-
European Journal of Clinical... Jun 2024Incorporation of AKT inhibitors into adjuvant therapy for advanced or metastatic breast cancer has improved clinical outcomes. However, the safety of AKT inhibitors...
INTRODUCTION
Incorporation of AKT inhibitors into adjuvant therapy for advanced or metastatic breast cancer has improved clinical outcomes. However, the safety of AKT inhibitors should be better evaluated, given the possibility of prolonging survival and impacting patient quality of life. Our aim was to assess how the addition of AKT inhibitors to adjuvant therapy affects treatment-related adverse events.
METHODS
We evaluated binary outcomes with risk ratios (RRs), with 95% confidence intervals (CIs). We used DerSimonian and Laird random-effect models for all endpoints. Heterogeneity was assessed using I statistics. R, version 4.2.3, was used for statistical analyses.
RESULTS
A total of seven RCTs comprising 1619 patients with BC. The adverse effects that show significance statistical favoring the occurrence of adverse effects in AKT inhibitor were diarrhea (RR 3.05; 95% CI 2.48-3.75; p < 0.00001; I = 49%), hyperglycemia (RR 3.4; 95% CI 1.69-6.83; p = 0.00058; I = 75%), nausea (RR 1.69; 95% CI 1.34-2.13; p = 0.000008; I = 42%), rash (RR 2.79; 95% CI 1.49-5.23; p = 0.0013; I = 82%), stomatitis (RR 2.24; 95% CI 1.69-2.97; p < 0.00001; I = 16%) and vomiting (RR 2.99; 95% CI 1.85-4.86; p = 0.00009; I = 42%). There was no significant difference between the groups for alopecia (p = 0.80), fatigue (p = 0.087), and neuropathy (p = 0.363380).
CONCLUSION
The addition of AKT inhibitors to adjuvant therapy was associated with an increase in treatment-related adverse events. These results provide safety information for further clinical trials evaluating AKT inhibitor therapy for patients with metastatic BC. Clinicians should closely monitor patients for treatment-related adverse events to avoid discontinuation of therapy and morbidity caused by these early-stage therapies.
PubMed: 38888626
DOI: 10.1007/s00228-024-03713-6 -
MBio Jun 2024The interferon (IFN) system protects mammals from diseases caused by virus infections. IFN synthesis is induced by pattern recognition receptor signaling pathways...
The interferon (IFN) system protects mammals from diseases caused by virus infections. IFN synthesis is induced by pattern recognition receptor signaling pathways activated by virus infection. IFN is secreted from the infected cells and acts upon neighboring cells by binding cell surface receptors and triggering induction of hundreds of IFN-stimulated genes and proteins, many of which block different steps of virus replication. The IFN-induced tetratricopeptide repeat proteins (IFIT) are a family of RNA-binding proteins. We and others have previously reported that IFIT2 protects mice from many neurotropic RNA viruses; indeed, Ifit2-/- mice are very susceptible to intranasal or subcutaneous infections with vesicular stomatitis virus (VSV). Here, using a newly generated conditional knockout mouse, we report that ablation of Ifit2 expression only in neuronal cells was sufficient to render mice susceptible to neuropathogenesis caused by intranasal, but not subcutaneous, infection of VSV. Another genetically modified mouse line, expressing a mutant IFIT2 that cannot bind RNA, was as susceptible to VSV infection as -/- mice. These results demonstrated that IFIT2 RNA-binding activity is essential for protecting mice against neurological diseases caused by intranasal infection of VSV.IMPORTANCEInterferon's (IFN's) antiviral effects are mediated by the proteins encoded by the interferon-stimulated genes. IFN-stimulated genes (IFIT2) is one such protein, which inhibits replication of many RNA viruses in the mouse brain and the resultant neuropathology. Our study sheds light on how IFIT2 works. By ablating Ifit2 expression only in neuronal cells, using a newly generated conditional knockout mouse line, we showed that Ifit2 induction in the neurons of the infected mouse was necessary for antiviral function of interferon. IFIT2 has no known enzyme activity; instead, it functions by binding to cellular or viral proteins or RNAs. We engineered a new mouse line that expressed a mutant IFIT2 that cannot bind RNA. These mice were very susceptible to infection with vesicular stomatitis virus indicating that the RNA-binding property of IFIT2 was essential for its antiviral function .
PubMed: 38888342
DOI: 10.1128/mbio.00568-24 -
Investigative Ophthalmology & Visual... Jun 2024The current study evaluated the lid margin microbiome of keratinized lid margins of patients with chronic Stevens-Johnson syndrome (SJS) and compared it with healthy...
PURPOSE
The current study evaluated the lid margin microbiome of keratinized lid margins of patients with chronic Stevens-Johnson syndrome (SJS) and compared it with healthy controls and historically reported lid margin microbiome of patients with meibomian gland dysfunction (MGD).
METHODS
Eyelid margin swabs of 20 asymptomatic adults (mean age = 29 ± 12 years) and 10 patients with chronic SJS (mean age = 31.2 ± 14 years) with lid margin keratinization were sequenced using next generation of 16S rDNA V3 to V4 variable region. Within SJS, the keratinized lid margin microbiome was compared with adjacent eyelid skin.
RESULTS
All patients had obstructive MGD, and mean Schirmer I value was 2.8 ± 1.9 mm. The phyla were similar in two groups, whereas at the genera level, an increase in the relative abundance of Corynebacterium, Haemophilus, Azotobacter, and Afipia and a decrease of Acinetobacter was noted in SJS compared to healthy lid margins. SJS-associated microbiota displayed lesser diversity and more heterogeneity than healthy controls. The Principal Components Analysis (PCA) plot revealed wide separation in the SJS and the control groups. Correlational network analysis revealed Corynebacterium and Sphingomonas forming a major hub of negative interactions with other bacterial genera in the SJS group. Significant differences exist in the prevalent genera between keratinized lid margins and historically reported meibum microbiome of patients with MGD. In addition, the eyelid skin of patients with SJS had predominant Staphylococcus, whereas Corynebacterium and Pseudomonas were more in the keratinized lid margins compared to the eyelid skin microbiome.
CONCLUSIONS
Lid margin microbiome is significantly altered in the keratinized lid margins of patients with SJS compared to the eyelid skin of patients with SJS, normal lid margins, and patients with MGD.
Topics: Humans; Male; Female; Adult; Microbiota; Dry Eye Syndromes; Eyelids; Stevens-Johnson Syndrome; Middle Aged; Young Adult; Bacteria; RNA, Ribosomal, 16S; DNA, Bacterial; Adolescent; Meibomian Glands; Meibomian Gland Dysfunction; Keratins
PubMed: 38888283
DOI: 10.1167/iovs.65.6.28 -
Planta Medica Jun 2024The search for new active substances against SARS-CoV-2 is still a central challenge after the COVID-19 pandemic. Antiviral agents to complement vaccination are an...
The search for new active substances against SARS-CoV-2 is still a central challenge after the COVID-19 pandemic. Antiviral agents to complement vaccination are an important pillar in the clinical situation. Selected cannabinoids such as cannabigerol, cannabicyclol, cannabichromene, and cannabicitran from and synthetic homologues of cannabigerol and cannabicyclol were evaluated for effects on the cell viability of Vero cells (CC of cannabigerol and cannabicyclol 40 resp. 38 µM) and reduced virus entry of vesicular stomatitis pseudotyped viruses with surface-expressed SARS-CoV-2 spike protein at 20 µM. In addition to a reduction of pseudotyped virus entry, a titer reduction assay on Vero cells after preincubation of Wuhan SARS-CoV-2 significantly confirmed antiviral activity. Investigations on the molecular targets addressed by cannabigerol and cannabicyclol indicated that both compounds are inhibitors of SARS-CoV-2 spike protein-mediated membrane fusion, as could be shown by a virus-free reporter fusion inhibition assay (EC for cannabigerol 5.5 µM and for cannabicyclol 10.8 µM) and by monitoring syncytia formation in Vero reporter cells. Selectivity indices were calculated as 7.4 for cannabigerol and 3.5 for cannabicyclol. Systematic semisynthetic alterations of cannabigerol and cannabicyclol indicated that the side chains of both compounds do not contribute to the observed anti-membrane fusion activity.
PubMed: 38885660
DOI: 10.1055/a-2320-8822 -
IScience Jun 2024The COVID-19 pandemic highlighted the need for antivirals against emerging coronaviruses (CoV). Inhibiting spike (S) glycoprotein-mediated viral entry is a promising...
The COVID-19 pandemic highlighted the need for antivirals against emerging coronaviruses (CoV). Inhibiting spike (S) glycoprotein-mediated viral entry is a promising strategy. To identify small molecule inhibitors that block entry downstream of receptor binding, we established a high-throughput screening (HTS) platform based on pseudoviruses. We employed a three-step process to screen nearly 200,000 small molecules. First, we identified hits that inhibit pseudoviruses bearing the SARS-CoV-2 S glycoprotein. Counter-screening against pseudoviruses with the vesicular stomatitis virus glycoprotein (VSV-G), yielded sixty-five SARS-CoV-2 S-specific inhibitors. These were further tested against pseudoviruses bearing the MERS-CoV S glycoprotein, which uses a different receptor. Out of these, five compounds, which included the known broad-spectrum inhibitor Nafamostat, were subjected to further validation and tested against pseudoviruses bearing the S glycoprotein of the Alpha, Delta, and Omicron variants as well as SARS-CoV-2. This rigorous approach revealed an unreported inhibitor and its derivative as potential broad-spectrum antivirals.
PubMed: 38883823
DOI: 10.1016/j.isci.2024.110019 -
Gan To Kagaku Ryoho. Cancer &... May 2024An 80-year-old male patient presented with a 2.5 cm-sized submucosal tumor on the greater curvature side of the upper gastric body during an endoscopic examination in...
An 80-year-old male patient presented with a 2.5 cm-sized submucosal tumor on the greater curvature side of the upper gastric body during an endoscopic examination in 200X. We diagnosed gastric GIST by biopsy and performed laparoscopic- assisted partial gastrectomy. Imatinib was started as postoperative adjuvant therapy, but was discontinued after 1 month due to eyelid edema. The patient was followed up with a contrast-enhanced CT scan and a PET-CT scan. A 7 cm-sized mass in the gastrosplenic region was discovered on a 200X+7 years CT scan; this mass was thought to be possible recurrence of peritoneal dissemination. The patient did not want to undergo surgery or drug treatment, and was followed up. Five months later he complained of abdominal pain. The CT scan showed that the mass had shrunk slightly, but a small amount of ascites was observed, and tumor rupture was suspected. Therefore, we performed resection of the tumor in the office. Numerous disseminated nodules were found in the intra-abdominal cavity. Pathological examination revealed recurrence of GIST, and the patient was started on imatinib 200 mg/day. The dose was temporarily increased to 300 mg/day, but was reduced again to 200 mg/day 1 month later due to eyelid edema. Thereafter, the dose was temporarily discontinued due to stomatitis, and from 200X+8 years, 200 mg/day was administered for 2 weeks and then discontinued for 2 weeks. At present, 14 years after the first surgery and 6 years after recurrence, he remains alive thanks to imatinib continuation.
Topics: Humans; Male; Gastrointestinal Stromal Tumors; Stomach Neoplasms; Aged, 80 and over; Imatinib Mesylate; Recurrence; Gastrectomy; Antineoplastic Agents; Time Factors; Combined Modality Therapy
PubMed: 38881066
DOI: No ID Found -
BMC Oral Health Jun 2024Few studies have examined health related Quality of Life (HR-QoL) during the treatment of head and neck cancer (HNC) with even fewer focusing on the impact of oral...
BACKGROUND
Few studies have examined health related Quality of Life (HR-QoL) during the treatment of head and neck cancer (HNC) with even fewer focusing on the impact of oral mucositis (OM) on HR-QoL. Studies performed during treatment of HNC makes it possible to follow fluctuations in HR-QoL, OM and other treatment related side effects. The aim was to prospectively analyze HR-QoL, changes in clinical variables and the impact of OM on HR-QoL during HNC treatment.
MATERIALS AND METHODS
Patients were recruited before commencing curative cancer treatment and were given professional oral care weekly during oncologic treatment. HR-QoL was reported before, during (week 2, 4 and 6) and three months after treatment using the EORTC Quality of Life questionnaires C30 and H&N35 and the stimulated whole salivary secretion rate was determined at the same time-points. OM (erythema and ulceration) was registered using the Oral Mucositis Assessment Scale (OMAS), at baseline, weekly during treatment and post treatment. Differences in HR-QoL between different timepoints were analyzed. To analyze the impact of OM on HR-QoL the patients were categorized into two groups: no/mild OM (OMAS ulceration score 0-1) or severe OM (OMAS ulceration score ≥ 2) and HR-QoL was compared between the two OM groups at three timepoints during treatment.
RESULTS
Fifty-seven patients (43 men, 14 women), with a mean age of 58 years were included. Patients reported progressively impaired HR-QoL, with peak issues noted at weeks 4 and 6, particularly in social eating, senses, appetite loss, sticky saliva, and decreasing salivary secretion rates were determined. Patients with severe OM reported worse HR-QoL compared to those with no/mild OM. Persistent problems 3 months post treatment were appetite loss, dry mouth, senses (smell and taste) and problems with social eating.
CONCLUSION
Patients experienced exacerbated symptoms and problems weeks 4 and 6 of oncological treatment, especially among those with severe OM, stressing the importance of clinically monitoring the patients to reduce and alleviate their symptoms. Persistent problems three months post treatment are likely associated with the reduced salivary secretion rate indicating that patients should be monitored also after completed oncological treatment.
Topics: Humans; Quality of Life; Stomatitis; Prospective Studies; Male; Female; Middle Aged; Head and Neck Neoplasms; Oral Health; Aged; Adult; Xerostomia; Follow-Up Studies; Saliva; Salivation; Surveys and Questionnaires
PubMed: 38879501
DOI: 10.1186/s12903-024-04466-5 -
Archives of Dermatological Research Jun 2024Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), grouped together under the terminology of epidermal necrolysis (EN), are a spectrum of... (Review)
Review
Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), grouped together under the terminology of epidermal necrolysis (EN), are a spectrum of life-threatening dermatologic conditions. A lack of standardization and validation for existing endpoints has been identified as a key barrier to the comparison of these therapies and development of evidenced-based treatment. Following PRISMA guidelines, we conducted a systematic review of prospective studies involving systemic or topical treatments for EN, including dressing and ocular treatments. Outcomes were separated into mortality assessment, cutaneous outcomes, non-cutaneous clinical outcomes, and mucosal outcomes. The COSMIN Risk of Bias tool was used to assess the quality of studies on reliability and measurement error of outcome measurement instruments. Outcomes across studies assessing treatment in the acute phase of EN were varied. Most data came from prospective case reports and cohort studies representing the lack of available randomized clinical trial data available in EN. Our search did not reveal any EN-specific validated measures or scoring tools used to assess disease progression and outcomes. Less than half of included studies were considered "adequate" for COSMIN risk of bias in reliability and measurement error of outcome measurement instruments. With little consensus about management and treatment of EN, consistency and validation of measured outcomes is of the upmost importance for future studies to compare outcomes across treatments and identify the most effective means of combating the disease with the highest mortality managed by dermatologists.
Topics: Humans; Stevens-Johnson Syndrome; Reproducibility of Results; Outcome Assessment, Health Care; Treatment Outcome; Bandages
PubMed: 38878166
DOI: 10.1007/s00403-024-03062-5 -
Journal of the American Dental... Jun 2024The aim of this study was to evaluate oral alterations among university students and explore possible associations with tobacco consumption in its various forms.
BACKGROUND
The aim of this study was to evaluate oral alterations among university students and explore possible associations with tobacco consumption in its various forms.
METHODS
A cross-sectional study was conducted in 2 phases: the first phase involved administering an electronic questionnaire to participants determine the prevalence of tobacco use and the second phase involved a physical examination of the participants. The participants were grouped on the basis of their reported habits and compared using statistical analysis (P < .05).
RESULTS
Of the 620 participants, 57.1% reported using tobacco in some form, with 47.4% reporting electronic cigarette (e-cigarette) use. In the clinical phase, comparing the presence of oral changes in tobacco users vs nonusers, e-cigarette users had a higher proportion of white-spot caries lesions (P = .041) and gingivitis (P = .012). When e-cigarette use was combined with other forms of tobacco use, additional oral changes were more prevalent, including coated tongue and nicotinic stomatitis (P < .05).
CONCLUSIONS
The use of alternative forms of tobacco consumption is common among university students, with e-cigarette use being the most prevalent form, and may lead to detrimental effects on the oral cavity, such as caries and gingivitis, particularly when used in conjunction with other tobacco products.
PRACTICAL IMPLICATIONS
The use of tobacco in alternative forms, such as e-cigarettes, can affect oral health directly or indirectly. Dentists should be familiar with the characteristics of this population and the potential oral repercussions associated with tobacco use to address the impact on health and raise awareness of the associated risks.
PubMed: 38878025
DOI: 10.1016/j.adaj.2024.04.012 -
Journal of Zoo and Wildlife Medicine :... Jun 2024This report describes infections in colubrid and viperid snakes. A captive eastern ratsnake () was presented for a large intraoral mass associated with the mandible....
This report describes infections in colubrid and viperid snakes. A captive eastern ratsnake () was presented for a large intraoral mass associated with the mandible. The mass was debulked and histologic examination revealed severe, granulomatous stomatitis with intralesional fungi exhibiting morphologic features consistent with . PCR and sequencing of affected tissues confirmed . Because of declining health, the ratsnake was euthanized and postmortem examination identified a disseminated infection involving the skeletal musculature, lung, kidney, mesentery, and mandible. A wild-caught timber rattlesnake (s) was presented for cutaneous lesions, weakness, and lethargy and later died. Postmortem examination revealed a mass-like structure in the esophagus characterized by high numbers of -like fungi associated with extensive granulomatous inflammation; the snake also had cutaneous mycosis suggestive of ophidiomycosis. This is the first report to document the unique morphologic features of in tissues and the presentation of schizangiellosis in snakes. Schizangiellosis should be considered as a differential diagnosis for nodular lesions involving the oral cavity and/or the gastrointestinal tract of snakes.
Topics: Animals; Crotalus; Colubridae; Mycoses; Thelazioidea; Animals, Zoo; Male; Female; Venomous Snakes
PubMed: 38875213
DOI: 10.1638/2023-0067