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International Journal of Surgery... Jun 2024Surgical resection is essential for treating solid tumors, with success largely dependent on the complete excision of neoplastic cells. However, neurosurgical procedures...
Surgical resection is essential for treating solid tumors, with success largely dependent on the complete excision of neoplastic cells. However, neurosurgical procedures must delicately balance tumor removal with the preservation of surrounding tissue. Achieving clear margins is particularly challenging in cases like glioblastoma due to the limitations of traditional white light visualization. These limitations often result in incomplete resections, leading to frequent recurrences, or excessive resection that harms vital neural structures, causing iatrogenic nerve damage which can lead to sensory and functional deficits. Current statistics reveal a 90% recurrence rate for malignant gliomas. Similarly, an 8% incidence of iatrogenic nerve trauma contributes to an estimated 25 million cases of peripheral nerve injury globally each year. These figures underscore the urgent need for improved intraoperative techniques for lesion margin and nerve identification and visualization. Recent advances in neurosurgical imaging, such as fluorescence-guided surgery (FGS), have begun to address these challenges. Fluorescent agents used in FGS illuminate target tissues, although not all do so selectively. Despite the promising results of agents such as 5-aminolevulinic acid and indocyanine green, their applications are mainly limited by issues of sensitivity and specificity. Furthermore, these agents do not effectively address the need for precise nerve visualization. Nerve Peptide 41, a novel systemically administered fluorescent nerve-targeted probe, shows promise in filling this gap. This review assesses the major fluorescent imaging modalities in neurosurgery, highlighting each of their benefits, limitations, and potential.
PubMed: 38913424
DOI: 10.1097/JS9.0000000000001847 -
Oncology Letters Aug 2024Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. Photodynamic therapy (PDT) is a promising therapeutic method for managing cSCC...
Increased CD56 expression after photodynamic therapy indicates an increased natural killer cell count following early photodynamic therapy for cutaneous squamous cell carcinoma.
Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. Photodynamic therapy (PDT) is a promising therapeutic method for managing cSCC due to its proven ability to target specific areas over time and its low risk of side effects. PDT may cause tissue damage and vascular shutdown, and may regulate local immunological responses. The present study aimed to investigate and compare the early lymphocyte modifications before and after PDT for SCC. A total of 10 patients with SCC were identified by pathological investigation. Initially, all wounds were treated with 20% aminolevulinic acid (ALA)-PDT as the initial stage in the therapeutic procedure. The wounds were treated by exposing them to red LED light with a wavelength of 635 nm, an energy density of 100 J/cm and an intensity of 80 mW/cm. The tumor tissue was surgically removed 24 h later, and another round of PDT therapy was administered. Immunohistochemistry for CD3 and CD56 was conducted on the wound tissue post-surgery. If the wound showed granulation, necrosis or secretion, debridement was added to the therapy. All patients were monitored for 0.6-1.0 year post-treatment. ALA-PDT combination surgery fully controlled the tumor tissue in all 10 patients. The immunohistochemical analysis of the wound tissues showed that the expression of CD56 increased, while the expression of CD3 was not different after photodynamic therapy. These results also indirectly indicated that the overall count of NK cells in the 10 patients increased, nevertheless, there was no alteration in the T lymphocyte count. In conclusion, the ALA-PDT combination surgical therapy for cSCC demonstrates favorable results. An increase in CD56 expression may be a mechanism for the effective treatment of cSCC with PDT.
PubMed: 38910905
DOI: 10.3892/ol.2024.14505 -
Dermatologie (Heidelberg, Germany) Jun 2024Porphyrias are predominantly genetic metabolic disorders caused by dysregulation of specific enzymes in porphyrin-heme biosynthesis. The enzymatic dysfunction leads to... (Review)
Review
Porphyrias are predominantly genetic metabolic disorders caused by dysregulation of specific enzymes in porphyrin-heme biosynthesis. The enzymatic dysfunction leads to formation and excretion of intermediate metabolic products in the form of porphyrins and/or their precursors δ‑aminolevulinic acid and porphobilinogen, which have cyto- and tissue-toxic properties. Clinically, porphyrias are extremely diverse, with symptoms ranging from skin changes on light-exposed areas of the body to potentially life-threatening neurovisceral attacks. Biochemical tests in urine, blood and stool are used for diagnosis, which can be supplemented by molecular genetic analyses. Treatment of the various forms of porphyria is complex and often requires close interdisciplinary cooperation between different medical specialties.
PubMed: 38902527
DOI: 10.1007/s00105-024-05370-3 -
Photodiagnosis and Photodynamic Therapy Jun 2024Although photodynamic-diagnosed transurethral resection of bladder cancer (PDD-TURBT) and Bacillus Calmette-Guérin (BCG) intravesical instillation are the two...
BACKGROUND
Although photodynamic-diagnosed transurethral resection of bladder cancer (PDD-TURBT) and Bacillus Calmette-Guérin (BCG) intravesical instillation are the two representative therapies for non-muscle invasive bladder cancer (NMIBC), no studies directly compare their efficacy. We evaluated the outcome of PDD-TURBT alone compared with white light TURBT with intravesical BCG therapy and analyzed the efficacy of both therapies depending on the characteristics of the tumors.
METHODS
We retrospectively analyzed intermediate- and high-risk NMIBC patients treated with PDD-TURBT alone (the PDD group) or white light TURBT with BCG therapy (the white light group) using propensity score matched analysis.
RESULTS
In the propensity score matched cohort, the 1-, 2-, and 3-year recurrence-free survival rates for the PDD group were 77.6 %, 64.1 %, and 48.1 %, respectively, compared to 84.6 %, 75.1 %, and 75.1 % for the white light group (p = 0.44, 0.27, 0.17, respectively). The difference in recurrence rates between the two groups tended to become more pronounced over time, although there was no significant difference. In the univariate and multivariate analysis, recurrence, multiplicity, and tumor grade were the significant prognostic factors of recurrence in the PDD group (p = 0.010, 0.047, 0.048, respectively). Long-term RFS was similar in the PDD and white light groups when the population was limited to the primary and single tumors, suggesting that PDD-TURBT alone may be sufficient in this spectrum of patients.
CONCLUSIONS
PDD-TURBT alone is insufficient to control the long-term recurrence of bladder cancer but can be effective in selected cases such as primary and single tumors.
PubMed: 38901718
DOI: 10.1016/j.pdpdt.2024.104254 -
Photodiagnosis and Photodynamic Therapy Jun 2024Photodynamic therapy (PDT) has been utilized as a promising alternative cancer treatment due to its minimum invasiveness over the years. Exogenous 5-aminolevulinic acid...
BACKGROUND
Photodynamic therapy (PDT) has been utilized as a promising alternative cancer treatment due to its minimum invasiveness over the years. Exogenous 5-aminolevulinic acid (ALA) triggers protoporphyrin IX (PpIX) accumulation, which happens in cancer cells. However, certain types of cancer exhibit reduced effectiveness in the PpIX accumulation mechanism. This study aimed to determine the effect of ALA-PDT combination with hemin on gastric carcinoma TMK-1 cells.
METHODS
This study utilized TMK-1 gastric cancer cell line to evaluate PpIX, ROS, and Fe accumulation following the administration of ALA, hemin, and a combination of ALA and hemin PDT. We also evaluate the mRNA expressions related to iron homeostasis and treatment impacts on cell viability.
RESULTS
The co-addition of ALA and hemin PDT for 4 h of treatment resulted in a significant decrease in cell viability by up to 18 %. While ALA-PDT enhanced PpIX metabolism, the addition of hemin influenced both the production of reactive oxygen species (ROS) and cellular iron homeostasis by inducing Fe accumulation and affecting mRNA levels of IRP, Tfr1, Ferritin, NFS1, and SDHB.
CONCLUSION
These findings suggest that the addition of ALA and hemin enhances phototoxicity in TMK-1 cells. The combination of ALA and hemin with PDT induces cell death, evidenced by increased cytotoxicity properties such as PpIX and ROS, along with significant changes in TMK-1 gastric cancer iron homeostasis. Therefore, the combination of ALA and hemin could be one of the alternatives in photodynamic therapy for cancer in the future.
PubMed: 38901716
DOI: 10.1016/j.pdpdt.2024.104253 -
Biosensors & Bioelectronics Oct 2024Light therapy is an effective approach for the treatment of a variety of challenging dermatological conditions. In contrast to existing methods involving high doses and...
Light therapy is an effective approach for the treatment of a variety of challenging dermatological conditions. In contrast to existing methods involving high doses and large areas of illumination, alternative strategies based on wearable designs that utilize a low light dose over an extended period provide a precise and convenient treatment. In this study, we present a battery-free, skin-integrated optoelectronic patch that incorporates a coil-powered circuit, an array of microscale violet and red light emitting diodes (LEDs), and polymer microneedles (MNs) loaded with 5-aminolevulinic acid (5-ALA). These polymer MNs, based on the biodegradable composite materials of polyvinyl alcohol (PVA) and hyaluronic acid (HA), serve as light waveguides for optical access and a medium for drug release into deeper skin layers. Unlike conventional clinical photomedical appliances with a rigid and fixed light source, this flexible design allows for a conformable light source that can be applied directly to the skin. In animal models with bacterial-infected wounds, the experimental group with the combination treatment of metronomic photodynamic and light therapies reduced 2.48 log CFU mL in bactericidal level compared to the control group, indicating an effective anti-infective response. Furthermore, post-treatment analysis revealed the activation of proregenerative genes in monocyte and macrophage cell populations, suggesting enhanced tissue regeneration, neovascularization, and dermal recovery. Overall, this optoelectronic patch design broadens the scope for targeting deep skin lesions, and provides an alternative with the functionality of standard clinical light therapy methods.
Topics: Animals; Photochemotherapy; Mice; Humans; Polyvinyl Alcohol; Aminolevulinic Acid; Biosensing Techniques; Hyaluronic Acid; Wound Infection; Photosensitizing Agents; Skin; Equipment Design
PubMed: 38901392
DOI: 10.1016/j.bios.2024.116467 -
Blood Jun 2024X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP) are uncommon diseases caused by loss-of-function and gain-of-function mutations, respectively, in...
X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP) are uncommon diseases caused by loss-of-function and gain-of-function mutations, respectively, in the erythroid form of 5-aminolevulinic acid synthetase, ALAS2, which encodes the first enzyme in heme biosynthesis. A related sideroblastic anemia is due to mutations in SLC25A38, which supplies mitochondrial glycine for ALAS2 (SLC25A38-CSA). The lack of viable animal models has limited studies on the pathophysiology and development of therapies for these conditions. Here, using CRISPR-CAS9 gene editing technology, we have generated knock-in mouse models that recapitulate the main features of XLSA and XLPP, and, using conventional conditional gene targeting in embryonic stem cells, we also developed a faithful model of the SLC25A38-CSA. In addition to examining the phenotypes and natural history of each disease, we determine the effect of restriction or supplementation of dietary pyridoxine (vitamin B6), the essential cofactor of ALAS2, on the anemia and porphyria. In addition to the well-documented response of XLSA mutations to pyridoxine supplementation, we also demonstrate the relative insensitivity of the XLPP porphyria, severe sensitivity of the XLSA models, and an extreme hypersensitivity of the SLC25A38-CSA model to pyridoxine deficiency, a phenotype that is not shared with another mouse hereditary anemia model, Hbbth3/+ -thalassemia intermedia. Thus, in addition to generating animal models useful for examining the pathophysiology and treatment of these diseases, we have uncovered an unsuspected conditional synthetic lethality between the heme synthesis-related CSAs and pyridoxine deficiency. These findings have the potential to inform novel therapeutic paradigms for the treatment of these diseases.
PubMed: 38900972
DOI: 10.1182/blood.2023023078 -
The Journal of Dermatological Treatment Dec 2024To evaluate the efficacy of Mohs micrographic surgery (MMS) combined with photodynamic therapy (PDT) in treating non-invasive extramammary Paget's disease (EMPD).
PURPOSE
To evaluate the efficacy of Mohs micrographic surgery (MMS) combined with photodynamic therapy (PDT) in treating non-invasive extramammary Paget's disease (EMPD).
MATERIALS AND METHODS
A 77-year-old male patient with non-invasive EMPD was treated with MMS followed by PDT. Preoperative fluorescence localization using 5-aminolevulinic acid (ALA) was performed to determine the surgical scope. MMS was conducted under lumbar anesthesia with intraoperative frozen-section pathology. Postoperative PDT was administered weekly for three sessions.
RESULTS
The patient achieved negative surgical margins after two rounds of intraoperative pathology. Postoperative follow-up over two years showed no recurrence, and the patient did not experience significant adverse reactions.
CONCLUSION
The combination of MMS and PDT was effective in treating non-invasive EMPD, demonstrating favorable clinical outcomes and no recurrence over the two-year follow-up period.
Topics: Humans; Male; Aged; Mohs Surgery; Paget Disease, Extramammary; Photochemotherapy; Aminolevulinic Acid; Skin Neoplasms; Photosensitizing Agents; Treatment Outcome; Combined Modality Therapy; Margins of Excision
PubMed: 38897607
DOI: 10.1080/09546634.2024.2368066 -
Biochemistry Jun 2024The conserved enzyme aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in certain bacteria and eukaryotes by catalyzing the condensation of glycine and...
The conserved enzyme aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in certain bacteria and eukaryotes by catalyzing the condensation of glycine and succinyl-CoA to yield aminolevulinic acid. In humans, the ALAS isoform responsible for heme production during red blood cell development is the erythroid-specific ALAS2 isoform. Owing to its essential role in erythropoiesis, changes in human ALAS2 (hALAS2) function can lead to two different blood disorders. X-linked sideroblastic anemia results from loss of ALAS2 function, while X-linked protoporphyria results from gain of ALAS2 function. Interestingly, mutations in the ALAS2 C-terminal extension can be implicated in both diseases. Here, we investigate the molecular basis for enzyme dysfunction mediated by two previously reported C-terminal loss-of-function variants, hALAS2 V562A and M567I. We show that the mutations do not result in gross structural perturbations, but the enzyme stability for V562A is decreased. Additionally, we show that enzyme stability moderately increases with the addition of the pyridoxal 5'-phosphate (PLP) cofactor for both variants. The variants display differential binding to PLP and the individual substrates compared to wild-type hALAS2. Although hALAS2 V562A is a more active enzyme , it is less efficient concerning succinyl-CoA binding. In contrast, the M567I mutation significantly alters the cooperativity of substrate binding. In combination with previously reported cell-based studies, our work reveals the molecular basis by which hALAS2 C-terminal mutations negatively affect ALA production necessary for proper heme biosynthesis.
PubMed: 38888931
DOI: 10.1021/acs.biochem.4c00066 -
Biotechnology For Biofuels and... Jun 20245-Aminolevulinic acid (ALA) recently received much attention due to its potential application in many fields such as medicine, nutrition and agriculture. Metabolic...
Metabolic engineering of Escherichia coli for the production of 5-aminolevulinic acid based on combined metabolic pathway modification and reporter-guided mutant selection (RGMS).
BACKGROUND
5-Aminolevulinic acid (ALA) recently received much attention due to its potential application in many fields such as medicine, nutrition and agriculture. Metabolic engineering is an efficient strategy to improve microbial production of 5-ALA.
RESULTS
In this study, an ALA production strain of Escherichia coli was constructed by rational metabolic engineering and stepwise improvement. A metabolic strategy to produce ALA directly from glucose in this recombinant E. coli via both C4 and C5 pathways was applied herein. The expression of a modified hemA gene and rational metabolic engineering by gene knockouts significantly improved ALA production from 765.9 to 2056.1 mg/L. Next, we tried to improve ALA production by RGMS-directed evolution of eamA gene. After RGMS, the ALA yield of strain A2-ASK reached 2471.3 mg/L in flask. Then, we aimed to improve the oxidation resistance of cells by overexpressing sodB and katE genes and ALA yield reached 2703.8 mg/L. A final attempt is to replace original promoter of hemB gene in genome with a weaker one to decrease its expression. After 24 h cultivation, a high ALA yield of 19.02 g/L was achieved by 108-ASK in a 5 L fermenter.
CONCLUSIONS
These results suggested that an industrially competitive strain can be efficiently developed by metabolic engineering based on combined rational modification and optimization of gene expression.
PubMed: 38886801
DOI: 10.1186/s13068-024-02530-4