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Sexually Transmitted Infections Jul 2024Condyloma acuminatum is caused by human papillomavirus (HPV), which typically presents as excrescent, pedunculated, papillomatous lesions which may be of a pale colour....
BACKGROUND
Condyloma acuminatum is caused by human papillomavirus (HPV), which typically presents as excrescent, pedunculated, papillomatous lesions which may be of a pale colour. On rare occasions, we have observed pigmented genital lesions that are similar to seborrhoeic keratoses, but with histological findings of condyloma acuminatum and positive genotyping for HPV. We have termed these 'seborrhoeic keratosis-like' type condylomas.
METHODS
This is an observational retrospective study. The following clinical data were collected: age, sex, time of evolution, location, isolated or multiple lesions, monomorphous or polymorphous/mixed lesions. HPV genotyping was performed in all cases, and excision for histological study in eight cases.
RESULTS
A total of 31 patients were diagnosed with this type of pigmented condylomata acuminata. Of these, 16 had isolated lesions (less than five lesions) and 15 had multiple lesions. 67% of the lesions exhibited slow growth, with an evolution period of greater than 1 year. The most frequent location was the base of the penis and pubis. HPV genotyping of the lesions was positive in all cases, with the HPV-6 genotype predominating (28 cases, 90.3%). The lesions exhibited dermoscopic differences from other pigmented lesions and histological findings attributable to HPV infection (pseudoparakeratosis, koilocytosis, etc) and others similar to those observed in seborrhoeic keratoses.
CONCLUSIONS
A total of 31 patients were diagnosed with pigmented verrucous lesions, excrescents, isolated or multiple, in the genital region. These lesions exhibited clinical characteristics similar to seborrhoeic keratoses, with positive genotyping for HPV. In the majority of cases, the genotype was HPV-6. These lesions have been named 'pigmented condylomata acuminata seborrhoeic keratosis-like'. Only 10 cases of these lesions have been described in the literature.
PubMed: 38964839
DOI: 10.1136/sextrans-2024-056143 -
BMJ Open Jul 2024Despite many technological advances, the diagnostic yield of bronchoscopic peripheral lung nodule analysis remains limited due to frequent mispositioning. Needle-based... (Randomized Controlled Trial)
Randomized Controlled Trial
Bronchoscopy with and without needle-based confocal laser endomicroscopy for peripheral lung nodule diagnosis: protocol for a multicentre randomised controlled trial (CLEVER trial).
INTRODUCTION
Despite many technological advances, the diagnostic yield of bronchoscopic peripheral lung nodule analysis remains limited due to frequent mispositioning. Needle-based confocal laser endomicroscopy (nCLE) enables real-time microscopic feedback on needle positioning, potentially improving the sampling location and diagnostic yield. Previous studies have defined and validated nCLE criteria for malignancy, airway and lung parenchyma. Larger studies demonstrating the effect of nCLE on diagnostic yield are lacking. We aim to investigate if nCLE-imaging integrated with conventional bronchoscopy results in a higher diagnostic yield compared with conventional bronchoscopy without nCLE.
METHODS AND ANALYSIS
This is a parallel-group randomised controlled trial. Recruitment is performed at pulmonology outpatient clinics in universities and general hospitals in six different European countries and one hospital in the USA. Consecutive patients with a for malignancy suspected peripheral lung nodule (10-30 mm) with an indication for diagnostic bronchoscopy will be screened, and 208 patients will be included. Web-based randomisation (1:1) between the two procedures will be performed. The primary outcome is diagnostic yield. Secondary outcomes include diagnostic sensitivity for malignancy, needle repositionings, procedure and fluoroscopy duration, and complications. Pathologists will be blinded to procedure type; patients and endoscopists will not.
ETHICS AND DISSEMINATION
Primary approval by the Ethics Committee of the Amsterdam University Medical Center. Dissemination involves publication in a peer-reviewed journal.
SUPPORT
Financial and material support from Mauna Kea Technologies.
TRIAL REGISTRATION NUMBER
NCT06079970.
Topics: Humans; Bronchoscopy; Microscopy, Confocal; Lung Neoplasms; Solitary Pulmonary Nodule; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Lung; Needles
PubMed: 38964802
DOI: 10.1136/bmjopen-2023-081148 -
Journal For Immunotherapy of Cancer Jul 2024Esophageal cancer (ESCA) is a form of malignant tumor associated with chronic inflammation and immune dysregulation. However, the specific immune status and key...
BACKGROUND
Esophageal cancer (ESCA) is a form of malignant tumor associated with chronic inflammation and immune dysregulation. However, the specific immune status and key mechanisms of immune regulation in this disease require further exploration.
METHODS
To investigate the features of the human ESCA tumor immune microenvironment and its possible regulation, we performed mass cytometry by time of flight, single-cell RNA sequencing, multicolor fluorescence staining of tissue, and flow cytometry analyses on tumor and paracancerous tissue from treatment-naïve patients.
RESULTS
We depicted the immune landscape of the ESCA and revealed that CD8 (tissue-resident memory CD8 T cells (CD8 TRMs) were closely related to disease progression. We also revealed the heterogeneity of CD8 TRMs in the ESCA tumor microenvironment (TME), which was associated with their differentiation and function. Moreover, the subset of CD8 TRMs in tumor (called tTRMs) that expressed high levels of granzyme B and immune checkpoints was markedly decreased in the TME of advanced ESCA. We showed that tTRMs are tumor effector cells preactivated in the TME. We then demonstrated that conventional dendritic cells (cDC2s) derived from intermediate monocytes (iMos) are essential for maintaining the proliferation of CD8 TRMs in the TME. Our preliminary study showed that hypoxia can promote the apoptosis of iMos and impede the maturation of cDC2s, which in turn reduces the proliferative capacity of CD8 TRMs, thereby contributing to the progression of cancer.
CONCLUSIONS
Our study revealed the essential antitumor roles of CD8 TRMs and preliminarily explored the regulation of the iMo/cDC2/CD8 TRM immune axis in the human ESCA TME.
Topics: Humans; Tumor Microenvironment; Esophageal Neoplasms; CD8-Positive T-Lymphocytes; Dendritic Cells; Monocytes; Male; Female; CDC2 Protein Kinase
PubMed: 38964786
DOI: 10.1136/jitc-2024-008889 -
The European Respiratory Journal Jul 2024Multiple host blood transcriptional signatures have been developed as non-sputum triage tests for tuberculosis (TB). We aimed to compare the diagnostic performance of 20...
BACKGROUND
Multiple host blood transcriptional signatures have been developed as non-sputum triage tests for tuberculosis (TB). We aimed to compare the diagnostic performance of 20 blood transcriptomic TB signatures for differentiating between symptomatic patients who have TB other respiratory diseases (ORD).
METHODS
As part of a nested case-control study, individuals presenting with respiratory symptoms at primary health care clinics in Ethiopia, Malawi, Namibia, Uganda, South Africa, and The Gambia were enrolled. TB was diagnosed based on clinical, microbiological, and radiological findings. Transcriptomic signatures were measured in whole blood using microfluidic RT-qPCR. Diagnostic performance was benchmarked against the WHO Target Product Profile (TPP) for a non-sputum TB triage test.
RESULTS
Among 541 participants, 158 had definite, microbiologically-confirmed TB, 32 had probable TB, while 389 participants had ORD. Nine signatures differentiated between ORD and TB with equivalent performance (Satproedprai7: area under the curve 0.83 [95% CI 0.79-0.87], Jacobsen3: 0.83 [0.79-0.86]; Suliman2: 0.82 [0.78-0.86]; Roe1: 0.82 [0.78-0.86]; Kaforou22: 0.82 [0.78-0.86]; Sambarey10: 0.81 [0.77-0.85]; Duffy9: 0.81 [0.76-0.86]; Gliddon3: 0.8 [0.75-0.85]; and Suliman4 0.79 [0.75-0.84]. Benchmarked against a 90% sensitivity, these signatures achieved specificities between 44% (95% CI 38-49) and 54% (49-59), not meeting the TPP criteria. Signature scores significantly varied by HIV status and country. In country-specific analyses several signatures, such as Satproedprai7 and Penn-Nicholson6, met the minimal TPP criteria for a triage test in Ethiopia, Malawi, and South Africa.
CONCLUSION
No signatures met the TPP criteria in a pooled analysis of all countries, but several signatures met the minimum criteria for a non-sputum TB triage test in some countries.
PubMed: 38964778
DOI: 10.1183/13993003.00153-2024 -
Bone & Joint Research Jul 2024Although low-intensity pulsed ultrasound (LIPUS) combined with disinfectants has been shown to effectively eliminate portions of biofilm in vitro, its efficacy in vivo...
AIMS
Although low-intensity pulsed ultrasound (LIPUS) combined with disinfectants has been shown to effectively eliminate portions of biofilm in vitro, its efficacy in vivo remains uncertain. Our objective was to assess the antibiofilm potential and safety of LIPUS combined with 0.35% povidone-iodine (PI) in a rat debridement, antibiotics, and implant retention (DAIR) model of periprosthetic joint infection (PJI).
METHODS
A total of 56 male Sprague-Dawley rats were established in acute PJI models by intra-articular injection of bacteria. The rats were divided into four groups: a Control group, a 0.35% PI group, a LIPUS and saline group, and a LIPUS and 0.35% PI group. All rats underwent DAIR, except for Control, which underwent a sham procedure. General status, serum biochemical markers, weightbearing analysis, radiographs, micro-CT analysis, scanning electron microscopy of the prostheses, microbiological analysis, macroscope, and histopathology evaluation were performed 14 days after DAIR.
RESULTS
The group with LIPUS and 0.35% PI exhibited decreased levels of serum biochemical markers, improved weightbearing scores, reduced reactive bone changes, absence of viable bacteria, and decreased inflammation compared to the Control group. Despite the greater antibiofilm activity observed in the PI group compared to the LIPUS and saline group, none of the monotherapies were successful in preventing reactive bone changes or eliminating the infection.
CONCLUSION
In the rat model of PJI treated with DAIR, LIPUS combined with 0.35% PI demonstrated stronger antibiofilm potential than monotherapy, without impairing any local soft-tissue.
PubMed: 38964744
DOI: 10.1302/2046-3758.137.BJR-2023-0339.R1 -
Annals of Oncology : Official Journal... Jul 2024Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a PD-1 monoclonal antibody) has shown potential clinical activity for locally advanced...
Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial.
BACKGROUND
Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a PD-1 monoclonal antibody) has shown potential clinical activity for locally advanced rectal cancer (LARC) in a phase II trial. This study aimed to further confirm the efficacy and safety of SCRT followed by CAPOX and camrelizumab compared to long-course chemoradiotherapy (LCRT) followed by CAPOX alone as neoadjuvant treatment for LARC.
PATIENTS AND METHODS
In this randomized, phase III trial, patients with T3-4/N rectal adenocarcinoma were randomly assigned (1:1) to receive SCRT or long-course chemoradiotherapy (LCRT), followed by 2 cycles of camrelizumab and CAPOX or CAPOX alone, respectively. After surgery, each arm underwent either 6 cycles of camrelizumab and CAPOX, followed by up to 17 doses of camrelizumab, or 6 cycles of CAPOX. The primary endpoint was pathological complete response (pCR) rate (ypT0N0) assessed by a blinded independent review committee. Key secondary endpoints tested hierarchically were 3-year event-free survival (EFS) rate and overall survival (OS).
RESULTS
Between July 2021 and March 2023, the intention-to-treat population comprised 113 patients in experimental arm and 118 patients in control arm, with surgery performed in 92% and 83.9%, respectively. At data cutoff (July 11, 2023), the pCR rate were 39.8% (95% CI, 30.7 to 49.5) in experimental arm compared to 15.3% (95% CI, 9.3 to 23.0) in control arm (difference, 24.6%; odds ratio, 3.7; 95% CI, 2.0 to 6.9; p < 0.001). In each arm, surgical complication rates were 40.0% and 40.8%, grade ≥ 3 treatment-related adverse events were 29.2% and 27.2%. 3-year EFS rate and OS continue to mature.
CONCLUSIONS
In LARC patients, neoadjuvant SCRT followed by camrelizumab plus CAPOX demonstrated a significantly higher pCR rate than LCRT followed by CAPOX, with a well-tolerated safety profile. SCRT followed by camrelizumab and chemotherapy can be recommended as a neoadjuvant treatment modality for these patients.
PubMed: 38964714
DOI: 10.1016/j.annonc.2024.06.015 -
Identification of DNase I hypersensitive sites in the human genome by multiple sequence descriptors.Methods (San Diego, Calif.) Jul 2024DNase I hypersensitive sites (DHSs) are chromatin regions highly sensitive to DNase I enzymes. Studying DHSs is crucial for understanding complex transcriptional...
DNase I hypersensitive sites (DHSs) are chromatin regions highly sensitive to DNase I enzymes. Studying DHSs is crucial for understanding complex transcriptional regulation mechanisms and localizing cis-regulatory elements (CREs). Numerous studies have indicated that disease-related loci are often enriched in DHSs regions, underscoring the importance of identifying DHSs. Although wet experiments exist for DHSs identification, they are often labor-intensive. Therefore, there is a strong need to develop computational methods for this purpose. In this study, we used experimental data to construct a benchmark dataset. Seven feature extraction methods were employed to capture information about human DHSs. The F-score was applied to filter the features. By comparing the prediction performance of various classification algorithms through five-fold cross-validation, random forest was proposed to perform the final model construction. The model could produce an overall prediction accuracy of 0.859 with an AUC value of 0.837. We hope that this model can assist scholars conducting DNase research in identifying these sites.
PubMed: 38964595
DOI: 10.1016/j.ymeth.2024.06.012 -
Topics in Companion Animal Medicine Jul 2024Fifteen male dogs with squamous cell carcinoma of the external genitalia were admitted for further investigation and surgical management between 1994 and 2020. The dogs...
Fifteen male dogs with squamous cell carcinoma of the external genitalia were admitted for further investigation and surgical management between 1994 and 2020. The dogs belonged to various breeds. Thirteen dogs were intact and two were castrated with a median age of 8 years and a median weight of 28 kg. Seven dogs were white-coated and eight nonwhite coated. Scrotal ablation and orchiectomy were performed in four dogs, partial penile amputation in two, partial penile amputation plus partial preputial ablation in one, penile amputation, and scrotal urethrostomy in seven, and local preputial excision in one dog. Postoperative complications included hemorrhage in 10 dogs, bruising at the urethrostomy site in seven, and urethrostomy dehiscence in one dog. Tumor recurrence was recorded in six dogs. Dogs with poorly differentiated tumors that had tumor recurrence had shorter survival and worse prognosis compared to those with well and moderately differentiated tumors. The mean survival time was 48.132 months. After a median follow-up of 23 months (range: 8 to 72 months), eight dogs were alive, five were euthanized and two dogs died from unrelated causes. Surgical excision seems to be a treatment option for dogs with squamous cell carcinoma of the external genitalia.
PubMed: 38964542
DOI: 10.1016/j.tcam.2024.100887 -
Molecular and Cellular Probes Jul 2024The progression and pathogenesis of membranous glomerulonephritis (MGN) are inextricably linked to chronic inflammation. Despite improving clinical remission rates due...
The progression and pathogenesis of membranous glomerulonephritis (MGN) are inextricably linked to chronic inflammation. Despite improving clinical remission rates due to the application of cyclophosphamide (CYC), treatment of MGN still requires further exploration. Ruxolitinib (Ruxo) negatively affects the signaling pathways participating in the production of pro-inflammatory cytokines. Hence, we investigated whether the combination of CYC and Ruxo can modulate inflammation through influencing T helper 17 (Th17) lineages and regulatory T cells (Tregs). Passive Heymann nephritis (PHN), an experimental model of MGN, was induced in a population of rats. Then, the animals were divided into five groups: PHN, CYC-receiving, Ruxo-receiving, CYC-Ruxo-receiving PHN rats, and healthy controls. After 28 days of treatment, biochemistry analysis was performed and splenocytes were isolated for flowcytometry investigation of Th17 cells and Tregs. The correlative transcription factors of the cells, alongside their downstream cytokine gene expressions, were also assessed using real-time PCR. Furthermore, serum cytokine signatures for the lymphocytes were determined through ELISA. The combination of CYC and Ruxo significantly reduced the serum values of urea in rats versus the PHN group (24.62±7.970 vs. 40.60±10.81 mg/dL). In contrast to Treg's activities, the functionality of Th17 cells noticeably increased not only in PHN rats but also in CYC or Ruxo-receiving PHN animals when compared with the control (10.60±2.236, 8.800±1.465, 8.680±1.314 vs. 4.420±1.551 %). However, in comparison to the PHN group, the incidence of Th17 cells notably fell in rats receiving CYC and Ruxo (10.60±2.236 vs. 6.000±1.373 %) in favor of the Treg's percentage (5.020±1.761 vs. 8.980±1.178 %), which was verified by the gene expressions and cytokine productions correlative to these lymphocytes. The combination of CYC and Ruxo was able to decline Th17 cells in favor of Tregs improvement in PHN rats, suggesting an innovative combination therapy in MGN treatment approaches.
PubMed: 38964425
DOI: 10.1016/j.mcp.2024.101969 -
Molecular Cell Jul 2024DNA repair is directly performed by hundreds of core factors and indirectly regulated by thousands of others. We massively expanded a CRISPR inhibition and Cas9-editing...
DNA repair is directly performed by hundreds of core factors and indirectly regulated by thousands of others. We massively expanded a CRISPR inhibition and Cas9-editing screening system to discover factors indirectly modulating homology-directed repair (HDR) in the context of ∼18,000 individual gene knockdowns. We focused on CCAR1, a poorly understood gene that we found the depletion of reduced both HDR and interstrand crosslink repair, phenocopying the loss of the Fanconi anemia pathway. CCAR1 loss abrogated FANCA protein without substantial reduction in the level of its mRNA or that of other FA genes. We instead found that CCAR1 prevents inclusion of a poison exon in FANCA. Transcriptomic analysis revealed that the CCAR1 splicing modulatory activity is not limited to FANCA, and it instead regulates widespread changes in alternative splicing that would damage coding sequences in mouse and human cells. CCAR1 therefore has an unanticipated function as a splicing fidelity factor.
PubMed: 38964321
DOI: 10.1016/j.molcel.2024.06.011