteers (microinvasion). In this study, we focused on the regulation of epithelial microinvasion by pneumococcal lipoproteins. We found that pneumococcal lipoproteins induce epithelial inflammation but that differing lipoprotein repertoires do not significantly impact the magnitude of microinvasion. Targeting mucosal innate immunity and epithelial microinvasion alongside the induction of an adaptive immune response may be effective in preventing pneumococcal colonization and disease.
Topics: Streptococcus pneumoniae; Humans; Lipoproteins; Epithelial Cells; Pneumococcal Infections; Bacterial Proteins; Toll-Like Receptor 2; Nasopharynx; Mutation; Bacterial Adhesion
PubMed: 38629841
DOI: 10.1128/iai.00447-23 -
Acta Veterinaria Scandinavica Apr 2024Benzalkonium chloride (BAC) is a quaternary ammonium compound (QAC), that can be found in a wide variety of household products-from disinfectants to medicaments and home... (Review)
Review
BACKGROUND
Benzalkonium chloride (BAC) is a quaternary ammonium compound (QAC), that can be found in a wide variety of household products-from disinfectants to medicaments and home fragrances-but also professional products. In pets, cats have long been reported as more sensitive than dogs to QACs; in fact, signs of irritation such as oral ulcerations, stomatitis and pharyngitis can be observed after contact with concentrations of 2% or lower. In a review of 245 cases of BAC exposure in cats, reported by the Veterinary Poisons Information Service (United Kingdom) only 1.2% of the cases died or were euthanized. Nevertheless, BAC toxidromes in cats can result in transitory CNS and respiratory distress, as well as severe mucosal and cutaneous lesions. Currently, only a few reports are available concerning BAC poisoning in this species.
CASE PRESENTATION
A 4 month-old kitten presented with severe glossitis, lameness in the hindlimbs and episodes of vomiting and diarrhoea. The cause was unknown until the owners reported use of a BAC-containing mould remover (5%) 4 days later. The patient developed severe oral burns requiring a pharyngeal tube for feeding and severe cutaneous chemical burns. The kitten was managed with supportive therapy and required hospitalization for 10 days. The symptoms disappeared completely 3 weeks after exposure.
CONCLUSIONS
BAC is a very common compound contained in several household and professional products but, to the best of our knowledge, no previous case had been reported in Italy. We hope that this report will help raise awareness on the hazards of BAC products for cats in both domestic and work contexts.
Topics: Cats; Animals; Female; Dogs; Benzalkonium Compounds; Quaternary Ammonium Compounds; Disinfectants; Italy
PubMed: 38622748
DOI: 10.1186/s13028-024-00737-x -
Cells Mar 2024Nasopharyngeal carcinoma (NPC) is a type of cancer that originates from the mucosal lining of the nasopharynx and can invade and spread. Although contemporary...
Nasopharyngeal carcinoma (NPC) is a type of cancer that originates from the mucosal lining of the nasopharynx and can invade and spread. Although contemporary chemoradiotherapy effectively manages the disease locally, there are still challenges with locoregional recurrence and distant failure. Therefore, it is crucial to have a deeper understanding of the molecular basis of NPC cell movement in order to develop a more effective treatment and to improve patient survival rates. Cancer cell line models are invaluable in studying health and disease and it is not surprising that they play a critical role in NPC research. Consequently, scientists have established around 80 immortalized human NPC lines that are commonly used as in vitro models. However, over the years, it has been observed that many cell lines are misidentified or contaminated by other cells. This cross-contamination leads to the creation of false cell lines that no longer match the original donor. In this commentary, we discuss the impact of misidentified NPC cell lines on the scientific literature. We found 1159 articles from 2000 to 2023 that used NPC cell lines contaminated with HeLa cells. Alarmingly, the number of publications and citations using these contaminated cell lines continued to increase, even after information about the contamination was officially published. These articles were most commonly published in the fields of oncology, pharmacology, and experimental medicine research. These findings highlight the importance of science policy and support the need for journals to require authentication testing before publication.
Topics: Humans; Nasopharyngeal Carcinoma; HeLa Cells; Nasopharyngeal Neoplasms; Cell Line, Tumor; Neoplasm Recurrence, Local; Nasopharynx
PubMed: 38606998
DOI: 10.3390/cells13070559 -
Annual Review of Genomics and Human... Apr 2024The development and deployment of single-cell genomic technologies have driven a resolution revolution in our understanding of the immune system, providing unprecedented... (Review)
Review
The development and deployment of single-cell genomic technologies have driven a resolution revolution in our understanding of the immune system, providing unprecedented insight into the diversity of immune cells present throughout the body and their function in health and disease. Waldeyer's ring is the collective name for the lymphoid tissue aggregations of the upper aerodigestive tract, comprising the palatine, pharyngeal (adenoids), lingual, and tubal tonsils. These tonsils are the first immune sentinels encountered by ingested and inhaled antigens and are responsible for mounting the first wave of adaptive immune response. An effective mucosal immune response is critical to neutralizing infection in the upper airway and preventing systemic spread, and dysfunctional immune responses can result in ear, nose, and throat pathologies. This review uses Waldeyer's ring to demonstrate how single-cell technologies are being applied to advance our understanding of the immune system and highlight directions for future research.
PubMed: 38594932
DOI: 10.1146/annurev-genom-120522-012938 -
Stem Cell Research & Therapy Apr 2024Oral ulcers are a common side effect of chemotherapy and affect patients' quality of life. While stem cell transplantation is a potential treatment for oral ulcers, its...
BACKGROUND
Oral ulcers are a common side effect of chemotherapy and affect patients' quality of life. While stem cell transplantation is a potential treatment for oral ulcers, its efficacy is limited as the stem cells tend to remain in the affected area for a short time. This study aims to develop a treatment for oral ulcers by using trimethyl chitosan (TMC) hydrogel with human tonsil-derived stem cells (hTMSCs) to increase the therapeutic effect of stem cells and investigate their effectiveness.
METHODS
Animals were divided into four experimental groups: Control, TMC hydrogel, hTMSCs, and hTMSCs loaded in TMC hydrogel (Hydrogel + hTMSCs) (each n = 8). Oral ulcers were chemically induced by anesthetizing the rats followed by injection of dilute acetic acid in the right buccal mucosa. After confirming the presence of oral ulcers in the animals, a single subcutaneous injection of 100 µL of each treatment was applied to the ulcer area. Histological analyses were performed to measure inflammatory cells, oral mucosal thickness, and fibrosis levels. The expression level of inflammatory cytokines was also measured using RT-PCR to gauge therapeutic the effect.
RESULTS
The ulcer size was significantly reduced in the TMC hydrogel + hTMSCs group compared to the control group. The stem cells in the tissue were only observed until Day 3 in the hTMSCs treated group, while the injected stem cells in the TMC Hydrogel + hTMSCs group were still present until day 7. Cytokine analysis related to the inflammatory response in the tissue confirmed that the TMC Hydrogel + hTMSCs treated group demonstrated superior wound healing compared to other experimental groups.
CONCLUSION
This study has shown that the adhesion and viability of current stem cell therapies can be resolved by utilizing a hydrogel prepared with TMC and combining it with hTMSCs. The combined treatment can promote rapid healing of oral cavity wounds by enhancing anti-inflammatory effects and expediting wound healing. Therefore, hTMSC loaded in TMC hydrogel was the most effective wound-healing approach among all four treatment groups prolonging stem cell survival. However, further research is necessary to minimize the initial inflammatory response of biomaterials and assess the safety and long-term effects for potential clinical applications.
Topics: Humans; Rats; Animals; Oral Ulcer; Ulcer; Chitosan; Hydrogels; Palatine Tonsil; Quality of Life; Models, Animal; Cytokines; Mesenchymal Stem Cells
PubMed: 38589946
DOI: 10.1186/s13287-024-03694-4 -
International Journal of Radiation... Apr 2024Recurrent head and neck cancer presents a therapeutic challenge because of cumulative toxicity from initial radiation therapy, limiting reirradiation options. Boron...
Clinical Results and Prognostic Factors in Boron Neutron Capture Therapy for Recurrent Squamous Cell Carcinoma of the Head and Neck Under the Japan National Health Insurance System: A Retrospective Study of the Initial 47 Patients.
PURPOSE
Recurrent head and neck cancer presents a therapeutic challenge because of cumulative toxicity from initial radiation therapy, limiting reirradiation options. Boron neutron capture therapy (BNCT) offers a promising alternative, selectively delivering a radical dose to tumors while sparing adjacent normal tissue. This study investigates the initial clinical outcomes and prognostic factors associated with BNCT for recurrent squamous cell carcinoma of the head and neck.
METHODS AND MATERIALS
This retrospective analysis investigated the initial 47 patients treated with BNCT between May 2020 and February 2021 in Japan. All patients had received radiation therapy with a median dose of 70 Gy (range, 44-176) before BNCT. Median tumor size was 11 cm (range, 1-117 cm), with 23% of tumors larger than 30 cm, and 87% of patients had prior systemic therapy. The most common prescribed dose to the pharyngeal mucosa was 15 Gy-Eq (36%), followed by 18 Gy-Eq (34%). The minimum dose given to tumor was 27.4 Gy-Eq (range, 13.3-45.2). In 23 patients, F-fluoro-borono-phenylalanine positron emission tomography was performed within 1 week before BNCT, and the tumor-to-blood B ratio was 3.5 (range, 2.0-8.7).
RESULTS
Efficacy analysis revealed a 51% complete response rate and a 74% overall response rate. Disease-free survival rates at 1 and 2 years were 34.6% and 26.6%, respectively. Overall survival rates at 1 and 2 years were 86.1% and 66.5%, respectively. Multivariate analysis revealed that, among the patient characteristics, whether the lesion was mucosal had a significant effect on achieving complete response.
CONCLUSIONS
This study provided valuable insights into the early integration of BNCT into routine clinical practice, highlighting its efficacy and safety. Technical improvements are needed to ensure precise dose administration. Ongoing prospective studies, such as the phase II REBIVAL study, will further elucidate the role of BNCT in recurrent head and neck cancer.
PubMed: 38580084
DOI: 10.1016/j.ijrobp.2024.03.041 -
Clinical Journal of Gastroenterology Jun 2024Atezolizumab is an immune checkpoint inhibitor specific for the programmed death-1 (PD-1) receptor. In this case report, we describe two cases of oral mucositis that...
Atezolizumab is an immune checkpoint inhibitor specific for the programmed death-1 (PD-1) receptor. In this case report, we describe two cases of oral mucositis that developed following the initiation of a systemic chemotherapy regimen comprising atezolizumab and bevacizumab for recurrent hepatocellular carcinoma. After 2 or 3 cycles of treatment, each patient presented with mucosal ulcers in the mouth, oral pain, difficulty in speech and oral intake, and both were admitted to our hospital for management. Following rule out of other conditions such as pharyngeal ulcers, herpetic mucositis, denture or oral trauma, or necrotizing mucositis, both patients were diagnosed with oral mucositis as a severe immune-related adverse event. Oral candidiasis was observed in both cases and should be considered a risk factor for the development of oral mucositis. Chemotherapy was discontinued and treatment with prednisolone was started, along with supportive care. The oral mucositis improved, and prednisolone was gradually reduced; however, in one patient, discontinuation of chemotherapy led to a recurrence of hepatocellular carcinoma. The other patient was lost to follow-up. In patients with risk factors, attention must be paid to the development of oral mucositis during immune checkpoint inhibitor treatment.
Topics: Humans; Liver Neoplasms; Carcinoma, Hepatocellular; Stomatitis; Antibodies, Monoclonal, Humanized; Male; Bevacizumab; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Aged; Female; Prednisolone; Neoplasm Recurrence, Local; Immune Checkpoint Inhibitors
PubMed: 38512635
DOI: 10.1007/s12328-024-01947-6 -
Vestnik Otorinolaringologii 2024Children's and adults' rhinosinusitis are two diseases that have both similarities and differences in anatomy, epidemiology, causes, pathogenesis, diagnosis and...
Children's and adults' rhinosinusitis are two diseases that have both similarities and differences in anatomy, epidemiology, causes, pathogenesis, diagnosis and treatment. At the same rhinosinusitis is one of the most common in otorhinolaryngology's practice, both in children and adults. The of adults paranasal sinuses (PNS) anatomy differs from children's PNS anatomy. Although ostiomeatal complex occlusion is recognized as a major cause of poor ventilation and drainage of the adult paranasal sinuses, it does not have a strong effect on pediatric rhinosinusitis, but adenoids play a key role. Adenoids are bacteria and biofilms reservoirs that cause chronic refractory rhinosinusitis regardless of pharyngeal tonsil size. The prevalence of chronic rhinosinusitis (CRS) is lower in children than in adults. Diagnosis of children's rhinosinusitis is more difficult because nasal cavity endoscopic examination is performed rarely due to the occasional need of general anesthesia during the procedure. Moreover, it's necessary to take into account prevailing etiological role of viruses in ARS at children's age and chronic adenoiditis often accompanies pediatric CRS, which requires attention prescribing medical therapy as the basis of rhinosinusitis treatment. The DysheLORz based on roots is highly effective and safe for children's and adults ARS and CRS treatment, both as monotherapy and in combination with topical steroids and antibiotics. This herbal medicine immunomodulatory effect is mediated mainly by stimulating the production of TNF-α, IL-1, IL-12 and IFN-γ. It activates macrophages and improves their phagocytic activity. IL-12, together with TNF-α, enhances NK and cytotoxic CD8 lymphocytes' activity against infected cells. IL-12 effect on Th1 lymphocytes maturation provides a link between innate and adaptive immunity. This is also increasing MCP-1, IP-10 and MIP-1β chemokines synthesis and decreasing MIP-1α, ENA-78, GROα and IL-8 production in PNS and nasal mucosa. This leads to decrease of neutrophils chemotaxis to the inflammation site, and decline of serine proteases concentration (neutrophils main enzymes), that increases mucous membrane epithelial barrier permeability, reducing bacterial infections risk. Additionally, increases epithelial cells beating cilia frequency and inhibits hemagglutinin and neuraminidase present on influenza virus surface. The drug increases antimicrobial peptides production as defensins, human neutrophil peptides (HNP) and bactericidal permeability-increasing protein (BPI), which is also important for rapid inflammation regression in rhinosinusitis. It causes bacterial adhesion to epithelial cells inhibition, phagocytosis stimulation, nitric oxide (NO) release and oxidative burst. The medicine had a direct effect on and . Based on these data, it is possible to explain the high effectiveness and safety of the drugs based on in ENT organs inflammation treatment, for both adults and children over 1 year old.
Topics: Adult; Humans; Child; Infant; Rhinitis; Rhinosinusitis; Tumor Necrosis Factor-alpha; Sinusitis; Nasal Mucosa; Inflammation; Interleukin-12; Chronic Disease
PubMed: 38506028
DOI: 10.17116/otorino20248901164