Development of a Stable Peptide-Major Histocompatibility Complex (MHC) via Sortase and Click Chemistry.

T cells play a crucial role in antitumor immune responses and the clearance of infected cells. They identify their targets through the binding of T-cell receptors (TCRs) to peptide-major histocompatibility complex (pMHC) molecules present in cancer cells, infected cells, and antigen-presenting cells. This interaction is often weak, requiring multimeric pMHC molecules to enhance the avidity for identifying antigen-specific T cells. Current exchangeable pMHC-I tetramerization methods may overlook TCRs recognizing less stable yet immunogenic peptides. In vivo applications targeting antigen-specific T cells demand the genetic synthesis of a pMHC fusion for each unique peptide antigen, which poses a significant challenge. To address these challenges, we developed a sortase and click chemistry-mediated approach for generating stable pMHC molecules. Leveraging sortase technology, we introduced an azide click-handle near the N-terminus of ß2m, proximal to the MHC-peptide-binding groove. Simultaneously, the peptide was engineered with a multi glycine linker and a C-terminal alkyne click-handle. Azide-alkyne click reactions efficiently immobilized the peptide onto the MHC molecule, providing a versatile and efficient method for pMHC generation. The resulting peptide-clicked-MHC specifically binds to its cognate TCR and remains stable for over 3 months at 4 °C in the absence of any additional free peptide. The stability of the pMHC and its affinity to cognate TCRs are influenced by the linker's nature and length. Multi glycine linkers outperform poly(ethylene glycol) (PEG) linkers in this regard. This technology expands the toolkit for identifying and targeting antigen-specific T cells, enhancing our understanding of cancer-specific immune responses, and has the potential to streamline the development of personalized immunotherapies.

Factors associated with the healing time of pemphigus vulgaris oral lesions: A prospective study.

OBJECTIVES: This study determines the healing time of lesions on different locations and the contributing factors to the healing time in patients with pemphigus. METHODS: In this prospective study, newly diagnosed patients with mucosal lesions were included. A dermatologist evaluated the lesions, disease status, side effects and assigned the PDAI. Follow-up visits were conducted monthly until the patient reached complete remission and every three months thereafter. A Tzanck smear was performed on lesions clinically suspected to be herpetic in origin. RESULTS: Sixty patients enrolled in the study with a mean age of 45.9 ± 11.7 years. The buccal lesions took the longest to resolve (73[33.5-105.5] days). However, the posterior pharynx lesions showed the shortest healing time (20[13.0-25.5] days). The likelihood of improvement in buccal and soft palate lesions decreased by 5% and 3% with each additional year of age, respectively. Also, the resolution duration of soft palate lesions was significantly shorter in female patients than males (median of 24.0 days vs. 38.5 days). In contrast, lower gingival lesions resolve significantly faster in male patients by a median of 9 days. Herpes simplex virus infection increases the healing time of lesions by 26 days (median of 55 days vs. 29 days, hazard ratio 2.62, 95% CI: 1.04-5.92). CONCLUSIONS: Buccal and lower gingival lesions are more recalcitrant to treatment, while posterior pharynx lesions heal most rapidly. Furthermore, older age was also associated with a lower rate of lesion improvement.

Applicability of glucocorticoid toxicity index in pemphigus: Comparison between two groups of rituximab-treated and rituximab-naïve patients.

Rituximab (RTX) combined with short-term glucocorticoids (GC) is an effective therapeutic option for pemphigus. The newly developed Glucocorticoid Toxicity Index (GTI) tool provides the possibility to measure GC toxicities over time. To compare 1-year GTI between two groups of RTX-treated and RTX-naïve patients with pemphigus. The responsiveness of the GTI was also investigated. A prospective cohort of 129 adults with newly diagnosed pemphigus was conducted. GC-related toxicities were assessed at 3-month intervals according to Composite and Specific lists of the GTI. Of the patients, 76.7% (n = 99) received RTX. Throughout the time intervals, RTX-treated patients had lower GTI compared to RTX-naïve ones (p = 0.036). The mean GTI at 1-year was 34.3 in the RTX-treated group and 50.8 in the RTX-naïve group (p = 0.04). The most commonly observed GC-related toxicity was neuropsychiatric manifestations for 34% (224 events). The relapse rate of RTX-treated patients (1%) was significantly lower than RTX-naïve patients (10%) (p = 0.037). The GTI showed no correlation with cumulative GC consumption in both groups (p > 0.05, both). Patients treated with GC alone had remarkably higher GTI than patients treated with GC plus RTX. The GTI is an applicable tool to quantitatively capture GC toxicities at the patient level in pemphigus.

Risk factors of dislocation after total hip arthroplasty in patients with developmental dysplasia of the hip.

PURPOSE: Dislocation following total hip arthroplasty (THA) is a well-known complication. However, there is little data on its rate and predictors in patients with developmental dysplasia of the hip (DDH). The current study is aimed to determine the rate and specific risk factors of dislocation following THA in DDH patients. METHODS: All the medico-surgical records of primary THAs from January 2014 to January 2019 were retrospectively reviewed. They were categorized into three main groups: primary OA, DDH, and others. Pre-operative and post-operative radiographs, past medical and surgical history, and surgical notes were reviewed in DDH cases. RESULTS: In a total of 171 patients with DDH, 21 suffered from dislocation after THA (12%) which was significantly more frequent than those with primary OA. In univariate analysis, higher grade of dysplasia, smaller head size, intra-operative fracture, Wagner Cone stem, failure of offset restoration, and implanting the cup outside the Lewinnek's safe zone were identified as predictors of dislocation. In multiple regression analysis, however, only higher Crowe grade, intra-operative fracture, and post-operative acetabular offset less than 16 mm were independent predictors of dislocation. CONCLUSION: Dysplastic hips can be more prone to post-THA dislocation than those with primary OA. Higher grades of dysplasia, failure of offset restoration, and intra-operative fracture can increase the rate of dislocation in this group of patients.

Comparing efficacy and safety of potassium hydroxide 5% solution with 5-fluorouracil cream in patients with actinic keratoses: a randomized controlled trial.

BACKGROUND: Actinic keratosis (AK) is a pre-cancerous skin lesion, associated with development of squamous cell carcinoma. Current treatment options are limited. OBJECTIVES: To compare the efficacy and safety of topical 5-fluorouracil cream (5-FU) and potassium hydroxide 5% (KOH) in the treatment of AK. METHODS: Eighteen patients with AK applied KOH solution or 5-FU on each side of their scalp/face, randomly. The efficacy and safety of these treatments were compared. RESULTS: Thirteen (118 lesions) and ten (83 lesions) patients were successfully followed for one and three months, respectively. After one month, KOH showed a better clinical response (81% vs. 58%; p-value = 0.007) and dermoscopic response (KOH, 65% vs. 5-FU, 46%; p-value = 0.04); while no differences were noted after three months (clinical response, 83% vs.70%, p-value = 0.1; dermoscopic response, 76% vs. 59%, p-value = 0.1). No significant differences in the recurrence rate of the lesion between the two groups were noted at the end of the third month (p-value = 0.5). Regarding the safety of the treatments, the risk of developing erythema, scaling, sand swelling was higher in 5-FU group (p-value < 0.0001, for all), while more patients in KOH group had erosion and ulcer (p-value < 0.001 for both). KOH was up to 96% less expensive than 5-FU. LIMITATIONS: Low number of patients and short-term follow-up limited the analysis. CONCLUSION: KOH solution offers a faster and less expensive resolution of AK lesions than does 5-FU. CLINICAL TRIAL CODE (IRCT.IR): IRCT20180909040978N1.

Oral isotretinoin combined with topical clobetasol 0.05% and tacrolimus 0.1% for the treatment of frontal fibrosing alopecia: a randomized controlled trial.

BACKGROUND: Frontal fibrosing alopecia (FFA) is a scarring alopecia with no promising treatment. OBJECTIVE: To evaluate the additive efficacy of oral isotretinoin to topical treatments. METHODS: Between November 2017 and August 2018, FFA patients were randomly assigned to receive either isotretinoin (20 mg/d) plus topical treatments (clobetasol 0.05% and tacrolimus 0.1%) or monotherapy with topical treatments. Treatments' efficacy was evaluated through Frontal Fibrosing Alopecia Severity Index (FFASI) after two and 6 months. RESULTS: From 38 participants, 28 patients completed the study. Facial papules improved after 6 months (p value < .001) in the isotretinoin group. Moreover, frontotemporal hairline (p values for frontal < .001; R lateral: 0.03; L Lateral: 0.02), total scalp margins, total additional features' scores, and total combined (p value < .001 for all) improved more in the isotretinoin group than in the control group. Frontal band improved in the treatment group (p value: .02). Frontal margin (p value: .01), R lateral (p value: .01), total scalp (p value < .01), and combined total scores (p value: .01) worsened in the control group. Isotretinoin-related side-effects included lip dryness, telogen effluvium, and malaise. LIMITATIONS: Small sample size and lost to follow-up. CONCLUSION: Isotretinoin combined with topical treatments is more effective than monotherapy with clobetasol and tacrolimus for FFA. CLINICAL TRIAL CODE: (IRCT.ir) IRCT2017091736173N1.

Pharmacotherapeutic Potential of Garlic in Age-Related Neurological Disorders.

Age-related Neurological Disorders (ANDs) involve Neurodegenerative Diseases (NDDs), such as Alzheimer's Disease (AD), the most frequent kind of dementia in elderly people, and Parkinson's Disease (PD), and also other disorders like epilepsy and migraine. Although ANDs are multifactorial, aging is a principal risk factor for them. The common and most main pathologic features among ANDs are inflammation, oxidative stress, and misfolded proteins accumulation. Since failing brains caused by ANDs impose a notable burden on public health and their incidence is increasing, a lot of works have been conducted to overcome them. Garlic, Allium sativum, has been used for different medical purposes globally and more than thousands of publications have reported its health benefits. Garlic and aged garlic extract are considered potent anti-inflammatory and antioxidants agents and can have remarkable neuroprotective effects. This review is aimed to summarize knowledge on the pharmacotherapeutic potential of garlic and its components in ANDs.

Current status and prospects for the diagnosis of pemphigus vulgaris.

Introduction: Pemphigus vulgaris (PV) is an intraepidermal autoimmune bullous disease (AIBD) characterized by autoantibodies against desmosomal adhesion proteins, most commonly desmoglein (Dsg)3, leading to the suprabasal cleft formation and acantholysis.Areas covered: Direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) studies display the intercellular deposition of IgG/C3 throughout the epidermis and presence of circulating autoantibodies respectively, as a net-like pattern. However, the target antigen remains unknown using immunofluorescence techniques. Thanks to the development of Dsg ELISA, using recombinant technology, circulating antibodies against Dsg1 and 3 could be detected sensitively. It is possible to differentiate PV from pemphigus foliaceus (PF) using this assay. BIOCHIP mosaic and multivariant ELISA are two novel serologic methods with the added value of the ability to screen several AIBDs simultaneously.Non-Dsg1/3 antigens are also involved in the pathogenesis of PV and investigated more deeply thanks to the protein microarrays technique. Additionally, patients with high values of anti-Dsg1/3 may be lesion-free, suggesting the presence of nonpathogenic autoantibodies.Expert opinion: Newer diagnostic methods to replace traditional techniques should possess high sensitivity and specificity and be widely available, noninvasive, and relatively cheap. The newly developed methods need to be further evaluated before being recommended for routine use.

Complications of dual growing rod with all-pedicle screw instrumentation in the treatment of early-onset scoliosis.

BACKGROUND: Treatment of early-onset scoliosis (EOS) is still a challenge to patients, families, and surgeons. Previous studies have indicated that EOS patients are at high risk for complications following growth-friendly surgery. This study was performed to evaluate the results and complications of all-pedicle screw dual growing rod instrumentation in the treatment of EOS. METHODS: In an IRB-approved retrospective study, we searched the electronic medical records of our institution for all patients who underwent posterior spinal instrumentation for scoliosis between March 2014 and March 2017. Patients under the age of 10 at the time of surgery who were treated with a growth-friendly technique were then selected. Patients with incomplete records and less than 2 years of follow-up were excluded. Charts, operative notes, clinic visits, and radiographs were extracted. Radiographs were reviewed, and the main curve Cobb angle, thoracic kyphosis, pelvic tilt, pelvic incidence, sacral slope, and proximal junctional angles were measured. We specifically looked for any intra-operative or post-operative complications. Statistical analysis was performed to determine the risk factors of complications. RESULTS: A total of 42 patients with a mean age of 4.8 ± 2.1 years (range, 1.5-8 years) were included in the final analysis. Patients were followed for a median of 34 months (range, 24-55). The major curve was corrected from a mean of 42.9° ± 10.7° to 28.8° ± 9.6° at the latest follow-up. Proximal junctional angles and thoracic kyphosis increased significantly during the follow-up period (both P values < 0.001). A total of 7 complications (17%) were observed. Four patients (10%) developed superficial surgical site infections, all of which resolved with antibiotics and one round of surgical debridement. Three cases (7%) of proximal junctional kyphosis (PJK) were encountered during the study period, none of which required revision surgery. Pre-operative thoracic kyphosis was the only significant risk factor for the development of PJK. CONCLUSIONS: Our findings suggest that in settings without access to magnetically controlled growing rods, dual growing rods with all-pedicle screw instrumentation is still a viable treatment strategy with comparable results and complications. The most common complications are infection and PJK, with the latter being associated with a larger pre-operative thoracic kyphosis.

Evaluating the efficacy and safety of topical sirolimus 0.2% cream as adjuvant therapy with pulsed dye laser for the treatment of port wine stain: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Port Wine Stain (PWS) is a congenital capillary malformation. Although multiple treatments are required, the gold standard treatment for PWS is Pulsed Dye Laser (PDL). Given its anti-angiogenic effects, sirolimus can be considered as an adjuvant to PDL in PWS. AIM: To evaluate the efficacy and safety of topical sirolimus (Rapamycin) 0.2% cream as adjuvant therapy for PDL for PWS. METHODS: In this randomized double-blind placebo-controlled trial, 15 patients with PWS were enrolled. Each lesion was divided into upper and lower parts, and each part was assigned randomly to receive PDL (4 sessions, 2 months apart) plus sirolimus vs PDL and placebo. The response was evaluated using colorimetry, investigator global assessment (IGA), and patient global assessment (PGA) every two months for eight continuous months. RESULTS: According to the colorimetric analysis, medial and lateral sides of the treatment and placebo parts did not differ significantly (both P-value > .05). However, according to PGA and IGA, there was a significant difference in favor of sirolimus (P-values = .041 and .039, respectively). Itching and dryness (86.7%), contact dermatitis (20%) were the most common adverse effects in the sirolimus group, while none of them were observed in placebo. CONCLUSION: Although the improvement was significant subjectively, topical sirolimus 0.2% as an adjuvant to PDL does not appear to improve PWS erythema using calorimetric assessment.

Rituximab in practice: Clinical evaluation of patients with pemphigus after rituximab administration.

Pemphigus Vulgaris (PV) is a rare autoimmune blistering disease, which mainly causes mucosal and/or cutaneous lesions. In June 2018, FDA approved Rituximab (RTX)-a B-cell depleting agent-for the management of patients with moderate-to-severe pemphigus. Although the majority of patients respond well to this drug, some do not reach complete remission with a single cycle of RTX. In this review, following an overview of RTX and its clinical outcomes, we have focused on the possible outcomes after RTX therapy in patients with PV. The response is defined into four main categories; complete responders, partial responders, nonresponders, and paradoxical reactions, based on three possibilities of reaching the consolidation phase after 3 months, reaching remission until 6 months, and the ability of corticosteroid tapering in 6 months after RTX administration. Concerning the safety of RTX, three categories of infusion reactions, short and long-term side effects are discussed. Additionally, we have suggested approaches for the evaluation of clinical and serological responses at different critical time-points, including 1, 2, 3, and 6 months after RTX administration. Finally, available markers to predict the response to RTX and research gaps in the field of RTX therapy have been summarized.

Remdesivir: A beacon of hope from Ebola virus disease to COVID-19.

Since the emergence of coronavirus disease 2019 (Covid-19), many studies have been performed to characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and find the optimum way to combat this virus. After suggestions and assessments of several therapeutic options, remdesivir (GS-5734), a direct-acting antiviral drug previously tested against Ebola virus disease, was found to be moderately effective and probably safe for inhibiting SARS-CoV-2 replication. Finally, on 1 May 2020, remdesivir (GS-5734) was granted emergency use authorization as an investigational drug for the treatment of Covid-19 by the Food and Drug Administration. However, without a doubt, there are challenging days ahead. Here, we provide a review of the latest findings (based on preprints, post-prints, and news releases in scientific websites) related to remdesivir efficacy and safety for the treatment of Covid-19, along with covering remdesivir history from bench-to-bedside, as well as an overview of its mechanism of action. In addition, active clinical trials, as well as challenging issues related to the future of remdesivir in Covid-19, are covered. Up to the date of writing this review (19 May 2020), there is one finished randomized clinical trial and two completed non-randomized studies, in addition to some ongoing studies, including three observational studies, two expanded access studies, and seven active clinical trials registered on the clinicaltrials.gov and isrctn.com websites. Based on these studies, it seems that remdesivir could be an effective and probably safe treatment option for Covid-19. However, more randomized controlled studies are required.

Autoimmune Bullous Disease Quality of Life (ABQoL) questionnaire: Validation of the translated Persian version in pemphigus vulgaris.

BACKGROUND: Autoimmune bullous diseases are a group of rare, chronic, blistering diseases, with pemphigus vulgaris (PV) being the most common type in Iran. Skin and mucosal involvement and therapy may have a dismal impact on the quality of life of affected patients. OBJECTIVE: We aimed to assess the validity and reliability of the Farsi (Persian) version of the Autoimmune Bullous Quality of Life (ABQoL) index in Iranian patients with PV. METHODS: Forward and backward translation procedures were used to prepare the Persian version of the ABQoL questionnaire. A total of 180 patients were asked to complete the questionnaires, and 24 cases repeated the test after 2 weeks. For validity and reliability, an exploratory factor analysis was performed along with a parallel analysis to determine the number of factors. The multi-trait, multi-method matrix assessed convergent and discriminant validity. To evaluate internal reliability and reliability over time, Cronbach's alpha and intraclass correlation coefficients were reported. RESULTS: Two factors explained a total variance of 54.9% in the data. The first and second factors comprised questions 1-3, 5, 7, 9, and 12-17 (symptoms-social) and questions 4, 6, 8, 10, and 11 (mucosal-psychological), respectively. The internal reliability of the Persian version of the ABQoL index was also acceptable, with a Cronbach's alpha of .855 for total items, .918 for the first factor, and .6 for the second factor. Our results suggest an acceptable convergent and discriminant validity of the Persian version of the ABQoL questionnaire. CONCLUSION: The Persian version of ABQoL index is a valid and reliable tool to monitor quality of life in patients with PV. Further studies are needed to assess the sensitivity of this instrument to changes in different disease activity and correlation with more general tools for the measurement of quality of life.

Acute generalized exanthematous pustulosis with a focus on hydroxychloroquine: A 10-year experience in a skin hospital.

OBJECTIVE: Acute generalized exanthematous pustulosis (AGEP) is a severe skin pustular drug reaction that can lead to life-threatening consequences. In this study, we have investigated the characteristics and outcomes of patients with AGEP in a tertiary skin hospital. METHODS: From March 2007 to December 2019, medical records of all patients diagnosed with AGEP, were assessed. Demographic data, culprit drug, past medical history, laboratory tests, recurrence, and systemic organ involvement were all documented as well. RESULTS: Seventy-four patients, including 54 women (73%) and 20 men (27%), with a mean age of 44.3 ± 16.5 years were evaluated. The most common comorbidities among the patients were rheumatoid arthritis and diabetes. In addition, hydroxychloroquine, cephalosporin, and amoxicillin were found as the three most common medications associated with AGEP induction. Among the study group, seventeen (23%) patients had systemic organ involvement (nine (12.2%), six (8.1%), and five (6.8%) had hepatic, renal and pulmonary involvement, respectively). All patients responded to oral prednisolone within a median of five days (IQR = 4; ranged 2-14). The median duration of treatment was significantly longer in hydroxychloroquine group compared to other drugs (8 versus 5 days; HR 0.57,95%CI 0·35-0.91). Likewise, the median duration of treatment was significantly longer in febrile patients compared to the afebrile ones (7 versus 4 days; HR 0.46, 95%CI 0.25-0.85). Recurrence occurred in six patients after resuming treatment with the same medication. The mean Naranjo score was 7.6 ± 0.9 denoting a probable causal relationship. CONCLUSION: In this study, we found that using hydroxychloroquine and presence of fever are the risk factors potentially leading to a prolonged treatment duration of AGEP.

Closed Antegrade/Retrograde intramedullary fixation of central metatarsal fractures: Surgical technique and clinical outcomes.

BACKGROUND: Intramedullary fixation with k-wires is a surgical option in the management of fractures of the shaft and neck of central metatarsals. The current study aimed at investigating the clinical outcomes of closed antegrade/retrograde intramedullary pinning technique. PATIENTS AND METHODS: A total of 34 patients (26 males and eight females) with 58 metatarsal neck and shaft fractures (28 shaft and 26 neck fractures) were operated using the antegrade/retrograde intramedullary fixation technique. At the final follow-up visit, pain intensity was assessed using the visual analog scale (VAS) and foot function was evaluated by the American Orthopedic Foot and Ankle Society (AOFAS) forefoot scoring system. RESULTS: Mean follow-up period was 18 months, ranged 12 to 34. Mean time to clinical fracture healing was 6.5 weeks, ranged 5 to 9. Bony union was occurred in all the cases. No surgical site infection was noted. Mean VAS score at the final follow-up visit was 0.28, ranged 0 to 3. At the final follow-up, the mean AOFAS score was 95.2, ranged 81 to 100. CONCLUSION: Closed antegrade/retrograde intramedullary pinning is a minimally invasive technique to manage central metatarsal fractures. Using this technique, metatarsal alignment can be restored and good clinical outcome is achieved.