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Irofulven cytotoxicity depends on transcription-coupled nucleotide excision repair and is correlated with XPG expression in solid tumor cells.

BACKGROUND: Irofulven is a novel alkylating agent with promising clinical activity, particularly toward ovarian and hormone-refractory prostate cancers. To facilitate additional clinical development, we have aimed to identify biological markers associated with sensitivity to the compound. METHODS: Fibroblasts derived from patients with xeroderma pigmentosum or Cockayne's syndrome along with a panel of 20 human cancer cell lines (eight different tumor types) were examined to establish the importance of nucleotide excision repair proteins in the sensitivity to irofulven. RESULTS: Human cells deficient in nucleotide excision repair are up to 30-fold more sensitive to the cytotoxic effects of irofulven compared with repair-proficient controls, clearly indicating that nucleotide excision repair plays a crucial role in the sensitivity to the drug. Interestingly, our results show that irofulven-induced lesions are recognized by transcription-coupled repair but not by global genome repair. Another unique feature is the pronounced sensitivity of XPD and XPB helicase-deficient cells to the drug. Comparison of the IC50 values for irofulven, cisplatin, and ecteinascidin 743 with the expression levels of ERCC1, XPD, and XPG genes in different solid tumor cell lines shows no correlation between the expression levels of any of the three nucleotide excision repair proteins and the sensitivity to ecteinascidin 743. In contrast, expression of the XPG endonuclease was correlated with the cytotoxicity for irofulven and, to a lesser degree, for cisplatin. Importantly, XPG expression was also correlated with cellular nucleotide excision repair activity. CONCLUSIONS: Increasing evidence indicates that compromised nucleotide excision repair activity is frequent in several solid tumor types. The results presented here suggest that XPG expression in such tumors may be a useful marker to predict their sensitivity to irofulven.

Antineoplastic Agents, Alkylating↗

[Rectum carcinoma. Optimizing therapy by deep resection or excision].

Abdominoperineal excision of the rectum has been the surgical treatment of choice for rectal cancer of the middle and lower third for decades. However, subsequent to technical developments, particularly stapling instruments, sphincter saving procedures such as low anterior or intersphincteric resection superseded abdominoperineal excision in the majority of tumors of the middle and even lower third of the rectum. Within the last seven years (1990-1997), 253 patients with distal rectal cancer underwent surgery--in 204 patients surgery was carried out for the cure of malignancy, whereas in 49 patients surgery was performed for palliation. In the meantime, the rate of abdominoperineal excision with permanent stoma was steadily decreased from 25% (1990-1993) to 9% (1994-1997). Concerning oncologic quality, sphincter saving resections showed evidence that cure rates (3- and 5-year survival) were not compromised by these techniques; conversely, sphincter saving resections offered oncologic cure rates superior to abdominoperineal excision of the rectum. Complete lymphadenectomy with high ligation of the inferior mesenteric artery and total mesorectal excision (TME) are fundamental components of this approach. Moreover, the adverse effects of a permanent colostomy and the consecutively diminished quality of life following abdominoperineal excision can be avoided in approximately 80% of cases. In conclusion, at present 80-85% of rectal carcinomas of the middle or lower third can be surgically treated by sphincter saving low resections without compromising oncologic radicality.

Anastomosis, Surgical↗

Occurrence of subclinical tumor in excised facial subunits.

OBJECTIVE: To determine the incidence of subclinical tumor in excised facial subunits in patients undergoing reconstruction after Mohs surgery. DESIGN: The study group comprised 45 patients who had their Mohs defects repaired by a facial plastic surgeon at a tertiary care center (university hospital). In the group, there were 74 biopsy-proved cutaneous neoplasms of the face. The median age of the group was 67 years. Nineteen patients (42%) had multiple tumors. There were 63 basal cell carcinomas (85%) and 11 squamous cell carcinomas (15%). Forty-seven tumors (64%) were primary and 27 (36%) were recurrent. Reconstruction of the defects was based on the principle of aesthetic subunits. Excised subunits were examined by the Mohs surgeon. Further excisions were performed, as necessary, if tumor was present in the subunit. RESULTS: Five patients (11%) had subclinical basal cell carcinomas in their excised facial subunits. Four patients underwent further resections. CONCLUSIONS: In patients with severe sun damage, recurrent tumors, and a history of skin cancer, clinically normal tissue excised during the reconstruction of their Mohs defects may contain subclinical tumor. Consequently, when these "high-risk" patients undergo reconstruction, excised facial subunits should be submitted for pathologic examination.

Adult↗

Open excision of subglottic hemangiomas to avoid tracheostomy.

OBJECTIVE: To assess the efficacy of open excision as an alternative to tracheostomy in the management of subglottic hemangioma. DESIGN: A retrospective review of patients undergoing open surgical excision of subglottic hemangiomas over a 10-year period. SETTING: A tertiary pediatric center. PATIENTS: The study included 22 children ranging in age from 2 to 42 months (median age, 5 months) who underwent open excision of subglottic hemangioma over a 10-year period. RESULTS: Twenty-one patients were treated with single-stage procedures, with postoperative endotracheal intubation for an average of 5 days. One patient who had a preexisting tracheostomy was treated with a 2-stage procedure and underwent decannulation 2 months after excision. Seven other patients were tracheostomy dependent at the time of excision and underwent decannulation at the time of the procedure. Cartilage grafts were inserted in 10 patients. There were no problems with subglottic stenosis. Twenty-one patients reported good voice and no airway symptoms after a mean follow-up period of 42 months. Five patients had significant postoperative problems. Three patients required further endoscopic procedures for removal of granulation tissue, and 1 patient, who remains minimally symptomatic, developed an anterior glottic web. One patient required a 6-month course of steroids after surgery to treat residual glottic hemangioma. CONCLUSIONS: Open surgical excision of subglottic hemangiomas can be performed as a single procedure, avoiding a tracheostomy, when modern surgical techniques developed for laryngotracheal reconstruction are incorporated. This approach can avoid repeated endoscopic procedures, prolonged treatment with corticosteroids, and years spent with a tracheostomy waiting for spontaneous involution of the hemangioma.

Child, Preschool↗

Stapled vs excision hemorrhoidectomy: long-term results of a prospective randomized trial.

HYPOTHESIS: Stapled hemorrhoidectomy offers several advantages over excision hemorrhoidectomy, including reduced postoperative pain, a reduced hospital stay, and an earlier recovery time. Furthermore, stapled hemorrhoidectomy is associated with lower hemorrhoidal recurrence on long-term follow-up. DESIGN: A randomized prospective trial. Patients were blinded to the operation technique used. Follow-up occurred at 1 and 3 weeks and 12 months postoperatively. SETTING: A university hospital providing primary, secondary, and tertiary care. PATIENTS: Forty patients with second- and third-degree hemorrhoid disease were randomized to undergo either stapled or excision hemorrhoidectomy. Two patients were excluded. All patients were subject to a follow-up examination. INTERVENTIONS: Stapled hemorrhoidectomy (Longo technique) vs excision hemorrhoidectomy (Ferguson technique). MAIN OUTCOME MEASURES: Operating time, postoperative pain (measured by the visual analog scale), hospital stay, histologic features, morbidity, defecation habit, continence, recovery time (return to work), and hemorrhoid recurrence at 1 year. RESULTS: Stapled vs excision hemorrhoidectomy was associated with a significantly reduced operating time (30 vs 43.25 minutes; P<.001), reduced postoperative pain scores (visual analog score) on the first 4 postoperative days (day 1: 2.7 vs 6.3; day 2: 1.7 vs 6.3; day 3: 0.8 vs 5.4; and day 4: 0.5 vs 4.8, where 0 indicates no pain, and 10, maximum pain; P < or = .001), and an earlier return to work (6.7 vs 20.7 days;P =.001). There were no differences for stapled vs excision hemorrhoidectomy in length of hospital stay (2.4 vs 2.1 days), complications (3 [15%] of 20 patients vs 5 [25%] of 20 patients), and recurrence rate (1 [5%] of 20 patients vs 1 [5%] of 20 patients). CONCLUSIONS: Stapled hemorrhoidectomy is associated with reduced postoperative pain, earlier recovery time and return to work, and a similar recurrence rate compared with the excision technique. Provided further clinical trials confirm these findings, stapled hemorrhoidectomy may become a future gold standard.

Adult↗

Effects of delayed wound excision and grafting in severely burned children.

HYPOTHESIS: Advances in burn treatment including early excision of the wound have increased survival in patients treated at specialized burn centers. We hypothesized that the patients with delayed wound excision and grafting would experience deleterious outcomes. METHODS: From 1995 to 1999, 157 children with acute burns covering 40% or more of total body surface area and having more than 10% of full-thickness burns were admitted to our institution within 2 weeks of injury. Among them, 86, 42, and 29 patients underwent first operation on days 0 to 2, days 3 to 6, and days 7 to 14 after burn, respectively. Outcomes observed were mortality, number of operative procedures, length of hospitalization, blood transfused, incidence of wound bacterial and fungal contamination, invasive wound infection, and sepsis. RESULTS: Demographic data for the groups showed no differences in sex or total body surface area burned. Mortality and number of operative procedures and blood transfusions were not different between groups. Hospitalizations were longer in the delayed groups, which was associated with a higher incidence of significant wound contamination (P =.008). Invasive wound infection also increased significantly with delay of excision (P<.001). An increased incidence of sepsis was seen in patients with delayed wound excision and grafting (P =.04). CONCLUSIONS: Delays in excision were associated with longer hospitalization and delayed wound closure, as well as increased rates of invasive wound infection and sepsis. Our data indicate that early excision within 48 hours is optimal for pediatric patients with massive burns.

Anti-Infective Agents, Local↗

Modulation of inflammatory and catabolic responses in severely burned children by early burn wound excision in the first 24 hours.

HYPOTHESIS: Early burn wound excision modulates the hypermetabolic response in severe pediatric burn injuries. DESIGN: Before-after trial. SETTING: A 30-bed burn referral center in a private, university-affiliated hospital. METHODS: We studied 35 severely burned children who were divided into 2 groups. One group (n = 20) was treated with early burn wound excision within 24 hours after the injury. The second group (n = 15) was treated conservatively with silver sulfadiazine in other burn facilities for 5 days, and burn wounds were surgically excised when patients were admitted to our burn center on day 6 after the injury. Data compiled included oxygen consumption and acute-phase protein, interleukin 1beta; interleukin 6, interleukin 10, tumor necrosis factor alpha, and anabolic hormone (growth hormone, insulinlike growth factor type 1) levels preoperatively and 24 hours and 5 days postoperatively. MAIN OUTCOME MEASURES: Acute-phase and hypermetabolic responses. RESULTS: Early burn wound excision abrogated the hypermetabolic response in pediatric burn patients. Patients who underwent conservative treatment had a significantly more severe inflammatory and hypermetabolic response at the same time interval and significantly lower levels of anabolic hormones. CONCLUSIONS: Early burn wound excision is a safe therapeutic approach that modulates the hypermetabolic response after burn injury. It was superior to the conservative treatment of silver sulfadiazine and delayed excision, and it should be considered when treating all severe full-thickness burns.

Acute-Phase Reaction↗

Early burn wound excision and skin grafting postburn trauma restores in vivo neutrophil delivery to inflammatory lesions.

This study assessed the effect of early vs delayed postburn wound excision and skin grafting on the in vivo neutrophil delivery to a delayed-type hypersensitivity (DTH) reaction and a bacterial skin lesion (BSL). Male Lewis rats were presensitized to keyhole-limpet hemocyanin. Group 1 comprised sham controls. Groups 2 through 4 were given a 30% 3 degrees scald burn, but the burn wounds were excised, and skin was grafted on days 1, 3, and 7, respectively, after the burn. Group 5 comprised burn controls. Twelve days after burn trauma, all rats were injected at different intervals (during a 24-hour period) with a trio of intradermal injections of keyhole-limpet hemocyanin, Staphylococcus aureus 502A, and saline at different sites. In vivo neutrophil delivery to these dermal lesions was determined by injecting indium in 111 oxyquinoline-labeled neutrophils isolated from similarly treated groups of rats. Neutrophil delivery to DTH and BSL lesions was restored to normal by excision and skin grafting of the burn wound one day after burn trauma. Waiting three days after burn trauma to excise and skin graft the wound partially, but not completely, restored the in vivo neutrophil delivery to DTH and BSL lesions. Waiting one week to excise and skin graft a burn wound resulted in no improvement in neutrophil delivery to DTH and BSL dermal lesions. It was concluded that burn wound excision and skin grafting immediately after burn trauma restored in vivo neutrophil delivery to a BSL and DTH dermal lesion. This may, in part, explain the beneficial effect of early aggressive burn wound debridement in patients with burn injuries.

Animals↗

Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma.

We analyzed the results at 8 years of an international, randomized, prospective study carried out by the World Health Organization Melanoma Programme aimed at evaluating the efficacy of 1-cm-margin excision of primary melanomas not thicker than 2 mm. Data for 612 patients were assessable; 305 were randomized to receive 1-cm-margin excision and 307 to receive wide excision (margins of greater than or equal to 3 cm). The major prognostic criteria were similar in the two groups. Breslow thickness was 0.99 mm in the narrow excision group and 1.02 mm in the wide excision group. Disease-free and overall survival rates (mean follow-up period, 90 months) were similar in the two groups. Only four patients had a local recurrence as a first relapse. All underwent narrow excision, and each had primary melanomas thicker than 1 mm.

Adult↗

The effects of excision repair and the plasmid pKM101 on the induction of his+ revertants by chemical agents in Salmonella typhimurium.

Expansion of the Ames Salmonella/microsome mutagenesis test to include plasmid pKM101-bearing, excision repair-proficient derivatives permits 1) the identification of mutagens that require both factors for activity; 2) the identification of genotoxins through the enhancement of survival by excision repair; and 3) the classification of substances according to the effects of excision repair on their mutagenesis. Class I includes substances that require excision repair to effect mutagenesis. Class II contains substances whose mutagenesis is not affected by excision repair. Class III mutagens cause premutational lesions in DNA which are readily removed by excision repair. This classification scheme is suggested as a preliminary step in making a risk estimation for a mutagen.

4-Nitroquinoline-1-oxide↗

Differential repair of excision gaps generated by transposable elements of the 'Ac family'.

Studies on transposable elements of the Ac family have led to different models for excision gap repair in either plants or Drosophila. Excision products generated by the plant transposable elements Ac and Tam3 imply a more or less straightforward ligation of broken ends; excision products of the Drosophila P element indicate the involvement of 'double-strand break' (DSB) repair. Recent findings that excision products of Ac and Tam3 can also contain traces of the element ends indicate, however, that DSB repair might be an alternative repair mechanism in plants. A functional DSB repair mechanism in plants can also be deduced from the observed rapid increases of Ac copy number during plant development and from the involvement of Ac in the generation of internal Ac deletions. On the other hand, alternative repair mechanisms may also be functional in Drosophila, because some of the 'footprints' generated upon P excision can be explained by a mechanism that has been postulated for excision gap repair in plants. It is concluded that plants and Drosophila can use similar repair mechanisms, but that the predominance of a certain repair mechanism is determined by the host.

Animals↗

Local excision and mucosal advancement for anorectal ulceration in patients infected with human immunodeficiency virus.

In patients infected with human immunodeficiency virus (HIV) no effective surgical procedure has been described for anorectal ulceration that is resistant to medical therapy. This study was designed to determine the effectiveness of surgical excision of anorectal ulcers, with or without mucosal advancement. The medical records of patients with HIV and anorectal pathology diagnosed between 1984 and 1994 were reviewed. Patients with anorectal ulcers were divided into group A which was treated only with excision and group B in which excision was combined with mucosal advancement. Surgical treatment was considered successful if relief of symptoms was achieved within 4 weeks of the operation. Excision of anorectal ulcers was successful in seven of 16 patients (44 per cent) in group A. Relief of symptoms was achieved in 12 of 13 patients (92 per cent) in group B when surgical excision was combined with mucosal advancement, which is significantly better than the results in group A (P = 0.02). This non-randomized study indicates that after unsuccessful medical treatment persistent symptomatic ulcers should be treated operatively by excision with mucosal advancement.

AIDS-Related Opportunistic Infections↗

Local recurrence following total mesorectal excision for rectal cancer.

Early results after rectal cancer surgery in a defined population were compared before and after the introduction of total mesorectal excision. In the first period (1984-1986) 211 cases of rectal cancer were diagnosed and in the second (1990-1992) 230. Of these, 134 patients in the first period (group 1) had anterior resection or abdominoperineal excision which was considered curative. In the second period 128 curative anterior resections and abdominoperineal excisions were performed by a limited number of surgeons familiar with total mesorectal excision (group 2). No differences between the groups were found in stage distribution, rate of curative operations, postoperative complications or postoperative mortality. Local recurrence had developed in 19 patients in group 1 and in eight in group 2, 1 year after the end of the study periods (P = 0.03). Local radicality was in doubt in 13 patients in group 1 and in eight in group 2. In the remaining 121 and 120 patients, 13 and four local recurrences respectively were present (P = 0.03). Actuarial analysis showed a significant reduction in local recurrence rate (P = 0.03) and an increase in crude survival (P = 0.03) at 4 years in group 2 compared with group 1. Total mesorectal excision reduces the local recurrence rate after excision of rectal cancer.

Actuarial Analysis↗

Causes and outcomes of pouch excision after restorative proctocolectomy.

BACKGROUND: Pouch failure occurs in up to 10 per cent of patients after ileal pouch-anal anastomosis (IPAA). The aims of this study were to determine the reasons for pouch excision and to evaluate the outcome of the perineal wound after pouch excision. METHODS: Between 1984 and 2002, 91 patients with severe ileal pouch dysfunction were treated. This was a retrospective analysis of data collected prospectively from 24 patients who underwent pouch excision. RESULTS: Patients were grouped according to the final histological diagnosis. Fourteen patients with Crohn's disease developed extensive fistulous disease and/or recurrent abscesses, of whom six had a persistent perineal sinus after pouch excision. Five patients had familial adenomatous polyposis, in three of whom desmoid tumours were the cause of failure. Three patients had chronic ulcerative colitis and developed recurrent pelvic sepsis. Finally, two patients with multiple colorectal adenocarcinoma developed recurrent cancer (one) or sepsis (one). CONCLUSION: Sepsis was the principal reason for pouch excision and was usually associated with recrudescent Crohn's disease in the pouch. Perineal wound healing was problematic after pouch excision for Crohn's disease.

Adenomatous Polyposis Coli↗

MammoSite excision volume as a predictor for residual disease.

BACKGROUND: The MammoSite catheter is a brachytherapy device used for accelerated partial breast irradiation. Currently, it is available as 2 spherically shaped balloons meant to fill 70-cc and 120-cc cavity volumes. This study was designed to define the relation of these excision volumes to the likelihood of microscopically detectable, residual disease based on tumor size, margin status, patient age, and histology. METHODS: The study data base was comprised of 531 patients with Stage 0, I, and II breast carcinoma (using American Joint Committee on Cancer staging criteria) who received breast-conserving therapy and underwent surgical reexcision. Patients in the data base were stratified based on the volume of their initial excision: < or = 70 cc versus > 70 cc and < or = 120 cc versus > 120 cc. RESULTS: Surgical margin size was found to be a strong predictor of residual disease both for patients with smaller excision volumes (P = 0.0014) and patients with larger excision volumes (P = 0.0003); histology (extensive intraductal component [EIC] or pure ductal carcinoma in situ [DCIS]) also was a strong predictor. Tumor size was significant only for the larger volume group (P = 0.029). On multivariate analysis, only histology and initial margin status were significant correlates with residual disease. The adjusted odds ratio for residual disease with pure DCIS was 0.79, and the adjusted odds ratio for invasive ductal or lobular carcinoma (IDC/ILC) without EIC was 0.44 relative to IDC/ILC with EIC (P = 0.008). The adjusted odds ratio for residual disease with a positive initial margin versus a negative initial margin was 2.65 (P < or = 0.0001). CONCLUSIONS: For excisions amenable to use of the MammoSite catheter, a margin > or = 1.0 mm appeared to afford at most a 35% risk of microscopically detectable residual tumor. Evidence of EIC on excision of IDC/ILC connoted a significantly higher risk. Age did not appear to be predictive for residual disease.

Adult↗

Developmental and genetic aspects of Mutator excision in maize.

The regulation of excision of Mu elements of the Mutator transposable element family of maize is not well understood. We have used somatic instability of Mu receptor elements from the Bronze 1 and Bronze 2 loci to monitor the frequency and the timing of excision of Mu elements in several tissues. We show that spot size in the aleurone of a bz2::mu1 stock varies between one to approximately 256 cells. This indicates that excision events begin eight divisions prior to full aleurone differentiation and end after the last division of the aleurone. We show that excision is equally biased for late events in all other tissues studied. A locus on chromosome 5 has been identified that affects spot size, possibly by altering the timing of Mu excision. Using somatic excision as an assay of Mutator activity, we found that activity can change in small sectors of the tassel; however, there are no overall activity changes in the tassel during the period of pollen shedding. We also report the recovery of germinal revertants for the bz1::mu1 and bz2::mu1 alleles. One of these revertant alleles was characterized by Southern blot analysis and found to be similar to the progenitor of the mutable allele.

Alleles↗

Comparison of local tumor recurrence following excision with the CO2 laser, Nd:YAG laser, and Argon Beam Coagulator.

This study compares the incidence of local tumor recurrence following primary excision with the CO2 laser, Nd:YAG laser (contact), Argon Beam Coagulator, or electrocautery. One hundred eight Fisher 344 rats with R3230AC mammary tumors (1.6 +/- 0.04 [SD] cm diameter) were used. All animals were randomized into groups of similar tumor size. In groups C and CS, excision was performed with a Sharplan 1060 CO2 laser (TEMoo, 25 W, continuous wave [CW], 0.2-mm spot size). Wounds in group CS were "sterilized" (0.5-mm spot size, 25 W, CW) by gently heating the wound without causing blanching or charring. In group N, a 0.4-mm contact Laser Blade and a Cooper 8000 Nd:YAG laser at 20 W CW was used. In groups SA1 and SA2, tumors were excised with the scalpel, and hemostasis and wound "sterilization" were accomplished with the Bard System 6000 Argon Beam Coagulator (ABC) at 40 W and 4 liters/min argon gas flow in SA1 and 12 liters/min in SA2. In group E, excision was accomplished at 40 W blend mode, 10 W spray mode. In group EA, excision was accomplished at 60 W cutting current, and hemostasis was achieved with the ABC. The animals were examined for evidence of recurrence for 34 days postoperatively. Mortalities were excluded from analysis. The incidence of recurrence was 11/14 (79%) in C, 6/16 (38%) in CS, 10/14 (71%) in SA1, 6/13 (46%) in SA2, 6/15 (40%) in N, 7/10 (70%) in EA, and 3/15 (20%) in E. Group E is statistically different (P less than .01) from groups EA, C, and SA1. Group C was different (P less than .01) from groups E, CS, and N. These results demonstrate an inverse relationship between tumor recurrence and local thermal effects at the surgical site. The ABC did not increase tumor recurrence. Contact YAG surgery was similar to CO2 laser excision and "sterilization." An attempt to study the influence of gas flow and pressure on local tumor recurrence and metastases should be made.

Adenocarcinoma↗

Augmentation of the systemic host anti-tumor response through laser excision.

This study examines whether primary laser excision results in augmentation of the systemic host anti-tumor response to tumor rechallenge. Single R3230AC mammary tumor implants, (0.5 x 0.5 x 1.0 mm), were grown in 112 female Fisher 344 rats. The animals were randomized. Group S tumors were excised by scalpel. Group E was excised with a Surgistat electrocautery (Valley Labs, Boulder, CO). Group CS was excised with a Sharplan 1100 CO2 laser (Sharplan, Allendale, NJ) at 25 watts (W) continuous wave (CW) (0.2 mm spot size) and the wound was "sterilized" with a 5-mm spot size by gently heating the tissue without blanching. Group K was excised with a KTP/532 laser (Laserscope, San Jose, CA) at 17 W CW using a 400 microns fiber. Group Y was excised with a Sharplan 2100 Nd:YAG laser set at 15W CW using a 0.2 mm clear sapphire tip. A second tumor implant, (0.5 x 0.5 x 1.0 mm), was placed at a remote site 14 days postoperatively. An unoperated control group was implanted. Secondary tumor volumes were measured for 36 days and the mean tumor volumes (MTV) were statistically compared. The MTV in groups CS, K, Y, and E was less than control (P less than 0.01). The MTV in groups CS, K, Y, and E was less than group S, although this was not statistically different. Lasers and cautery appear to increase the host response against subsequent tumor challenge. This study corroborates earlier studies of other modalities. Further studies to determine whether this host sensitization is an immune response and to elucidate the mechanisms of this effect are warranted.

Animals↗