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Metabolic Engineering May 2024The development of synthetic microorganisms that could use one-carbon compounds, such as carbon dioxide, methanol, or formate, has received considerable interest. In...
The development of synthetic microorganisms that could use one-carbon compounds, such as carbon dioxide, methanol, or formate, has received considerable interest. In this study, we engineered Pichia pastoris and Saccharomyces cerevisiae to both synthetic methylotrophy and formatotrophy, enabling them to co-utilize methanol or formate with CO fixation through a synthetic C1-compound assimilation pathway (MFORG pathway). This pathway consisted of a methanol-formate oxidation module and the reductive glycine pathway. We first assembled the MFORG pathway in P. pastoris using endogenous enzymes, followed by blocking the native methanol assimilation pathway, modularly engineering genes of MFORG pathway, and compartmentalizing the methanol oxidation module. These modifications successfully enabled the methylotrophic yeast P. pastoris to utilize both methanol and formate. We then introduced the MFORG pathway from P. pastoris into the model yeast S. cerevisiae, establishing the synthetic methylotrophy and formatotrophy in this organism. The resulting strain could also successfully utilize both methanol and formate with consumption rates of 20 mg/L/h and 36.5 mg/L/h, respectively. The ability of the engineered P. pastoris and S. cerevisiae to co-assimilate CO with methanol or formate through the MFORG pathway was also confirmed by C-tracer analysis. Finally, production of 5-aminolevulinic acid and lactic acid by co-assimilating methanol and CO was demonstrated in the engineered P. pastoris and S. cerevisiae. This work indicates the potential of the MFORG pathway in developing different hosts to use various one-carbon compounds for chemical production.
PubMed: 38759777
DOI: 10.1016/j.ymben.2024.05.002 -
Technology and Health Care : Official... May 2024In periprosthetic joint infections (PJIs), the surgeon's role becomes pivotal in addressing the infection locally, necessitating the surgical removal of infected and... (Review)
Review
BACKGROUND
In periprosthetic joint infections (PJIs), the surgeon's role becomes pivotal in addressing the infection locally, necessitating the surgical removal of infected and necrotic tissue. Opportunity to enhance the visualization of infected tissue during surgery could represent a game-changing innovation.
OBJECTIVE
The aim of this narrative review is to delineate the application of intraoperative fluorescence imaging for targeting infected tissues in PJIs.
METHODS
A systematic review, adhering to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, was carried out. The search included multiple online database; MEDLINE, Scopus, and Web of Science. For data extraction the following were evaluated: (i) diagnosis of musculoskeletal infection; (ii) use of intraoperative fluorescence imaging; (iii) infected or necrotic tissues as target.
RESULTS
Initially, 116 studies were identified through online database searches and reference investigations. The search was narrowed down to a final list of 5 papers for in-depth analysis at the full-text level. Subsequently, 2 studies were included in the review. The study included a total of 13 patients, focusing on cases of fracture-related infections of the lower limbs.
CONCLUSION
The primary and crucial role for orthopedic surgeons in PJIs is the surgical debridement and precise removal of necrotic and infected tissue. Technologies that enable clear and accurate visualization of the tissue to be removed can enhance the eradication of infections, thereby promoting healing. A promising avenue for the future involves the potential application of intraoperative fluorescence imaging in pursuit of this objective.
PubMed: 38759036
DOI: 10.3233/THC-240479 -
Journal of Neuro-oncology Jul 2024Glioblastoma remains incurable despite optimal multimodal management. The interim analysis of open label, single arm INDYGO pilot trial showed actuarial 12-months...
PURPOSE
Glioblastoma remains incurable despite optimal multimodal management. The interim analysis of open label, single arm INDYGO pilot trial showed actuarial 12-months progression-free survival (PFS) of 60% (median 17.1 months), actuarial 12-months overall survival (OS) of 80% (median 23.1 months). We report updated, exploratory analyses of OS, PFS, and health-related quality of life (HRQOL) for patients receiving intraoperative photodynamic therapy (PDT) with 5-aminolevulinic acid hydrochloride (5-ALA HCl).
METHODS
Ten patients were included (May 2017 - April 2021) for standardized therapeutic approach including 5-ALA HCl fluorescence-guided surgery (FGS), followed by intraoperative PDT with a single 200 J/cm dose of light. Postoperatively, patients received adjuvant therapy (Stupp protocol) then followed every 3 months (clinical and cerebral MRI) and until disease progression and/or death. Procedure safety and toxicity occurring during the first four weeks after PDT were assessed. Data concerning relapse, HRQOL and survival were prospectively collected and analyzed.
RESULTS
At the cut-off date (i.e., November 1st 2023), median follow-up was 23 months (9,7-71,4). No unacceptable or unexpected toxicities and no treatment-related deaths occurred during the study. Kaplan-Meier estimated 23.4 months median OS, actuarial 12-month PFS rate 60%, actuarial 12-month, 24-month, and 5-year OS rates 80%, 50% and 40%, respectively. Four patients were still alive (1 patient free of recurrence).
CONCLUSION
At 5 years-follow-up, intraoperative PDT with surgical maximal excision as initial therapy and standard adjuvant treatment suggests an increase of time to recurrence and overall survival in a high proportion of patients. Quality of life was maintained without any severe side effects.
TRIAL REGISTRATION NCT NUMBER
NCT03048240. EudraCT number: 2016-002706-39.
Topics: Humans; Glioblastoma; Male; Brain Neoplasms; Female; Middle Aged; Photochemotherapy; Follow-Up Studies; Aged; Aminolevulinic Acid; Photosensitizing Agents; Adult; Quality of Life; Pilot Projects; Survival Rate
PubMed: 38753093
DOI: 10.1007/s11060-024-04693-4 -
Lasers in Medical Science May 2024Photodynamic therapy (PDT) is a targeted treatment method that utilizes a photosensitizer (PS) to induce cytotoxicity in malignant and non-malignant tumors. Optimization...
Photodynamic therapy (PDT) is a targeted treatment method that utilizes a photosensitizer (PS) to induce cytotoxicity in malignant and non-malignant tumors. Optimization of PDT requires investigation of the selectivity of PS for the target tissues, irradiating light source, irradiation wavelengths, fluence rate, fluence, illumination mode, and overall treatment plan. In this study, we developed the Multi-mode Automatized Well-plate PDT LED Laboratory Irradiation System (MAWPLIS), an innovative device that automates time-consuming well plate light dosage/PS dose measurement experiment. The careful control of LED current and temperature stabilization in the LED module allowed the system to achieve high optical output stability. The MAWPLIS was designed by integrating a 3-axis moving system and motion controller, a quick-switching LED controller unit equipped with interchangeable LED modules capable of employing multiple wavelengths, and a TEC system. The proposed system achieved high optical output stability (1 mW) within the range of 0-500 mW, high wavelength stability (5 nm) at 635 nm, and high temperature stability (0.2 °C) across all radiation modes. The system's validation involved in vitro analysis using 5-ALA across varying concentrations, incubation periods, light exposures, and wavelengths in HT-29 colon cancer and WI-38 human lung fibroblast cell lines. Specifically, a combination of 405 nm and 635 nm wavelengths was selected to demonstrate enhanced strategies for colon cancer cell eradication and system validation. The MAWPLIS system represents a significant advancement in photodynamic therapy (PDT) research, offering automation and standardization of time-intensive experiments, high stability and precision, and improved PDT efficacy through dual-wavelength integration.
Topics: Photochemotherapy; Humans; Photosensitizing Agents; HT29 Cells; Aminolevulinic Acid
PubMed: 38750381
DOI: 10.1007/s10103-024-04083-2 -
Chinese Medical Journal Jun 2024
Topics: Humans; Keratosis, Actinic; Aminolevulinic Acid; Photochemotherapy; Prospective Studies; Male; Female; Middle Aged; Aged; Photosensitizing Agents; East Asian People
PubMed: 38749769
DOI: 10.1097/CM9.0000000000003014 -
Frontiers in Oncology 2024Glioblastoma is the most common type of primary brain malignancy and has a poor prognosis. The standard treatment strategy is based on maximal safe surgical resection...
PURPOSE
Glioblastoma is the most common type of primary brain malignancy and has a poor prognosis. The standard treatment strategy is based on maximal safe surgical resection followed by radiotherapy and chemotherapy. Surgical resection can be optimized by using 5-delta-aminolevulinic acid (5-ALA)-induced fluorescence, which is the current mainstay. Although 5-ALA-induced fluorescence has gained general acceptance, it is also limited by inter-observer variability and non-standardized fluorescence parameters. We present a new software for processing images analysis to better recognize the tumor infiltration margins using an intraoperative immediate safety map of 5-ALA-induced fluorescence. We tested this in a brain model using a commercial surgical exoscope.
METHODS
A dedicated software GLIOVIS (ACQuF-II, Advanced Colorimetry-based Quantification of Fluorescence) was designed for processing analysis of images taken on the Intraoperative Orbital Camera Olympus Orbeye (IOC) to determine the relative quantification of Protoporphyrin IX (5-ALA metabolite) fluorescence. The software allows to superpose the new fluorescence intensity map and the safety margins over the original images. The software was tested on gel-based brain models.
RESULTS
Two surrogate models were developed: PpIX agarose gel-integrated in gelatin-based brain model at different scales (1:25 and 1:1). The images taken with the IOC were then processed using GLIOVIS. The intensity map and safety margins could be obtained for all available models.
CONCLUSIONS
GLIOVIS for 5-ALA-guided surgery image processing was validated on various gelatin-based brain models. Different levels of fluorescence could be qualitatively digitalized using this technique. These results need to be further confirmed and corroborated and validated clinically in order to define a new standard of care for glioblastoma resection.
PubMed: 38741783
DOI: 10.3389/fonc.2024.1361022 -
Acta Neurochirurgica May 2024Glioblastoma is a malignant and aggressive brain tumour that, although there have been improvements in the first line treatment, there is still no consensus regarding...
PURPOSE
Glioblastoma is a malignant and aggressive brain tumour that, although there have been improvements in the first line treatment, there is still no consensus regarding the best standard of care (SOC) upon its inevitable recurrence. There are novel adjuvant therapies that aim to improve local disease control. Nowadays, the association of intraoperative photodynamic therapy (PDT) immediately after a 5-aminolevulinic acid (5-ALA) fluorescence-guided resection (FGR) in malignant gliomas surgery has emerged as a potential and feasible strategy to increase the extent of safe resection and destroy residual tumour in the surgical cavity borders, respectively.
OBJECTIVES
To assess the survival rates and safety of the association of intraoperative PDT with 5-ALA FGR, in comparison with a 5-ALA FGR alone, in patients with recurrent glioblastoma.
METHODS
This article describes a matched-pair cohort study with two groups of patients submitted to 5-ALA FGR for recurrent glioblastoma. Group 1 was a prospective series of 11 consecutive cases submitted to 5-ALA FGR plus intraoperative PDT; group 2 was a historical series of 11 consecutive cases submitted to 5-ALA FGR alone. Age, sex, Karnofsky performance scale (KPS), 5-ALA post-resection status, T1-contrast-enhanced extent of resection (EOR), previous and post pathology, IDH (Isocitrate dehydrogenase), Ki67, previous and post treatment, brain magnetic resonance imaging (MRI) controls and surgical complications were documented.
RESULTS
The Mantel-Cox test showed a significant difference between the survival rates (p = 0.008) of both groups. 4 postoperative complications occurred (36.6%) in each group. As of the last follow-up (January 2024), 7/11 patients in group 1, and 0/11 patients in group 2 were still alive. 6- and 12-months post-treatment, a survival proportion of 71,59% and 57,27% is expected in group 1, versus 45,45% and 9,09% in group 2, respectively. 6 months post-treatment, a progression free survival (PFS) of 61,36% and 18,18% is expected in group 1 and group 2, respectively.
CONCLUSION
The association of PDT immediately after 5-ALA FGR for recurrent malignant glioma seems to be associated with better survival without additional or severe morbidity. Despite the need for larger, randomized series, the proposed treatment is a feasible and safe addition to the reoperation.
Topics: Humans; Glioblastoma; Aminolevulinic Acid; Male; Brain Neoplasms; Female; Middle Aged; Photochemotherapy; Neoplasm Recurrence, Local; Aged; Cohort Studies; Surgery, Computer-Assisted; Photosensitizing Agents; Adult; Prospective Studies; Neurosurgical Procedures
PubMed: 38739282
DOI: 10.1007/s00701-024-06108-9 -
Photodiagnosis and Photodynamic Therapy Jun 2024Nodulocystic acne is a severe form of acne, which is commonly treated with oral isotretinoin, hormones, or antibiotics. However, drug therapy often has some side effects...
BACKGROUND
Nodulocystic acne is a severe form of acne, which is commonly treated with oral isotretinoin, hormones, or antibiotics. However, drug therapy often has some side effects and poor compliance. Fire needle combined with 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is a simple, effective, short-term treatment with few adverse reactions, which is expected to be an effective physiotherapy for nodulocystic acne. Moreover, the combination with isotretinoin can reduce the dosage of the drug, thereby reducing the side effects of isotretinoin.
OBJECTIVES
To evaluate the safety and efficacy of fire-needle pretreated ALA-PDT combined with low-dose isotretinoin in the treatment of severe refractory nodulocystic acne.
METHODS
This study reported 10 patients with refractory nodulocystic acne who received combined treatment. During the treatment period, all patients received a low dose of oral isotretinoin capsules daily. The acne lesions were pretreated with fire needle before ALA-PDT treatment. The number of acne lesions, including papules, pustules, and nodular cysts, was documented at weeks 0, 2, 4, 8, and 12 to assess the therapeutic efficacy. Concurrently, adverse reactions such as pain, pruritus, and pigmentation changes were recorded and evaluated throughout the treatment course.
RESULTS
After combined treatment, all patients achieved good therapeutic effects, with an overall effective rate of 90 % at week 12. After treatment, skin lesions such as nodules, and cysts subsided significantly. The combination therapy has no serious adverse effects and has a favorable safety profile.
CONCLUSION
Fire needle pretreatment ALA-PDT combined with low-dose isotretinoin is effective and safe in the treatment of severe refractory nodular cystic acne, which is worthy of clinical promotion and research.
Topics: Humans; Isotretinoin; Aminolevulinic Acid; Photochemotherapy; Acne Vulgaris; Photosensitizing Agents; Male; Female; Young Adult; Adult; Adolescent; Combined Modality Therapy; Dermatologic Agents; Dose-Response Relationship, Drug
PubMed: 38735352
DOI: 10.1016/j.pdpdt.2024.104215 -
Photobiomodulation, Photomedicine, and... Jun 2024Chronic hyperplastic candidiasis (CHC) is a chronic oral mucosal infection caused by Candida, which has potential for malignant transformation. Diagnosing CHC can be...
Minimally Invasive Semiconductor Laser Surgery Combined with 5-ALA Photodynamic Therapy for a Chronic Hyperplastic Candidiasis Patient Who Is Ineffective to Antifungal Therapy.
Chronic hyperplastic candidiasis (CHC) is a chronic oral mucosal infection caused by Candida, which has potential for malignant transformation. Diagnosing CHC can be challenging due to its various manifestations. In addition, fungal treatments often prove to be ineffective, highlighting the urgent need for a new safe and efficient treatment approach. Given the potential of CHC to transform into malignancy, it is crucial to emphasize dynamic monitoring and follow-up after treatment. We attempted to investigate the effect of semiconductor laser pretreatment combined with 5-amino-levulinic acid (5-ALA) photodynamic therapy (PDT) for CHC. We presented the successful treatment of CHC with mild dysplasia in a 30-year-old man using semiconductor laser and 5-ALA PDT after antifungal therapy proved ineffective. Toluidine blue staining, autofluorescence imaging, and DNA image cytometry were combined to dynamically monitor the progress of the disease. We have obtained positive outcomes with the use of laser combined with PDT treatment. The patients experienced only mild adverse reactions after the treatment, and there was no indication of recurrence or malignant transformation during the subsequent follow-up period, as observed through various auxiliary examinations. This case report suggests that semiconductor laser surgery combined with PDT could be a promising treatment option for patients with CHC who do not respond to antifungal therapy. In addition, the use of combined noninvasive examinations might provide a more accurate assessment of malignant transformation in patients with CHC.
Topics: Humans; Male; Aminolevulinic Acid; Adult; Photochemotherapy; Lasers, Semiconductor; Photosensitizing Agents; Antifungal Agents; Candidiasis, Oral; Hyperplasia; Minimally Invasive Surgical Procedures; Chronic Disease; Combined Modality Therapy
PubMed: 38717839
DOI: 10.1089/photob.2023.0174 -
Frontiers in Neurology 2024Acute hepatic porphyrias (AHP) represent a rare group of inherited metabolic disorders of heme biosynthesis pathway. This study aims to determine the diagnostic and...
BACKGROUND
Acute hepatic porphyrias (AHP) represent a rare group of inherited metabolic disorders of heme biosynthesis pathway. This study aims to determine the diagnostic and prognostic value of serum neurofilament light chain (NfL) as potential biomarker for AHP.
METHODS
We conducted a cross-sectional observational study to evaluate NfL levels in patients with AHP. They were divided in different groups: normal health individuals; patients with definitive diagnosis of AHP during acute episodes; patients with AHP and infrequent attacks; patients with AHP and recurrent attacks; asymptomatic individuals with positive genetic testing and urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels elevated 4 or more times ("high excretors"); asymptomatic individuals with exclusive positive genetic test; control group with Hereditary Amyloidosis related to Transthyretin with Polyneuropathy (ATTRv-PN).
RESULTS
During acute attacks, serum NfL levels were 68 times higher compared to normal controls and disclosed a strong correlation with ALA and PBG levels; also exhibited elevated levels in patients with chronic symptoms regardless of the number of disease attacks compared to healthy controls, and at similar levels to patients with ATTRv-PN, which is a model of progressive neuropathy.
CONCLUSION
This study represents the first to establish NfL as a biomarker for AHP, disclosing NfL as a sensitive biomarker for axonal damage and chronic symptom occurrence. This study not only underscores that neurological damage associated with the disease in any patient, irrespective of the number of attacks, but also reinforces the progressive and profoundly debilitating nature of acute and chronic symptoms observed in individuals with AHP.
PubMed: 38715693
DOI: 10.3389/fneur.2024.1384678