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From professional football to elite sport surgery, Professor Gordon Mackay details his journey throughout his career and what it takes to treat and operate on professional athletes. [ABSTRACT FROM AUTHOR]

Background: Reconstruction using autograft remains the gold standard surgical treatment for anterior cruciate ligament (ACL) injuries. However, up to 10% to 15% of patients will suffer a graft failure in the future. Cadaveric studies have demonstrated that the addition of suture tape augmentation to ACL autograft constructs can increase graft strength and reduce elongation under cyclical loading., Purpose/hypothesis: This study aimed to investigate the clinical outcomes and rerupture rates after ACL reconstruction (ACLR) with suture tape augmentation. We hypothesized that augmentation with suture tape would lead to lower rerupture rates., Study Design: Case series; Level of evidence, 4., Methods: Patients undergoing primary ACLR using hamstring or patellar tendon autografts augmented with suture tape between 2015 and 2019 were recruited prospectively. Patients with multiligament injuries or a concomitant lateral extra-articular procedure were excluded. Patients were observed in person for 6 months, and patient-reported outcome measures (PROMs) were collected at 2 and 5 years postoperatively. All patients were contacted, and records were reviewed to determine the incidence of graft failure. PROMs collected were as follows: Knee injury and Osteoarthritis Outcome Score (KOOS), Veterans RAND 12-Item Health Survey (VR-12), Tegner and Marx activity scores, and visual analog scale for pain (VAS)., Results: A total of 97 patients, with a mean age of 34.7 (±13.4) years, were included (76% men; 52 hamstring and 45 patellar tendon grafts). The mean graft diameter was 8 (±1) mm. There was 1 rerupture (1.1%) out of the 90 patients who were contactable at a mean of 5 years postoperatively. Median KOOS scores at 2 years were as follows: Pain, 94; Symptoms, 86; Activities of Daily Living, 99; Sport and Recreation, 82; and Quality of Life, 81. The postoperative scores were significantly higher than the preoperative scores ( P < .001). The VR-12 Physical score improved from 43 preoperatively to 55 at 2 years and remained at 56 at 5 years. The VAS pain, Tegner, and Marx scores were 0, 6, and 9, respectively, at 2 years postoperatively. There was no difference in PROMs between graft types., Conclusion: This study demonstrates encouraging results of suture tape augmentation of autograft ACLR for both hamstring and patellar tendon grafts. The failure rate of 1.1% at a mean follow-up of 5 years is lower than published rates for reconstruction, and PROMs results are satisfactory. The technique is safe to use and may permit a return to the preinjury sporting level with a lower chance of reinjury., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: G.M.M. receives consulting fees and royalties from Arthrex and holds a patent (US20120271416A1) for internal brace for tissue repairs and reinforcements that is used in this study. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Objectives: Anterior cruciate ligament (ACL) repair for proximal tears, where the ligament is re-attached and augmented with suture tape, can negate the need for graft harvest, thereby maintaining native anatomy. Autograft harvest has been associated with persistent deficits in lower limb muscle strength after recovery from ACL reconstruction. The aim of this study is to compare lower limb muscle strength following ACL repair and reconstruction., Methods: Nineteen ACL repair patients augmented with suture tape and nineteen ipsilateral semitendinosus-gracilis autograft ACL reconstruction patients (both mean 4 years postoperatively) were recruited, along with twenty healthy volunteers. Patient-reported outcome measures (PROMs) were obtained using the Knee Injury and Osteoarthritis Outcome Score (KOOS), Lysholm, and Tegner scores. Maximal isometric quadriceps and hamstring strength at 90° knee flexion were measured using a fixed Myometer after a warm-up and three maximal-effort contractions., Results: Mean hamstring strength of the reconstructed legs was lower than that of healthy volunteers by 0.29 Nm/kg. The hamstring strength ratio of the operated side to the uninjured side was greater in the repair (95% ​± ​13) than in the reconstruction (81% ​± ​18) group. There were no statistically significant differences between sides for quadriceps peak torque or for hamstrings in the volunteer or repair group. PROMs scores for the reconstruction group were significantly lower than volunteers across all domains and lower than repair for KOOS activities of daily living and Lysholm scores., Conclusion: Hamstring weakness seen following ACL reconstruction is not evident following ACL repair with suture tape augmentation. Strength asymmetry could contribute to re-injury risk and influence functional performance, while altered loads affect knee biomechanics and may lead to osteoarthritis progression. The absence of these deficits in the repair group demonstrates a potential benefit of this technique when used in appropriate patients., Level of Evidence: II., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gordon MacKay reports a relationship with Arthrex Inc. that includes: consulting or advisory and speaking and lecture fees., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Interest in anterior cruciate ligament (ACL) repair has been increasing as an alternative to traditional reconstructive techniques and encouraging results have been demonstrated using internal bracing with suture tape augmentation (FiberTape®, Arthrex, Naples, Florida). ACL repair is challenging if the rupture is mid-substance or distal. We describe the case of a hybrid ACL reconstruction with internal brace augmentation., Materials and Methods: This retrospective case report documents the rehabilitation process of a 31-year-old professional footballer who had an isolated ACL rupture. The patient underwent a hybrid ACL reconstruction with bone-patellar tendon-bone autograft and suture tape augmentation 10 days after his injury. A task-based rehabilitation programme defined by six progressive phases relevant to performance-based outcome measures was undertaken. Each phase had clear, functional, progressive goals incorporating exercises to improve mobility, neuromuscular control, strength, and a progressive return to running and sport-specific movements., Results: Using the rehabilitation framework outlined, this player produced excellent results in all objective criteria postoperatively and was able to return to unrestricted full team training in under five months (146 days) following surgery., Conclusions: This case presentation demonstrates the safe and accelerated return to professional football following ACL reconstruction augmented with internal bracing. The player was able to meet all criteria-based aspects of return to play.

Purpose: The aim of this study was to determine the frequency of secondary surgery following anterior cruciate ligament (ACL) repair with suture tape augmentation in comparison to conventional hamstring ACL reconstruction. We hypothesised that there would be no differences between the groups., Methods: This was a retrospective comparison study of patients undergoing ACL surgery between September 2011 and April 2018. Two hundred and 73 patients underwent ACL reconstruction using hamstring autograft. During the same timeframe, 137 patients with an acute proximal ACL rupture underwent ACL repair with suture tape augmentation. One patient was lost to follow-up in the ACL reconstruction group leaving 272 patients (99.6%) for the final analysis. In the ACL repair group, three patients were lost to follow-up leaving 134 patents (97.8%) for the final analysis. Secondary surgery was identified by contacting the patients by email/telephone and reviewing patient notes at the time of this analysis., Results: Re-rupture occurred in 32 patients (11.8%) in the ACL reconstruction group compared to 22 patients (16.4%) in the ACL repair group (p = 0.194). Contralateral ACL rupture occurred in four patients (1.5%) in the ACL reconstruction group compared to three patients (2.2%) in the ACL repair group (p = 0.224). In the ACL reconstruction group, nine patients (3.3%) required secondary meniscal surgery whilst five patients (3.7%) required meniscal surgery in the ACL repair group (p = 0.830). Seven other operations were performed in the ACL reconstruction group (2.6%) compared to three other operations in the ACL repair group (2.2%) (p = 0.374). The overall number of patients undergoing secondary surgery in the ACL reconstruction group was 52 (19.1%) in comparison to 30 (22.4%) in the ACL repair group (p = 0.114)., Conclusion: ACL repair with suture tape augmentation for acute proximal ruptures demonstrated comparable rates of secondary surgery with hamstring ACL reconstruction., (© 2022. The Author(s).)

Introduction: The medial patellofemoral ligament (MPFL) is the main restraining force against lateral patellar displacement in the first 20 degrees of knee flexion and is often disrupted following patellar subluxation or dislocation. MPFL reconstruction is commonly performed to restore patellar stability but requires autograft harvest with associated donor site morbidity. The aim of this study was to assess the five-year outcomes of MPFL repair performed with suture tape augmentation., Materials and Methods: All patients who underwent isolated MPFL repair for recurrent patellar instability between 2011 and 2017 were included. Patients requiring any additional surgery, such as osteotomy, were excluded. Patient-reported outcomes were measured at two-year follow up using the Knee Injury and Osteoarthritis Outcome (KOOS) Score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Visual Analogue Pain Scale (VAS-pain), Veterans RAND 12-Item Health Survey (VR-12), Marx Activity Scale, and an overall satisfaction questionnaire. At the end of the study period, any complications or secondary surgeries were determined., Results: Eighteen patients underwent MPFL repair with one lost to follow up. There was a significant improvement in all subscales of the KOOS scoring systems, the WOMAC functional score, and the VR-12 physical score. A significant decrease was seen in the VAS-pain score. A non-significant decrease was seen in the Marx activity scale from pre-injury. The majority of patients reported satisfaction with reduction in pain and return to sporting activities. There were no complications with no further instability episodes., Conclusion: This is the first study that describes the five-year follow-up results of patients treated with MPFL repair and suture tape augmentation. Our results show that this technique is an alternative treatment to traditional MPFL reconstruction with comparable outcomes and avoidance of autograft harvest.

Introduction: Rupture of the anterior cruciate ligament (ACL) often occurs in conjunction with meniscal tears. In this study, we investigate the rates and outcomes of meniscal repair surgery performed with ACL reconstruction compared with acute ACL repair surgery., Materials and Methods: Data was collected for all patients undergoing surgery for ACL ruptures between 2012 and 2018, including ACL reconstruction with hamstring autograft and primary ACL repair augmented with suture tape. Patients undergoing multi-ligament surgery were excluded. Meniscal injury was evaluated intraoperatively and the treatment was determined by type of tear, reducibility, and quality of meniscal tissue. If possible, tears were repaired using all-inside anchors and all others were resected., Results: There were 272 ACL reconstructions and 134 ACL repairs, and mean age was 28 (±9) and 35 (±14) years, respectively (p <0.01). The mean Tegner activity score was 6.6 in both groups. The mean interval from injury to surgery was longer in the reconstruction group (26.2 vs. 1.3 months, p <0.01). Fifty-five percent of reconstructions and 43% of ACL repairs required meniscal surgery at the time of their ACL procedure. In the reconstruction group, 123 (70%) were meniscectomies and 53 (30%) were meniscal repairs, compared to 31 (50%) of each in the ACL repair group. Meniscal repair was more likely to be possible when carried out as part of acute ACL repair surgery, c2(1, n=238)=7.94, p <0.01. The success rate of meniscal repair was 97% in both groups., Conclusions: The rate of meniscal repair is 67% higher when performed early with ACL repair. When ACL reconstruction is performed, meniscal resection was more likely. Rates of post-traumatic osteoarthritis are high after ACL reconstruction when performed with meniscal resection. Furthermore, the success rate of meniscal repair in conjunction with ACL surgery is high (97%). Therefore, meniscal repair should be encouraged whenever possible to improve long-term outcomes.

Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Primary repair of anterior cruciate ligament (ACL) ruptures has re-emerged as a treatment option for proximal tears, with internal brace augmentation often utilised. The aim of this study is to provide an overview of the current evidence presenting outcomes of ACL repair with internal bracing to assess the safety and efficacy of this technique., Methods: All studies reporting outcomes of arthroscopic primary repair of proximal ACL tears, augmented with internal bracing from 2014-2021 were included. Primary outcome was failure rate and secondary outcomes were subjective patient reported outcome measures (PROMs) and objective assessment of anteroposterior knee laxity., Results: Nine studies were included, consisting of 347 patients, mean age 32.5 years, mean minimum follow up 2 years. There were 36 failures (10.4%, CI 7.4% - 14.1%). PROMs reporting was variable across studies. KOOS, Lysholm and IKDC scores were most frequently used with mean scores > 87%. The mean Tegner and Marx scores at follow-up were 6.1 and 7.8 respectively. The mean side to side difference measured for anteroposterior knee laxity was 1.2mm., Conclusions: This systematic review with meta-analysis shows that ACL repair with internal bracing is a safe technique for treatment of proximal ruptures, with a failure rate of 10.4%. Subjective scores and clinical laxity testing also revealed satisfactory results. This suggests that ACL repair with internal bracing should be considered as an alternative to ACL reconstruction for acute proximal tears, with the potential benefits of retained native tissue and proprioception, as well as negating the need for graft harvest., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Multiligament injury of the knee usually occurs as a result of high-energy trauma causing tibiofemoral dislocation. These are rare but potentially limb-threatening injuries, frequently involving nerve or arterial damage and often leading to severe complex instability. Management generally favours surgical reconstruction of the affected ligaments, with controversy regarding optimal treatment. We present a severe multiligament knee injury (Schenk classification KD-IV involving both cruciate and both collateral ligaments) in a competitive showjumper. A combined arthroscopic/open technique of single-stage surgical repair and suture augmentation was used, repairing all affected ligaments. The patient made an excellent recovery, returning to work after 12 weeks and riding after 22 weeks. After 5-year follow-up, she has regained her previous level of competition without subsequent injury. Multiligament repair with suture augmentation is a viable approach to the management of knee dislocation injuries. We propose that this could provide superior outcomes to traditional reconstruction techniques using autograft or synthetic reconstruction., Competing Interests: Competing interests: GMM is a paid consultant for Arthrex, whose products were used in this case., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: An enhanced understanding of anterior cruciate ligament (ACL) healing and advancements in arthroscopic instrumentation has resulted in a renewed interest in ACL repair. Augmentation of a ligament repair with suture tape reinforces the ligament and acts as a secondary stabilizer. This study assesses the 5-year patient-reported outcomes of primary repair with suture tape augmentation for proximal ACL tears., Methods: Thirty-seven consecutive patients undergoing ACL repair with suture tape augmentation for an acute proximal rupture were prospectively followed up for a minimum of 5 years. Patients with midsubstance and distal ruptures, poor ACL tissue quality, retracted ACL remnants and multiligament injuries were excluded. Patient-reported outcome measures were collated using the Knee Injury and Osteoarthritis Outcomes Score (KOOS), Visual Analogue Pain Scale (VAS-pain), Veterans RAND 12-Item Health Survey (VR-12) and the Marx Activity Scale. Patients with a re-rupture were identified., Results: Three patients were lost to follow-up leaving 34 patients in the final analysis (91.9%). The mean KOOS at 5 years was 88.5 (SD 13.8) which improved significantly from 48.7 (SD 18.3) preoperatively (p < 0.01). The VAS score improved from 2.3 (SD 1.7) to 1.0 (SD 1.5) and the VR-12 score improved from 35.9 (SD 10.3) to 52.4 (SD 5.9) at 5 years (p < 0.01). However, the Marx activity scale decreased from 12.4 (SD 3.4) pre-injury to 7.3 (SD 5.2) at 5 years (p = 0.02). Six patients had a re-rupture (17.6%) and have since undergone a conventional ACL reconstruction for their revision surgery with no issues since then. These patients were found to be younger and have higher initial Marx activity scores than the rest of the cohort (p < 0.05)., Conclusion: Primary repair with suture tape augmentation for proximal ACL tears demonstrates satisfactory outcomes in 28 patients (82.4%) at 5-year follow-up. Six patients sustained a re-rupture and have no ongoing problems following treatment with a conventional ACL reconstruction. These patients were significantly younger and had higher initial Marx activity scores., Level of Evidence: Level IV., (© 2021. The Author(s).)

Androgen deprivation therapy (ADT) is the standard of care for treatment of nonresectable prostate cancer. Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three in vivo , androgen receptor (AR)-responsive orthograft models of matched hormone-naïve prostate cancer and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome. In vivo, SLFN5 depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signaling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in patients with CRPC and further highlight SLFN5 as a clinically relevant target for CRPC. SIGNIFICANCE: This study identifies SLFN5 as a novel regulator of the LAT1 amino acid transporter and an essential contributor to mTORC1 activity in castration-resistant prostate cancer., (©2021 American Association for Cancer Research.)

Purpose: The posterior cruciate ligament (PCL) is an important stabilizer of the knee and can be damaged in up to 20% of ligamentous injuries. Numerous techniques for surgical treatment have been described in the literature with none shown to be clearly superior. The aim of this study was to assess the 2-year outcomes of PCL repair with suture tape augmentation., Methods: Seventeen patients undergoing PCL repair with suture tape augmentation were prospectively followed up for a minimum of two years. One patient was lost to follow-up leaving sixteen patients in the final analysis (94.1%). Indications for this procedure were acute Grade III PCL ruptures, symptomatic chronic tears and PCL tears as part of a multi-ligament injury. Exclusion criteria were patients with retracted PCL remnants or poor tissue quality. Patient-reported outcomes were measured using the Knee Injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Visual Analogue Pain Scale (VAS-pain), Veterans RAND 12 Item Health Survey (VR-12) and Marx Activity Scale. Patients with any postoperative complications were identified. Mean differences between the outcomes pre-operatively and at two years postoperatively were evaluated using paired t-tests with significance set at p < 0.05., Results: The mean KOOS at 2 years was 87.0, 75.5, 93.0, 69.6 and 54.2 for pain, symptoms, ADL, sport/recreation and QOL respectively. These improved significantly from 60.2, 49.8, 65.0, 33.0 and 34.2 preoperatively (p < 0.05). The mean WOMAC scores at 2 years were 91.0, 78.3 and 93.0 for pain, stiffness and function respectively. These improved significantly from 63.0, 51.7 and 65.0 preoperatively (p < 0.01). The VAS score improved from 3.0 to 0.8 (p < 0.01) and the VR-12 score improved from 34.9 to 50.9 at 2 years (p < 0.001). However, the Marx activity scale decreased from 8.7 pre-injury to 6.3 at 2 years (N.S.). One patient (6.3%) suffered a re-rupture., Conclusion: PCL repair with suture tape augmentation demonstrates satisfactory patient reported outcome measures at minimum 2-year follow-up. These figures compare favorably with success rates described in the literature for PCL reconstruction techniques. Therefore, PCL repair with suture tape augmentation is an effective treatment option in selected patients., Level of Evidence: IV.

The anterior cruciate ligament (ACL) is the most commonly injured ligament in the knee, with injury usually occurring as a result of multidirectional sports. The incidence of ACL injury has continued to increase, with most patients opting for surgery to improve stability as well as permit a return to sport. Traditional methods of ACL reconstruction can achieve this but are not without their problems, including graft rupture, residual laxity, and donor-site morbidity. There is therefore a requirement for further research into newer, innovative surgical techniques to help improve complication rates. This article describes, with video illustration, ACL reconstruction using a reduced-size bone-patellar tendon-bone autograft with suture tape augmentation. The augmentation acts as a stabilizer during the early stages of graft incorporation while resisting against reinjury during an accelerated recovery. The ability to use a reduced-size graft decreases the donor-site burden, and retention of residual native ACL tissue, when possible, may help with proprioception., (Crown Copyright © 2020 Published by Elsevier on behalf of the Arthroscopy Association of North America.)

Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.

Background: The anterolateral ligament (ALL) contributes to anterolateral rotational stability of the knee. Internal bracing of the anterior cruciate ligament (ACL) and ALL reinforces the ligaments and encourages natural healing by protecting both during the healing phase and supporting early mobilization., Purpose/hypothesis: To assess the 2-year patient-reported outcomes of combined ACL repair and ALL internal brace augmentation. We hypothesized that significant improvements in outcomes would be seen., Study Design: Case series; Level of evidence, 4., Methods: A total of 43 consecutive patients with acute proximal ACL ruptures were prospectively evaluated for a minimum of 2 years. The mean age at the time of surgery was 25.7 years (range, 13-56 years). Indications for the combined ACL/ALL procedure were associated Segond fractures, grade 3 pivot shift, or high levels of sporting activity. Patients with chronic ruptures or with multiligament injuries were excluded. The Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analog scale (VAS) for pain, Veterans RAND 12-Item Health Survey (VR-12), and Marx activity scale were collected preoperatively and at 12 and 24 months postoperatively. Patients with any postoperative complications were identified at the time of this analysis., Results: The mean follow-up period was 44.8 months. Five patients were lost to follow-up, leaving 38 patients (88.4%) in the final analysis. The mean KOOS for Pain, Symptoms, Activities of Daily Living, Sport/Recreation, and Quality of Life improved from a respective 64.9, 58.6, 75.0, 33.7, and 28.9 preoperatively to 91.1, 81.8, 96.1, 82.8, and 74.3 at the 2-year follow-up ( P < .0001). The mean WOMAC scores for pain, stiffness, and function improved from 77.5, 65.3, and 75.0 preoperatively to 94.6, 88.6, and 96.0 at the 2-year follow-up ( P < .0001). The VAS pain score improved from 3.4 preoperatively to 0.7 at the 2-year follow-up, and the VR-12 physical score improved from 34.4 preoperatively to 52.7 at the 2-year follow-up ( P < .0001 for both ). However, the Marx activity score decreased from 13.3 preinjury to 10.6 at the 2-year follow-up ( P = .01). Two patients (5.3%) sustained a rerupture., Conclusion: Combined ACL repair and ALL internal brace augmentation demonstrated excellent outcomes in 94.7% of the study patients. Based on our experience with this cohort as well as our isolated ACL repair data, we suggest that high-risk patients with ACL ruptures have an additional ALL procedure to provide rotational stability., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: G.M.M. is a consultant for and receives royalties from Arthrex. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2020.)

The most common injury sustained to the ankle ligaments is a result of inversion of the foot. This mechanism results in injury to the anterior talofibular ligament alone or in conjunction with the calcaneofibular ligament and posterior talofibular ligament. Patients experiencing recurrent ankle sprains despite nonoperative measures often require surgical management. Recent focus has been on augmentation procedures to improve the stability of a lateral ankle ligament repair by protecting it during the healing phase and supporting early mobilization. This article describes, with video illustration, anterior talofibular ligament repair with suture tape augmentation., (© 2020 by the Arthroscopy Association of North America. Published by Elsevier.)

BH3-mimetics are a new class of anti-cancer drugs that inhibit anti-apoptotic Bcl-2 proteins. In doing so, BH3-mimetics sensitise to cell death. Venetoclax is a potent, BCL-2 selective BH3-mimetic that is clinically approved for use in chronic lymphocytic leukaemia. Venetoclax has also been shown to inhibit mitochondrial metabolism, this is consistent with a proposed role for BCL-2 in metabolic regulation. We used venetoclax to understand BCL-2 metabolic function. Similar to others, we found that venetoclax inhibited mitochondrial respiration. In addition, we also found that venetoclax impairs TCA cycle activity leading to activation of reductive carboxylation. Importantly, the metabolic effects of venetoclax were independent of cell death because they were also observed in apoptosis-resistant BAX/BAK-deficient cells. However, unlike venetoclax treatment, inhibiting BCL-2 expression had no effect on mitochondrial respiration. Unexpectedly, we found that venetoclax also inhibited mitochondrial respiration and the TCA cycle in BCL-2 deficient cells and in cells lacking all anti-apoptotic BCL-2 family members. Investigating the basis of this off-target effect, we found that venetoclax-induced metabolic reprogramming was dependent upon the integrated stress response and ATF4 transcription factor. These data demonstrate that venetoclax affects cellular metabolism independent of BCL-2 inhibition. This off-target metabolic effect has potential to modulate venetoclax cytotoxicity.

Aldehyde dehydrogenase class 3, encoded by ADH5 in humans, catalyzes the glutathione dependent detoxification of formaldehyde. Here we show that ADH5 deficient cells turn over formaldehyde using alternative pathways starting from the reaction of formaldehyde with free amino acids. When mammalian cells are exposed to formaldehyde, the levels of the reaction products of formaldehyde with the amino acids cysteine and histidine - timonacic and spinacine - are increased. These reactions take place spontaneously and the formation of timonacic is reversible. The levels of timonacic are higher in the plasma of Adh5 -/- mice relative to controls and they are further increased upon administration of methanol. We conclude that mammals possess pathways of cysteine and histidine dependent formaldehyde metabolism and that timonacic is a formaldehyde reservoir., (© 2020. The Author(s).)

Meniscal tears are the most common indication for knee surgery. An appreciation of the limitations associated with the gold-standard inside-out meniscal repair technique has resulted in the development of newer all-inside techniques that overcome many of these issues. This paper describes, with a video illustration available online, a one-handed all-inside meniscal repair technique using the Meniscal Cinch™ II (Arthrex, Inc., Naples, FL).

Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this study, we perform a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors (ARI). Combined proteomics and metabolomics analyses implicate an acquired metabolic phenotype common in ARI-resistant cells and associated with perturbed glucose and lipid metabolism. To exploit this phenotype, we delineate a subset of proteins consistently associated with ARI resistance and highlight mitochondrial 2,4-dienoyl-CoA reductase (DECR1), an auxiliary enzyme of beta-oxidation, as a clinically relevant biomarker for CRPC. Mechanistically, DECR1 participates in redox homeostasis by controlling the balance between saturated and unsaturated phospholipids. DECR1 knockout induces ER stress and sensitises CRPC cells to ferroptosis. In vivo, DECR1 deletion impairs lipid metabolism and reduces CRPC tumour growth, emphasizing the importance of DECR1 in the development of treatment resistance.

Formate is a precursor for the de novo synthesis of purine and deoxythymidine nucleotides. Formate also interacts with energy metabolism by promoting the synthesis of adenine nucleotides. Here we use theoretical modelling together with metabolomics analysis to investigate the link between formate, nucleotide and energy metabolism. We uncover that endogenous or exogenous formate induces a metabolic switch from low to high adenine nucleotide levels, increasing the rate of glycolysis and repressing the AMPK activity. Formate also induces an increase in the pyrimidine precursor orotate and the urea cycle intermediate argininosuccinate, in agreement with the ATP-dependent activities of carbamoyl-phosphate and argininosuccinate synthetase. In vivo data for mouse and human cancers confirms the association between increased formate production, nucleotide and energy metabolism. Finally, the in vitro observations are recapitulated in mice following and intraperitoneal injection of formate. We conclude that formate is a potent regulator of purine, pyrimidine and energy metabolism.

The medial collateral ligament (MCL) is among the most commonly injured structures of the knee. Most cases are managed nonoperatively; however, grade III injuries and injuries associated with multiligament injuries to the knee are often managed surgically. MCL reconstruction procedures are the most widely used surgical option, but modern advancements have seen a renewed interest in ligamentous repair that avoids graft-site morbidity. In addition, augmentation of the repair protects the ligament during the healing phase and allows early mobilization. This article describes, with video illustration, percutaneous MCL repair and posteromedial corner repair with suture tape augmentation., (© 2020 by the Arthroscopy Association of North America. Published by Elsevier.)

The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Anterior cruciate ligament (ACL) reconstruction with hamstring or patellar tendon autograft has been the gold standard for the operative treatment of an ACL rupture for many years. Repair with Internal Brace Ligament Augmentation (IBLA) is a new technique that uses ultra-high strength tape (FiberTape, Arthrex, Naples, FL, USA) to bridge the ligament. This technique reinforces the ligament as a secondary stabiliser, encouraging natural healing of the ligament by protecting it during the healing phase and supporting early mobilisation., Case Description: This retrospective case report focuses on the rehabilitation of a 21-year-old male professional soccer player who ruptured his ACL in a contact injury whilst playing a competitive game. He underwent ACL repair with IBLA two weeks following injury. The six-month rehabilitation programme consisted of gradual progressions for mobility, proprioception, strengthening, cardiovascular maintenance and running in conjunction with physiotherapy to assist with the maintenance of soft tissue quality, pain management and control of oedema., Results: After completing the rehabilitation programme, the patient returned to unrestricted sporting activity within six months. At 18-month follow-up, the patient continues to play at the same competitive level without any issues., Conclusion: This rehabilitation programme after ACL repair with IBLA successfully enabled a professional soccer player to return to his pre-injury playing level.

Background: Serum and urine metabolites have been investigated for their use as cancer biomarkers. The specificity of candidate metabolites can be limited by the impact of other disorders on metabolite levels. In particular, the increasing incidence of obesity could become a significant confounding factor., Methods: Here we developed a multinomial classifier for the stratification of cancer, obesity and healthy phenotypes based on circulating glucose and formate levels. We quantified the classifier performance from the retrospective analysis of samples from breast cancer, lung cancer, obese individuals and healthy controls., Results: We discovered that circulating formate levels are significantly lower in breast and lung cancer patients than in healthy controls. However, the performance of a cancer classifier based on formate levels alone is limited because obese patients also have low serum formate levels. By introducing a multinomial classifier based on circulating glucose and formate levels, we were able to improve the classifier performance, reaching a true positive rate of 79% with a false positive rate of 8%., Conclusions: Circulating formate is reduced in HER2+ breast cancer, non-small cell lung cancer and highly obese patients relative to healthy controls. Further studies are required to determine the relevance of these observations in other cancer types and diseases., Competing Interests: For the healthy controls, diabetes patients and long cancer patients, written informed consent was obtained from all participants as required by the ethics committee of the Hospital Universitari Sant Joan de Reus (Reus, Spain). For the breast cancer cohort, written informed consent was obtained from all participants as required by the ethics committee of the Dr. Josep Trueta Hospital (Girona, Spain) and independent Institutional Review Boards at each site participating in the METTEN study. All procedures were in accordance with the ethical standards of the institutional research committees and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.Not applicable.The authors declare that they have no competing interest.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Purpose: The treatment of acute anterior cruciate ligament (ACL) ruptures with a repair technique has recently regained interest. A novel ACL repair technique was described using Independent Suture Tape Reinforcement with 2-year follow-up results., Methods: Forty-two consecutive patients with an acute ACL rupture undergoing repair using this technique were followed up for a minimum of 2 years. Patients with mid-substance, distal ACL ruptures, poor ACL tissue quality or retracted ACL remnants as well as patients with multi-ligament injuries were excluded. Knee Injury and Osteoarthritis Outcome Score (KOOS), Visual Analogue Pain Scale (VAS-pain), Veterans RAND 12 Item Health Survey (VR-12) and the Marx Activity scale were collected by online questionnaires. Two-year postoperative patients were asked by telephone if they had experienced a rerupture., Results: All the KOOS subscales improved significantly in comparison to the preoperative score. The largest improvement of all scores was seen at 3 months postoperatively which is significant in all cases. The KOOS sport and recreation showed a meaningful change and the largest improvement of the KOOS subscales at 3 months postoperatively, as well as the highest total improvement at 1 year postoperatively compared to preoperatively. The VAS-pain and VR-12 physical score improved significantly, however the Marx activity scale decreased significantly in comparison to preoperative scores. Two patients reported a rerupture (4.8%, CI 1.7-11.2%)., Conclusions: This is the first case series that described the 2-year follow-up results of patients with an acute, proximal ACL rupture, treated with the Independent Suture Tape Reinforcement repair technique. A meaningful KOOS sport and recreation change and significant improvements in the KOOS, VAS-pain and VR-12 physical scores as well as a significant decrease of the Marx activity scale in comparison to preoperative scores are demonstrated. Two of the 42 patients (4.8%) reported an ACL rerupture. Repair with this technique could be clinically relevant as a treatment option for patients with an acute, proximal ACL rupture which is not retracted and of good tissue quality., Level of Evidence: IV.

The ulnar collateral ligament (UCL) is the primary restraint to valgus angulation at the elbow. Injury to the UCL is increasingly common and can lead to instability, especially in athletes involved in overhead throwing. Conventional treatment is reconstruction using tendon autograft but performance levels are often restricted after long periods of rehabilitation. Modern surgical techniques have led to renewed interest in repair of the ligament, with the aim of restoring native anatomy. This has the benefit of retained proprioception and no graft harvest morbidity. Furthermore, augmentation of the repair with an Internal Brace protects the healing ligament, while allowing early rehabilitation and accelerated return to play. Here we present the first patient treated with this technique who achieved excellent recovery with return to college level American Football after 4 months. Five years later he has good elbow function and plays at the same level., Competing Interests: Competing interests: GMM is a consultant for Arthrex (see attached COI form)., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

The medial patellofemoral ligament (MPFL) is the main restraining force in the first 20° of flexion against lateral patellar displacement and is disrupted after patellar subluxation or dislocation. MPFL reconstruction is frequently performed when conservative management fails and the patient has recurrent patellar dislocations. However, a variety of complications have been reported in the literature with this procedure. Internal bracing with suture tape augmentation encourages healing and allows early mobilization. This article describes, with video illustration, MPFL repair with suture tape augmentation.

The posterior cruciate ligament (PCL) acts as the primary restraint to posterior tibial translation of the knee. Injuries to the PCL are rare in isolation and more often are associated with multiligament injuries to the knee. Several PCL reconstruction and PCL repair techniques have been described in the literature, but no single technique has been shown to be the most superior. Internal bracing with suture tape augmentation encourages natural healing and allows early mobilization. This article describes, with video illustration, PCL repair with suture tape augmentation.

The posterolateral corner (PLC) of the knee is the main restraint to varus forces of the knee as well as posterolateral rotation of the tibia relative to the femur. Primary PLC repairs have been associated with a high failure rate in past literature. However, with modern improved arthroscopic instrumentation and devices, there has been a renewed interest in repair of the ligaments around the knee. Internal bracing with suture tape augmentation encourages healing and allows early mobilization. This article describes, with video illustration, PLC repair with suture tape augmentation.

Recent insights into the structure and function of the anterolateral ligament (ALL) of the knee has resulted in a recognition of its contribution in rotational control of the knee. Several ALL reconstruction techniques have been described in the literature. This article describes, with video illustration, a percutaneous repair technique using suture tape augmentation. A tendon graft is not needed. This technique allows early mobilization and encourages natural healing of the ligament by protecting the ligament during the healing phase as a secondary stabilizer.

Introduction: Injury of the acromioclavicular joint (AC joint) is one of the most common conditions affecting the shoulder girdle in athletes, particularly in contact sports. It is generally agreed that surgical management provides superior outcomes in high-grade injuries (Rockwell Grades IV-VI), with nonoperative management preferred in low-grade injuries (Grades I-II). Controversy still exists regarding the optimal treatment for Grade III injuries, with various sources reporting quicker return to activity and reduced complications with nonoperative management, but superior long-term function and satisfaction in cases managed surgically. Mean predicted return to sporting action in surgical cases varies in the literature from four months to 9.5 months.

Recently there has been renewed interest in primary repair of the anterior cruciate ligament (ACL). Repair of the acute proximal ruptured ACL can be achieved with the independent suture tape reinforcement ACL repair technique. The independent suture tape reinforcement technique reinforces the ligament as a secondary stabilizer, encouraging natural healing of the ligament by protecting it during the healing phase and supporting early mobilization. The purpose of this article is to describe, with video illustration, this ACL repair technique.

Formate overflow coupled to mitochondrial oxidative metabolism\ has been observed in cancer cell lines, but whether that takes place in the tumor microenvironment is not known. Here we report the observation of serine catabolism to formate in normal murine tissues, with a relative rate correlating with serine levels and the tissue oxidative state. Yet, serine catabolism to formate is increased in the transformed tissue of in vivo models of intestinal adenomas and mammary carcinomas. The increased serine catabolism to formate is associated with increased serum formate levels. Finally, we show that inhibition of formate production by genetic interference reduces cancer cell invasion and this phenotype can be rescued by exogenous formate. We conclude that increased formate overflow is a hallmark of oxidative cancers and that high formate levels promote invasion via a yet unknown mechanism.

Melanoma cells steer out of tumours using self-generated lysophosphatidic acid (LPA) gradients. The cells break down LPA, which is present at high levels around the tumours, creating a dynamic gradient that is low in the tumour and high outside. They then migrate up this gradient, creating a complex and evolving outward chemotactic stimulus. Here, we introduce a new assay for self-generated chemotaxis, and show that raising LPA levels causes a delay in migration rather than loss of chemotactic efficiency. Knockdown of the lipid phosphatase LPP3 - but not of its homologues LPP1 or LPP2 - diminishes the cell's ability to break down LPA. This is specific for chemotactically active LPAs, such as the 18:1 and 20:4 species. Inhibition of autotaxin-mediated LPA production does not diminish outward chemotaxis, but loss of LPP3-mediated LPA breakdown blocks it. Similarly, in both 2D and 3D invasion assays, knockdown of LPP3 diminishes the ability of melanoma cells to invade. Our results demonstrate that LPP3 is the key enzyme in the breakdown of LPA by melanoma cells, and confirm the importance of attractant breakdown in LPA-mediated cell steering.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

This corrects the article DOI: 10.1038/nature22056.

Despite extensive research, the management of acute ruptures of the Achilles tendon remains an area of controversy, and there is no consensus regarding the optimal treatment. An InternalBrace™ (Arthrex, Inc., Naples, Florida) is a ligament augmentation repair using high strength sutures/tape and knotless bone anchors which encourages healing and allows early mobilization. This article describes, with video illustration, a knotless Achilles tendon repair technique using the InternalBrace™ principle.

The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis, many others rely on exogenous serine for optimal growth. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

Rupture of the Achilles tendon is an increasingly common injury, particularly in physically active males, and current evidence favors minimally invasive surgical repair. We describe the case of a 36-year-old male elite bobsled athlete with complete rupture of the Achilles tendon. He was treated with surgical repair of the ruptured tendon using an innovative, minimally invasive procedure based on an internal bracing concept and was able to undergo early mobilization and aggressive physiotherapy rehabilitation. His recovery was such that he returned to training at 13 weeks postoperatively and participated in an international competition at 18 weeks, winning a World Cup silver medal. He subsequently raced at the 2014 Winter Olympic Games at 29 weeks after surgery. At >2 years since his injury, he has experienced no complications or reinjury. This represents an exceptional recovery that far exceeds the standard expected for such injuries. The use of this technique for athletes could enable accelerated return to sporting activity and attainment of their preinjury activity levels., (Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Serine catabolism to glycine and a one-carbon unit has been linked to the anabolic requirements of proliferating mammalian cells. However, genome-scale modeling predicts a catabolic role with one-carbon release as formate. We experimentally prove that in cultured cancer cells and nontransformed fibroblasts, most of the serine-derived one-carbon units are released from cells as formate, and that formate release is dependent on mitochondrial reverse 10-CHO-THF synthetase activity. We also show that in cancer cells, formate release is coupled to mitochondrial complex I activity, whereas in nontransformed fibroblasts, it is partially insensitive to inhibition of complex I activity. We demonstrate that in mice, about 50% of plasma formate is derived from serine and that serine starvation or complex I inhibition reduces formate synthesis in vivo. These observations transform our understanding of one-carbon metabolism and have implications for the treatment of diabetes and cancer with complex I inhibitors.

Background: Anterior cruciate ligament (ACL) reconstruction using tendon or ligament autograft is the gold standard surgical treatment for acute ruptures; however, this is still associated with subsequent problems and variable outcomes. Renewed interest in healing of injured ACL tissue has led to new surgical repair techniques., Case Description: We report the case of one of the first patients to undergo this novel procedure of ACL repair with internal bracing. An internal brace is a bridging concept using braided suture tape and knotless bone anchors to reinforce ligament strength. We followed the case of one of the first patients to undergo this technique over two years post-operatively., Outcomes: In this case, we present a good functional outcome along with radiographic and arthroscopic evidence of a healed ACL with normal appearance. The successful application of this technique has been demonstrated., Discussion: ACL repair techniques are re-emerging as a promising treatment option for acute proximal ruptures. Repair of the ACL can be performed successfully and has the advantage of retaining the natural proprioceptive fibres of the ligament. The internal brace acts as a secondary stabiliser after repair, which may allow accelerated rehabilitation and return to sports, whilst resisting injury recurrence when this is possible., Conclusions: Repair with internal bracing of the ACL provides an unobtrusive support which allows accelerated recovery. In this case, we demonstrate with radiographic and arthroscopic evidence, a robustly healed ACL after repair with internal bracing. Functional outcomes are excellent over two years following surgery and long term; retained proprioception may prevent re-injury and development of post-traumatic osteoarthritis.

Chemotaxis is fundamentally important, but the sources of gradients in vivo are rarely well understood. Here, we analyse self-generated chemotaxis, in which cells respond to gradients they have made themselves by breaking down globally available attractants, using both computational simulations and experiments. We show that chemoattractant degradation creates steep local gradients. This leads to surprising results, in particular the existence of a leading population of cells that moves highly directionally, while cells behind this group are undirected. This leading cell population is denser than those following, especially at high attractant concentrations. The local gradient moves with the leading cells as they interact with their surroundings, giving directed movement that is unusually robust and can operate over long distances. Even when gradients are applied from external sources, attractant breakdown greatly changes cells' responses and increases robustness. We also consider alternative mechanisms for directional decision-making and show that they do not predict the features of population migration we observe experimentally. Our findings provide useful diagnostics to allow identification of self-generated gradients and suggest that self-generated chemotaxis is unexpectedly universal in biology and medicine.

This article reviews the surgical decision-making considerations when preparing to undertake an anatomic ligament repair with augmentation using the InternalBrace™. Lateral ankle ligament stabilization of the Broström variety and ACL repair in particular are used to illustrate its application. The InternalBrace™ supports early mobilization of the repaired ligament and allows the natural tissues to progressively strengthen. The principle established by this experience has resulted in its successful application to other distal extremity ligaments including the deltoid, spring, and syndesmosis complex. Knee ligament augmentation with the InternalBrace™ has been successfully applied to all knee ligaments including anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), lateral collateral ligament (LCL), anterolateral ligament (ALL), and patellofemoral ligament (PFL). The surgical technique and early results will be reviewed including multi-ligament presentations. Upper limb experience with acromioclavicular (AC) joint augmentation and ulnar collateral ligament (UCL) repair of the elbow with the InternalBrace™ will also be discussed. This article points to a change in orthopaedic practice positioning reconstruction as a salvage procedure that has additional surgical morbidity and should be indicated only if the tissues fail to heal adequately after augmentation and repair.

Here we discuss our methods to analyze small polar compounds involved in central carbon metabolism using LC-MS. Methods described include sample extraction procedures for cells and medium, as well as for plasma/serum, urine, CSF, and tissue samples. Different extraction solvents are assessed. Our methods for using (13)C stable isotope tracers to examine the kinetics and distributions of mass isotopologues of many metabolites are discussed. Quantification methods are described for (13)C stable isotope tracer experiments as well as for unlabeled experiments. These methods were applied in a fumarate hydratase deficient cell model to show how isotope tracing can demonstrate shifts in metabolic pathways and, together with metabolite exchange rates, can be used to gain insights into changes in cell metabolism., (© 2015 Elsevier Inc. All rights reserved.)

Previous work has shown that some cancer cells are highly dependent on serine/glycine uptake for proliferation. Although serine and glycine can be interconverted and either might be used for nucleotide synthesis and one-carbon metabolism, we show that exogenous glycine cannot replace serine to support cancer cell proliferation. Cancer cells selectively consumed exogenous serine, which was converted to intracellular glycine and one-carbon units for building nucleotides. Restriction of exogenous glycine or depletion of the glycine cleavage system did not impede proliferation. In the absence of serine, uptake of exogenous glycine was unable to support nucleotide synthesis. Indeed, higher concentrations of glycine inhibited proliferation. Under these conditions, glycine was converted to serine, a reaction that would deplete the one-carbon pool. Providing one-carbon units by adding formate rescued nucleotide synthesis and growth of glycine-fed cells. We conclude that nucleotide synthesis and cancer cell proliferation are supported by serine--rather than glycine--consumption., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiac surgery involving extra-corporeal circulation can lead to cognitive dysfunction. As such surgery is associated with signs of inflammation and pro-inflammatory mediators activate tryptophan oxidation to neuroactive kynurenines which modulate NMDA receptor function and oxidative stress, we have measured blood concentrations of kynurenines and inflammatory markers in 28 patients undergoing coronary arterial graft surgery and, for comparison, 28 patients undergoing non-bypass thoracic surgery. A battery of cognitive tests was completed before and after the operations. The results show increased levels of tryptophan with decreased levels of kynurenine, anthranilic acid and 3-hydroxyanthranilic acid associated with bypass, and a later increase in kynurenic acid. Levels of neopterin and lipid peroxidation products rose after surgery in non-bypass patients whereas tumour necrosis factor-α and S100B levels increased after bypass. Changes of neopterin levels were greater after non-bypass surgery. Cognitive testing showed that the levels of tryptophan, kynurenine, kynurenic acid and the kynurenine/tryptophan ratio, correlated with aspects of post-surgery cognitive function, and were significant predictors of cognitive performance in tasks sensitive to frontal executive function and memory. Thus, anaesthesia and major surgery are associated with inflammatory changes and alterations in tryptophan oxidative metabolism which predict, and may play a role in, post-surgical cognitive function., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

There is substantial evidence that abnormal concentrations of oxidised tryptophan metabolites, produced via the kynurenine pathway, contribute to progressive neurodegeneration in Huntington's disease. We have now examined the blood levels of these metabolites in patients at different stages of Huntington's disease, assessed both in terms of clinical disease severity and numbers of CAG repeats. Close relatives of the patients were included in the study as well as unrelated healthy controls. Levels of lipid peroxidation products, the pro-inflammatory cytokine interleukin (IL)-23 and the soluble human leucocyte antigen-G (sHLA-G) were also measured. There were lower levels of tryptophan and a higher kynurenine : tryptophan ratio, indicating activation of indoleamine-2,3-dioxygenase, in the most severely affected group of patients, with increased levels of IL-23 and sHLA-G. Marked correlations were noted between IL-23 and the patient severity group, anthranilic acid levels and the number of CAG repeats, and between anthranilic acid and IL-23, supporting our previous evidence of a relationship between anthranilic acid and inflammatory status. Tryptophan was negatively correlated with symptom severity and number of CAG repeats, and positively correlated with sHLA-G. The results support the proposal that tryptophan metabolism along the kynurenine pathway in Huntington's disease is related to the degree of genetic abnormality, to clinical disease severity and to aspects of immunopathogenesis.