Design, Synthesis, and Evaluation of Glucose Transporter Inhibitor-SN38 Conjugates for Targeting Colorectal Cancer.

Irinotecan (1), a prodrug of SN38 (2) approved by the US Food and Drug Administration for treating colorectal cancer, lacks specificity and causes many side effects. To increase the selectivity and therapeutic efficacy of this drug, we designed and synthesized conjugates of SN38 and glucose transporter inhibitors (phlorizin (5) or phloretin (6)), which could be hydrolyzed by glutathione or cathepsin to release SN38 in the tumor microenvironment, as a proof of concept. These conjugates (8, 9, and 10) displayed better antitumor efficacy with lower systemic exposure to SN38 in an orthotopic colorectal cancer mouse model compared with irinotecan at the same dosage. Further, no major adverse effects of the conjugates were observed during treatment. Biodistribution studies showed that conjugate 10 could induce higher concentrations of free SN38 in tumor tissues than irinotecan at the same dosage. Thus, the developed conjugates exhibit potential for treating colorectal cancer.

Subunit vaccines with a saponin-based adjuvant boost humoral and cellular immunity to MERS coronavirus.

Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks have constituted a public health issue with drastic mortality higher than 34%, necessitating the development of an effective vaccine. During MERS-CoV infection, the trimeric spike protein on the viral envelope is primarily responsible for attachment to host cellular receptor, dipeptidyl peptidase 4 (DPP4). With the goal of generating a protein-based prophylactic, we designed a subunit vaccine comprising the recombinant S1 protein with a trimerization motif (S1-Fd) and examined its immunogenicity and protective immune responses in combination with various adjuvants. We found that sera from immunized wild-type and human DPP4 transgenic mice contained S1-specific antibodies that can neutralize MERS-CoV infection in susceptible cells. Vaccination with S1-Fd protein in combination with a saponin-based QS-21 adjuvant provided long-term humoral as well as cellular immunity in mice. Our findings highlight the significance of the trimeric S1 protein in the development of MERS-CoV vaccines and offer a suitable adjuvant, QS-21, to induce robust and prolonged memory T cell response.

Is anoplasty superior to scar revision surgery for post-hemorrhoidectomy anal stenosis? Six years of experience.

BACKGROUND: Anal stenosis is a rare but frustrating condition that usually occurs as a complication of hemorrhoidectomy. The severity of anal stenosis can be classified into three categories: mild, moderate, and severe. There are two main surgical treatments for this condition: scar revision surgery and anoplasty; however, no studies have compared these two approaches, and it remains unclear which is preferrable for stenoses of different severities. AIM: To compare the outcomes of scar revision surgery and double diamond-shaped flap anoplasty. METHODS: Patients with mild, moderate, or severe anal stenosis following hemorrhoidectomy procedures who were treated with either scar revision surgery or double diamond-shaped flap anoplasty at our institution between January 2010 and December 2015 were investigated and compared. The severity of stenosis was determined via anal examination performed digitally or using a Hill-Ferguson retractor. The explored patient characteristics included age, sex, preoperative severity of anal stenosis, preoperative symptoms, and preoperative adjuvant therapy; moreover, their postoperative quality of life was measured using a 10-point scale. Patients underwent proctologic follow-up examinations one, two, and four weeks after surgery. RESULTS: We analyzed 60 consecutive patients, including 36 men (60%) and 24 women (40%). The mean operative time for scar revision surgery was significantly shorter than that for double diamond-shaped flap anoplasty (10.14 ± 2.31 [range: 7-15] min vs 21.62 ± 4.68 [range: 15-31] min; P < 0.001). The average of length of hospital stay was also significantly shorter after scar revision surgery than after anoplasty (2.1 ± 0.3 vs 2.9 ± 0.4 d; P < 0.001). Postoperative satisfaction was categorized into four groups: 45 patients (75%) reported excellent satisfaction (scores of 8-10), 13 (21.7%) reported good satisfaction (scores of 6-7), two (3.3%) had no change in satisfaction (scores of 3-5), and none (0%) had scores indicating poor satisfaction (1-2). As such, most patients were satisfied with their quality of life after surgery other than the two who noticed no difference due owing to the fact that they experienced recurrences. CONCLUSION: Scar revision surgery may be preferable for mild anal stenosis upon conservative treatment failure. Anoplasty is unavoidable for moderate or severe stenosis, where cicatrized tissue is extensive.

Positive Association Between Fluoroquinolone Exposure and Tendon Disorders: A Nationwide Population-Based Cohort Study in Taiwan.

Introduction: Fluoroquinolone exposure is reportedly associated with a higher risk of tendon disorders, tendonitis, or tendon rupture. However, studies in East Asian populations have not confirmed these risks in patients with comorbidities or concomitant medication use. This cohort study was designed to investigate the associations among fluoroquinolone exposure, comorbidities, medication use, and tendon disorders in Taiwan. Materials and Methods: This population-based, nationwide, observational, cohort study used data from the National Health Insurance Research database in Taiwan, a nationwide claims database that covers more than 99% of the Taiwanese population. The study period was from January 2000 to December 2015, and the median follow-up time was 11.05 ± 10.91 years. Patients who were exposed to fluoroquinolones for more than three consecutive days were enrolled, and patients without fluoroquinolone exposure who were matched by age, sex, and index year were enrolled as controls. The associations of comorbidities and concomitant medication use with tendon disorder occurrence were analyzed using Cox regression models. Results: The incidence of tendon disorders were 6.61 and 3.34 per 105 person-years in patients with and without fluoroquinolone exposure, respectively (adjusted hazard ratio, 1.423; 95% confidence interval [1.02,1.87]; p = 0.021). Sensitivity analyses yielded similar results. Patients under 18 and over 60 years with fluoroquinolone exposure; those with chronic kidney disease, diabetes, rheumatologic disease, cardiac disease, lipid disorder, or obesity; and those who concomitantly used statins, aromatase inhibitors, or glucocorticoids, had a significantly higher risk of tendon disorders. Conclusion: The long-term risk of tendon disorders was higher in patients with fluoroquinolone exposure than in those without fluoroquinolone exposure. Clinicians should assess the benefits and risks of fluoroquinolone use in patients at high risk of tendon disorders who require fluoroquinolone administration.

The Relationship Between Renal Stones and Primary Aldosteronism.

Introduction: The association between primary aldosteronism (PA) and nephrolithiasis is still unclear. The hypercalciuria and hypocitraturia of PA patients might be the reason leading to recurrent calcium nephrolithiasis. This study aimed to evaluate the relationship between PA and renal stones, including stone size and density. Materials and Methods: From February 2010 to March 2021, we retrospectively collected 610 patients who presented to our medical center with hypertension history, and all these patients, suspicious of PA, had PA data survey. In total, 147 patients had kidney stone and were divided into 44 patients with essential hypertension as group 1 and 103 patients with PA as group 2. Pearson χ2 test and independent Student's t-test were performed to examine the differences among variables. Results: The mean age was 54.4 ± 12.0 years in group 1 and 53.0 ± 11.1 years in group 2. The incidence rate of renal stones in the PA group was around 24%. No significant differences between the two groups were found for gender, systolic/diastolic blood pressure, duration of hypertension, diabetes mellitus history, and laterality of kidney stone; however, mean stone size was 4.0 ± 3.3 mm in group 1 and 6.5 ± 7.2 mm in group 2, with a significantly larger renal stone size noted in the PA group than that in the essential hypertension group (p = 0.004). Hounsfield unit (HU) density was higher in the PA group vis-à-vis the essential hypertension cohort, although this did not reach a significant difference (p = 0.204). Conclusions: Our study revealed that PA patients had a higher incidence rate of renal stones compared to that of the general population. Besides, the PA-related renal stones also presented as larger and harder than those of the essential hypertension group. Further investigation concerning the association between PA and renal stones is warranted.

Betel Nut Chewing Is Associated with the Risk of Kidney Stone Disease.

(1) Background: Betel nut chewing injures bodily health. Although, the relationship between betel nut chewing and kidney stone disease (KSD) is unknown. (2) Methods: We analyzed 43,636 men from Taiwan Biobank. We divided them into two groups on the status of betel nut chewing, the never-chewer and ever-chewer groups. Self-reported diagnosed KSD was defined as the subject's medical history of KSD in the questionnaire. Logistic regression was used to analyze the association of betel nut chewing and the risk of KSD. (3) Results: The mean age of subjects in the present study was 50 years, and 16% were ever-chewers. KSD was observed in 3759 (10.3%) and 894 (12.6%) participants in the group of never-chewer and ever-chewer groups, respectively. Higher risk of KSD was found in participants with betel nut chewing compared with to without betel nut chewing (odds ratio (OR), 1.094; 95% confidence interval (95% CI), 1.001 to 1.196). Furthermore, the daily amounts of betel nut chewing >30 quids was associated with a more than 1.5-fold increase (OR, 1.571; 95% CI, 1.186 to 2.079) in the odds of KSD; (4) Conclusions: Our study suggests that betel nut chewing is associated with the risk of KSD and warrants further attention to this problem.

Risk factors that predict major amputations and amputation time intervals for hospitalised diabetic patients with foot complications.

Diabetes-related lower extremity amputations are an enormous burden on global health care and social resources because of the rapid worldwide growth of the diabetic population. This research aimed to determine risk factors that predict major amputation and analyse the time interval from first hospitalisation to amputation by using standard management protocols and Kaplan-Meier survival curves. Data from 246 patients with diabetes mellitus and diabetic foot ulcers from the Division of Plastic and Reconstructive Surgery of the Department of Surgery at XXX Hospital between January 2016 and May 2020 were analysed. Univariate and multivariate analyses of 44 potential risk factors, including invasive ulcer depth and C-reactive protein levels, showed statistically significant differences for those at increased risk for major amputation. The median time from hospitalisation to lower extremity amputation was approximately 35 days. Most patients with abnormal C-reactive protein levels and approximately 70% of patients with ulcers invading the bone were at risk for lower extremity amputations within 35 days. Therefore, invasive ulcer depth and C-reactive protein levels are significant risk factors. Other potential risk factors for major amputation and the time intervals from first hospitalisation to amputation should be analysed to establish further prediction strategies.

Intracardiac Migration of the Ureteral Double-J Stent during Percutaneous Nephrolithotomy.

The complications of percutaneous nephrolithotomy (PNL) include hemorrhage, damage to adjuvant organs, and other medical issues, although intracardiac migration of ureteral double-J stent has never been found during PNL and delaying the diagnosis might cause mortality. We report the case of a 60-year-old male who was admitted to receive one-stage PNL for right renal stones. During operation, an unexpected atrial fibrillation with a drop in blood pressure was suddenly encountered and the chest X-ray subsequently showed that the ureteral double-J had penetrated deep into the heart. Emergent endovascular intervention was performed to remove the stent and the patient was uneventfully discharged 2 days later.

Targeting Colorectal Cancer with Conjugates of a Glucose Transporter Inhibitor and 5-Fluorouracil.

Overexpression of glucose transporters (GLUTs) in colorectal cancer cells is associated with 5-fluorouracil (1, 5-FU) resistance and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting drug conjugate, triggered by glutathione in the tumor microenvironment, that releases 5-FU and GLUTs inhibitor (phlorizin (2) and phloretin (3)). Using an orthotopic colorectal cancer mice model, we showed that the conjugate exhibited better antitumor efficacy than 5-FU, with much lower exposure of 5-FU during treatment and without significant side effects. Our study establishes a GLUT-targeting theranostic incorporating a disulfide linker between the targeting module and cytotoxic payload as a potential antitumor therapy.

Negative-pressure wound therapy combined with artificial dermis (Terudermis) followed by split-thickness skin graft might be an effective treatment option for wounds exposing tendon and bone: A retrospective observation study.

ABSTRACT: Skin grafts are not suitable for closing tendon- or bone-exposing wounds, which require flap surgery. Dermal regeneration templates have value for closing such wounds, but the disadvantages of the technique include implantation failures because of infection, hematoma formation, or inappropriate immobilization. Negative-pressure wound therapy was reported to increase graft acceptance in difficult wounds.This retrospective case series of 65 patients evaluated negative-pressure therapy combined with artificial dermis for the treatment of acute or chronic tendon- or bone-exposing wounds. The artificial dermis was placed after adequate wound-bed preparation, with simultaneous application of a vacuum-assisted closure system. Split-thickness skin grafting was performed after the implanted artificial dermis had become established.The overall success rate was 88.1% (59/67): 88.6% (39/44) in the chronic wounds group and 87% (20/23) in the acute-trauma group separately. The overall mean survival time of artificial dermis in success cases was 13.24 ±â€Š7.14 days. In separately, the survival time of artificial dermis had no statistically difference in chronic wound group (13.64 ±â€Š7.53 vs 12.60 ±â€Š5.86. P = .943), but had significant statistical difference in acute trauma group (12.45 ±â€Š6.44 days vs 23.33 ±â€Š4.04 days, P = .018). Also, comorbidity of PAOD was found a strong risk factor of failure in chronic wound group (100% vs 23.1%, P < 0.001).We concluded that artificial dermis combined with negative-pressure therapy followed by split-thickness skin grafting might be a reliable and effective option for surgical reconstruction of tendon- or bone-exposing wounds, and could decreasing waiting periods of autologous skin graft.

Negative Pressure Wound Therapy in Conjunction With Artificial Dermis for Burned Hand Reconstruction.

INTRODUCTION: Proper wound care along with the use of skin grafts over deep burn wounds has been the standard treatment. However, the goal in burn wound care has shifted from achieving a satisfactory survival rate to improving long-term form and function of the healed wound, which is sometimes hindered by scar contracture. This has prompted surgeons to find alternative ways to treat burn wounds without compromising function. Among burn cases, hand injuries are the most problematic when it comes to delicate function recovery. METHODS: This study presents the results of conjunctive use of a bilayer artificial dermis, negative pressure wound therapy, and split-thickness skin grafts for grafting over acute burn wounds and scar-releasing defects after severe hand burns. RESULTS: Three months after the operation, the scar was soft and pliable, the aesthetic outcome was good, and the patients gained much improvement in hand function and quality oflife. CONCLUSIONS: The combined technique achieved a good scar quality and aesthetic effect on burned hands as well as excellent functional outcome, which resulted in major improvements and an independent life for the patient.

Clinical Performance of Hydrogel-based Dressing in Facial Burn Wounds: A Retrospective Observational Study.

ABSTRACT: Preserving both esthetic and functional outcome remains challenging in facial burn injuries. The major issue is the initial treatment of injury. In this study, we focused on patients with partial-thickness facial burns admitted to the burn unit of Tri-Service General Hospital, Taipei, from November 2016 to November 2018. In 21 included patients, customized mask-style, transparent hydrogel-based dressing was applied to the burns. The mean age of included patients was 37.4 years. The mean area of burn injury was 11.9% of total body surface area, and the mean area of second-degree facial burns was 162.3 cm2. Full reepithelialization took, on average, 10.86 days. Scarring was acceptable in terms of texture and color, and no hypertrophic or keloidal scarring was noted. The mean Vancouver Scar Scale score was 2.07. Use of the hydrogel-based dressing masks seems to be a promising means of reducing pain, providing uninterrupted wound healing, facilitating observation, and positively affecting scarring in patients with second-degree facial burns.

Successful Treatment of Lower Limb Burn Wounds With Long-Term Survived Human Skin Allograft in an Immunosuppressed Patient: A Case Report.

Early excision and autografting have been the principles in managing acute burn wounds. Despite the known benefits of early autografting, there are situations in which the placement of autograft is unsafe or even unavailable. In these clinical situations, skin substitutes like artificial dressings and human skin allografts are considered as useful for temporary wound coverage. We present an immunosuppressed patient with deep lower limb burn wound who received human skin allograft for wound management. The applied human skin allograft persisted for a longer period without infection or rejection and successfully improved her wound healing. Large and well-designed prospective studies are needed to confirm the encouraging results of the present case report.

Surgical treatment and strategy in patients with pressure sores: A single-surgeon experience.

With aging, pressure ulcers become a common health problem causing significant morbidity and mortality for physically limited or bedridden elderly persons. Here, we present our strategy for such patients. Between August 2010 and March 2019, 117 patients were enrolled. Patient age, etiology, defect size and location, flap reconstruction, outcome, and follow-up period were reviewed. Of these patients, 64 were female and 53 were male, with an age range of 21 to 96 years (mean 75.6). The mean area of defect was 61.5 cm. The most common etiology was dementia (33.3%), and ulcers were most frequently caused by sacral pressure (70.3%). The commonest surgical treatment was a V-Y advancement flap (50%). The complication rate was 27.5%, including dehiscence and late recurrence. Negative pressure wound therapy could be used if the initial defect was large. V-Y advancement flap is the most frequent surgical treatment for sacral pressure ulcers because it is simple and available for most types of defect. Primary closure may be considered as the simplest method if the defective area is <16 cm. Intraoperative indocyanine green angiography can help avoid secondary flap revisions. Our protocol ensures a short surgery time, little bleeding, and a low complication rate.

Synthesis, distribution analysis and mechanism studies of N-acyl glucosamine-bearing oleanolic saponins.

A series ofN-acyl glucosamine-bearingtriterpenoidsaponins has been synthesized with cytotoxic activities evaluated against HL-60, PC-3, HCT-116, and CT-26 tumor cells. Saponins incorporated anoleanolic acid (OA) triterpenoidal core exhibited the highest cytotoxic activity. To study the influence of the lengths of acyl-carbon chain onN-position of glucosamine, cells were treated with28-propargylamides and then reacted with an azido-fluorogenic probe under CuAACclickreactions to visualize the intact distributions of these compounds by confocal microscopy and flow cytometry; it was found that cytotoxic-active compounds (30-32) located in the cytosol and inactivecompounds bearing longer carbon chains (33-35) were impenetrable across cell membranes.Our study demonstrated the defined lipophilic acyl-carbon chain length can precisely regulate thecytotoxic activityof saponins, which is useful for the future development of cytotoxic agents.Furthermore, using quantitative proteomics and immunolabeling,the mechanism ofcytotoxicity induced by the synthetic saponin after membrane penetration could be a result of activation of death receptor pathway and inhibition of PI3K/Akt/mTOR pathway.

Scalp melanoma with rectus abdominis metastasis: A rare case report.

RATIONALE: The main cause of death in melanoma patients is widespread metastases as it can metastasize to almost every organ. However, melanoma skeletal muscle metastases (MSMM) are exceptional, and only a few cases of MSMM to the rectus abdominis muscles have been previously described. And our case maybe the first reported case in Asia region. PATIENT CONCERNS: A 45-year-old man with history of right scalp melanoma, pT3aN0M0, stage IIA status post wide excision with 2 cm safe margin and right neck lymph node dissection at 5 years before. He had an almost 5 years disease-free period but presented to our clinic due to intermittent abdominal sharp pain for 1 to 2 months, with a palpable soft tissue mass over his right abdomen. Metastatic melanoma to rectus abdominis muscles was highly suspected. INTERVENTIONS: The patient subsequently underwent radical en-block extraperitoneal 15 cm segmental resection of the right rectus abdominis muscle including tumor mass. The resected tumor was a black-gray colored solid mass, and the final histologic study showed a metastasis of melanoma. OUTCOMES: Postoperative course of the patient was uneventful, and the right abdominal pain was improved. The patient was referred for further target therapy, but passed away half a year later due to multiple metastasis. LESSONS: Scalp melanoma with isolated rectus muscle metastasis is extremely rare especially for a young aged patient who had an almost 5-year disease-free period. Surgery is a potentially curative therapy for patients with isolated metastatic melanoma. The goal is negative resection margins, in order to avoid local recurrences. Radical compartmental surgery should be considered for selected stage IV melanoma patients with sole rectus abdominis MSMM, whose disease could be amenable to complete resection, in preliminary procedure to prolong disease-free survival time. For oligometastatic disease, surgical resection is sometimes useful in carefully selected patients after systemic therapy; also, it could be performed as symptomatic treatment.

Efficacy and Safety of Botulinum Toxin A in Axillary Bromhidrosis and Associated Histological Changes in Sweat Glands: A Prospective Randomized Double-Blind Side-by-Side Comparison Clinical Study.

BACKGROUND: The efficacy of botulinum toxin A (BTX-A) therapy in axillary hyperhidrosis has been documented; however, there are a few studies reporting the efficacy of BTX-A in treating axillary bromhidrosis. The histological changes occurring in sweat glands after BTX-A treatment are also unknown. OBJECTIVE: The authors report on the efficacy and safety of BTX-A in the treatment of axillary bromhidrosis and on the histological changes in sweat glands after BTX-A treatment. MATERIALS AND METHODS: Nineteen patients were included in this study. The patients were administered BTX-A injection in one axilla and sterile normal saline as placebo in the other axilla. The degree of malodor was evaluated subjectively by the patients before and 3 months after treatment. Sweat secretion was quantified by the gravimetric method. All patients underwent standard apocrinectomy in both axillary regions. RESULTS: The mean degree of malodor and mean sweat production in the BTX-A-treated axilla were significantly lower than those in the control axilla (2.42 vs 8.00; p < .0001 and 13.33 vs 33.75 mg/min; p = .0028, respectively) at 3 months after therapy. The histological studies showed apocrine sweat glands with atrophic changes and hypoplasia in treated axilla. CONCLUSION: BTX-A injection is an easy, fast, noninvasive method of treating axillary bromhidrosis.

Use of split-thickness plantar skin grafts in the management of leg and foot skin defects.

The basic principle of donor site selection is to take skin from areas that will heal with minimal scarring while balancing the needs of the recipient site. For skin loss from the lower legs and feet, the most common harvest site for split-thickness skin grafts is the anterior or posterior thigh; grafts from the plantar areas have been mostly used to cover the volar aspect of digits and palms. Between September 2015 and September 2017, 42 patients with areas of skin loss on the legs or feet were treated with plantar skin grafts because of their cosmetic benefits and the convenience of the surgical procedure and postoperative wound care. Our technique of harvesting a single layer of split-thickness skin graft (0.014 in. thick) from a non-weight-bearing area of the foot of the injured leg is simple and provided good functional and cosmetic outcomes at both the donor and recipient sites. All patients were very satisfied with the recovery progress and final results. Therefore, in the management of skin defects in the lower legs or feet that comprise less than 1.5% of the total body surface area, our surgical method is a reliable alternative to anterior or posterior thigh skin grafting.

Reconstruction of a Sacral Pressure Ulcer With an Inferior Gluteal Artery Perforator Flap After Failed Reconstruction Using Bilateral V-Y Advancement Flaps.

Many types of flaps are available if surgical reconstruction of a pressure ulcer is indicated, including a gluteus maximus flap, V-Y advancement flap, and superior gluteal artery perforator flap. Regional flap failure can complicate treatment, requiring additional flap surgery. An 80-year old woman with a 2-year history of being unconscious following a cerebrovascular accident presented with a Stage 4 sacral pressure ulcer of 2 months' duration with eschar and abscess formation. Because the wound measured 15 × 10 cm2, bilateral V-Y advancement flaps were used for surgical closure. However, 1 week later, ischemic change of the wound edges and wound dehiscence were observed. The wound was subsequently closed with an artery perforator (IGAP) flap, an approach that took into consideration religious preference of keeping the body intact. The patient was discharged with a healed wound 6 weeks postoperatively; long-term postoperative surveillance was hindered by the patient's distance from the care facility (she lived on an outlying island). This is the first case report to describe IGAP flap application in a patient with a sacral pressure ulcer after failed reconstruction using bilateral V-Y advancement flaps.