Interventions for treating proximal humeral fractures in adults.

BACKGROUND: Fractures of the proximal humerus, often termed shoulder fractures, are common injuries, especially in older people. The management of these fractures varies widely, including in the use of surgery. This is an update of a Cochrane Review first published in 2001 and last updated in 2015. OBJECTIVES: To assess the effects (benefits and harms) of treatment and rehabilitation interventions for proximal humeral fractures in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, trial registries, and bibliographies of trial reports and systematic reviews to September 2020. We updated this search in November 2021, but have not yet incorporated these results. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that compared non-pharmacological interventions for treating acute proximal humeral fractures in adults.  DATA COLLECTION AND ANALYSIS: Pairs of review authors independently selected studies, assessed risk of bias and extracted data. We pooled data where appropriate and used GRADE for assessing the certainty of evidence for each outcome. We prepared a brief economic commentary for one comparison. MAIN RESULTS: We included 47 trials (3179 participants, mostly women and mainly aged 60 years or over) that tested one of 26 comparisons. Six comparisons were tested by 2 to 10 trials, the others by small single-centre trials only. Twelve studies evaluated non-surgical treatments, 10 compared surgical with non-surgical treatments, 23 compared two methods of surgery, and two tested timing of mobilisation after surgery. Most trials were at high risk of bias, due mainly to lack of blinding. We summarise the findings for four key comparisons below. Early (usually one week post injury) versus delayed (after three or more weeks) mobilisation for non-surgically-treated fractures Five trials (350 participants) made this comparison; however, the available data are very limited. Due to very low-certainty evidence from single trials, we are uncertain of the findings of better shoulder function at one year in the early mobilisation group, or the findings of little or no between-group difference in function at 3 or 24 months. Likewise, there is very low-certainty evidence of no important between-group difference in quality of life at one year. There was one reported death and five serious shoulder complications (1.9% of 259 participants), spread between the two groups, that would have required substantive treatment. Surgical versus non-surgical treatment Ten trials (717 participants) evaluated surgical intervention for displaced fractures (66% were three- or four-part fractures). There is high-certainty evidence of no clinically important difference between surgical and non-surgical treatment in patient-reported shoulder function at one year (standardised mean difference (SMD) 0.10, 95% confidence interval (CI) -0.07 to 0.27; 7 studies, 552 participants) and two years (SMD 0.06, 95% CI -0.13 to 0.25; 5 studies, 423 participants). There is moderate-certainty evidence of no clinically important between-group difference in patient-reported shoulder function at six months (SMD 0.17, 95% CI -0.04 to 0.38; 3 studies, 347 participants). There is high-certainty evidence of no clinically important between-group difference in quality of life at one year (EQ-5D (0: dead to 1: best quality): mean difference (MD) 0.01, 95% CI -0.02 to 0.04; 6 studies, 502 participants). There is low-certainty evidence of little between-group difference in mortality: one of the 31 deaths was explicitly linked with surgery (risk ratio (RR) 1.35, 95% CI 0.70 to 2.62; 8 studies, 646 participants). There is low-certainty evidence of a higher risk of additional surgery in the surgery group (RR 2.06, 95% CI 1.21 to 3.51; 9 studies, 667 participants). Based on an illustrative risk of 35 subsequent operations per 1000 non-surgically-treated patients, this indicates an extra 38 subsequent operations per 1000 surgically-treated patients (95% CI 8 to 94 more). Although there was low-certainty evidence of a higher overall risk of adverse events after surgery, the 95% CI also includes a slightly increased risk of adverse events after non-surgical treatment (RR 1.46, 95% CI 0.92 to 2.31; 3 studies, 391 participants). Open reduction and internal fixation with a locking plate versus a locking intramedullary nail Four trials (270 participants) evaluated surgical intervention for displaced fractures (63% were two-part fractures). There is low-certainty evidence of no clinically important between-group difference in shoulder function at one year (SMD 0.15, 95% CI -0.12 to 0.41; 4 studies, 227 participants), six months (Disability of the Arm, Shoulder, and Hand questionnaire (0 to 100: worst disability): MD -0.39, 95% CI -4.14 to 3.36; 3 studies, 174 participants), or two years (American Shoulder and Elbow Surgeons score (ASES) (0 to 100: best outcome): MD 3.06, 95% CI -0.05 to 6.17; 2 studies, 101 participants). There is very low-certainty evidence of no between-group difference in quality of life (1 study), and of little difference in adverse events (4 studies, 250 participants) and additional surgery (3 studies, 193 participants). Reverse total shoulder arthroplasty (RTSA) versus hemiarthroplasty There is very low-certainty evidence from two trials (161 participants with either three- or four-part fractures) of no or minimal between-group differences in self-reported shoulder function at one year (1 study) or at two to three years' follow-up (2 studies); or in quality of life at one year or at two or more years' follow-up (1 study). Function at six months was not reported. Of 10 deaths reported by one trial (99 participants), one appeared to be surgery-related. There is very low-certainty evidence of a lower risk of complications after RTSA (2 studies). Ten people (6.2% of 161 participants) had a reoperation; all eight cases in the hemiarthroplasty group received a RTSA (very low-certainty evidence). AUTHORS' CONCLUSIONS: There is high- or moderate-certainty evidence that, compared with non-surgical treatment, surgery does not result in a better outcome at one and two years after injury for people with displaced proximal humeral fractures. It may increase the need for subsequent surgery. The evidence is absent or insufficient for people aged under 60 years, high-energy trauma, two-part tuberosity fractures or less common fractures, such as fracture dislocations and articular surface fractures. There is insufficient evidence from randomised trials to inform the choices between different non-surgical, surgical or rehabilitation interventions for these fractures.

Interventions for treating wrist fractures in children.

BACKGROUND: Wrist fractures, involving the distal radius, are the most common fractures in children. Most are buckle fractures, which are stable fractures, unlike greenstick and other usually displaced fractures. There is considerable variation in practice, such as the extent of immobilisation for buckle fractures and use of surgery for seriously displaced fractures. OBJECTIVES: To assess the effects (benefits and harms) of interventions for common distal radius fractures in children, including skeletally immature adolescents. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group's Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, trial registries and reference lists to May 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing interventions for treating distal radius fractures in children. We sought data on physical function, treatment failure, adverse events, time to return to normal activities (recovery time), wrist pain, and child (and parent) satisfaction. DATA COLLECTION AND ANALYSIS: At least two review authors independently performed study screening and selection, 'Risk of bias' assessment and data extraction. We pooled data where appropriate and used GRADE for assessing the quality of evidence for each outcome. MAIN RESULTS: Of the 30 included studies, 21 were RCTs, seven were quasi-RCTs and two did not describe their randomisation method. Overall, 2930 children were recruited. Typically, trials included more male children and reported mean ages between 8 and 10 years. Eight studies recruited buckle fractures, five recruited buckle and other stable fractures, three recruited minimally displaced fractures and 14 recruited displaced fractures, typically requiring closed reduction, typically requiring closed reduction. All studies were at high risk of bias, mainly reflecting lack of blinding. The studies made 14 comparisons. Below we consider five prespecified comparisons:Removable splint versus below-elbow cast for predominantly buckle fractures (6 studies, 695 children)One study (66 children) reported similar Modified Activities Scale for Kids - Performance scores (0 to 100; no disability) at four weeks (median scores: splint 99.04; cast 99.11); low-quality evidence. Thirteen children needed a change or reapplication of device (splint 5/225; cast 8/219; 4 studies); very low-quality evidence. One study (87 children) reported no refractures at six months. One study (50 children) found no between-group difference in pain during treatment; very low-quality evidence. Evidence was absent (recovery time), insufficient (children with minor complications) or contradictory (child or parent satisfaction). Two studies estimated lower healthcare costs for removable splints.Soft or elasticated bandage versus below-elbow cast for buckle or similar fractures (4 studies, 273 children)One study (53 children) reported more children had no or only limited disability at four weeks in the bandage group; very low-quality evidence. Eight children changed device or extended immobilisation for delayed union (bandage 5/90; cast 3/91; 3 studies); very low-quality evidence. Two studies (139 children) reported no serious adverse events at four weeks. Evidence was absent, insufficient or contradictory for recovery time, wrist pain, children with minor complications, and child and parent satisfaction. More bandage-group participants found their treatment convenient (39 children).Removal of casts at home by parents versus at the hospital fracture clinic by clinicians (2 studies, 404 children, mainly buckle fractures)One study (233 children) found full restoration of physical function at four weeks; low-quality evidence. There were five treatment changes (home 4/197; hospital 1/200; 2 studies; very low-quality evidence). One study found no serious adverse effects at six months (288 children). Recovery time and number of children with minor complications were not reported. There was no evidence of a difference in pain at four weeks (233 children); low-quality evidence. One study (80 children) found greater parental satisfaction in the home group; low-quality evidence. One UK study found lower healthcare costs for home removal.Below-elbow versus above-elbow casts for displaced or unstable both-bone fractures (4 studies, 399 children)Short-term physical function data were unavailable but very low-quality evidence indicated less dependency when using below-elbow casts. One study (66 children with minimally displaced both-bone fractures) found little difference in ABILHAND-Kids scores (0 to 42; no problems) (mean scores: below-elbow 40.7; above-elbow 41.8); very low-quality evidence. Overall treatment failure data are unavailable, but nine of the 11 remanipulations or secondary reductions (366 children, 4 studies) were in the above-elbow group; very low-quality evidence. There was no refracture or compartment syndrome at six months (215 children; 2 studies). Recovery time and overall numbers of children with minor complications were not reported. There was little difference in requiring physiotherapy for stiffness (179 children, 2 studies); very low-quality evidence. One study (85 children) found less pain at one week for below-elbow casts; low-quality evidence. One study found treatment with an above-elbow cast cost three times more in Nepal.Surgical fixation with percutaneous wiring and cast immobilisation versus cast immobilisation alone after closed reduction of displaced fractures (5 studies, 323 children)Where reported, above-elbow casts were used. Short-term functional outcome data were unavailable. One study (123 children) reported similar ABILHAND-Kids scores indicating normal physical function at six months (mean scores: surgery 41.9; cast only 41.4); low-quality evidence. There were fewer treatment failures, defined as early or problematic removal of wires or remanipulation for early loss in position, after surgery (surgery 20/124; cast only 41/129; 4 studies; very low-quality evidence). Similarly, there were fewer serious advents after surgery (surgery 28/124; cast only 43/129; 4 studies; very low-quality evidence). Recovery time, wrist pain, and satisfaction were not reported. There was lower referral for physiotherapy for stiffness after surgery (1 study); very low-quality evidence. One USA study found similar treatment costs in both groups. AUTHORS' CONCLUSIONS: Where available, the quality of the RCT-based evidence on interventions for treating wrist fractures in children is low or very low. However, there is reassuring evidence of a full return to previous function with no serious adverse events, including refracture, for correctly-diagnosed buckle fractures, whatever the treatment used. The review findings are consistent with the move away from cast immobilisation for these injuries. High-quality evidence is needed to address key treatment uncertainties; notably, some priority topics are already being tested in ongoing multicentre trials, such as FORCE.

Rehabilitation for distal radial fractures in adults.

BACKGROUND: Fracture of the distal radius is a common clinical problem, particularly in older people with osteoporosis. There is considerable variation in the management, including rehabilitation, of these fractures. This is an update of a Cochrane review first published in 2002 and last updated in 2006. OBJECTIVES: To examine the effects of rehabilitation interventions in adults with conservatively or surgically treated distal radial fractures. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2014; Issue 12), MEDLINE, EMBASE, CINAHL, AMED, PEDro, OTseeker and other databases, trial registers, conference proceedings and reference lists of articles. We did not apply any language restrictions. The date of the last search was 12 January 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs evaluating rehabilitation as part of the management of fractures of the distal radius sustained by adults. Rehabilitation interventions such as active and passive mobilisation exercises, and training for activities of daily living, could be used on their own or in combination, and be applied in various ways by various clinicians. DATA COLLECTION AND ANALYSIS: The review authors independently screened and selected trials, and reviewed eligible trials. We contacted study authors for additional information. We did not pool data. MAIN RESULTS: We included 26 trials, involving 1269 mainly female and older patients. With few exceptions, these studies did not include people with serious fracture or treatment-related complications, or older people with comorbidities and poor overall function that would have precluded trial participation or required more intensive treatment. Only four of the 23 comparisons covered by these 26 trials were evaluated by more than one trial. Participants of 15 trials were initially treated conservatively, involving plaster cast immobilisation. Initial treatment was surgery (external fixation or internal fixation) for all participants in five trials. Initial treatment was either surgery or plaster cast alone in six trials. Rehabilitation started during immobilisation in seven trials and after post-immobilisation in the other 19 trials. As well as being small, the majority of the included trials had methodological shortcomings and were at high risk of bias, usually related to lack of blinding, that could affect the validity of their findings. Based on GRADE criteria for assessment quality, we rated the evidence for each of the 23 comparisons as either low or very low quality; both ratings indicate considerable uncertainty in the findings.For interventions started during immobilisation, there was very low quality evidence of improved hand function for hand therapy compared with instructions only at four days after plaster cast removal, with some beneficial effects continuing one month later (one trial, 17 participants). There was very low quality evidence of improved hand function in the short-term, but not in the longer-term (three months), for early occupational therapy (one trial, 40 participants), and of a lack of differences in outcome between supervised and unsupervised exercises (one trial, 96 participants).Four trials separately provided very low quality evidence of clinically marginal benefits of specific interventions applied in addition to standard care (therapist-applied programme of digit mobilisation during external fixation (22 participants); pulsed electromagnetic field (PEMF) during cast immobilisation (60 participants); cyclic pneumatic soft tissue compression using an inflatable cuff placed under the plaster cast (19 participants); and cross-education involving strength training of the non-fractured hand during cast immobilisation with or without surgical repair (39 participants)).For interventions started post-immobilisation, there was very low quality evidence from one study (47 participants) of improved function for a single session of physiotherapy, primarily advice and instructions for a home exercise programme, compared with 'no intervention' after cast removal. There was low quality evidence from four heterogeneous trials (30, 33, 66 and 75 participants) of a lack of clinically important differences in outcome in patients receiving routine physiotherapy or occupational therapy in addition to instructions for home exercises versus instructions for home exercises from a therapist. There was very low quality evidence of better short-term hand function in participants given physiotherapy than in those given either instructions for home exercises by a surgeon (16 participants, one trial) or a progressive home exercise programme (20 participants, one trial). Both trials (46 and 76 participants) comparing physiotherapy or occupational therapy versus a progressive home exercise programme after volar plate fixation provided low quality evidence in favour of a structured programme of home exercises preceded by instructions or coaching. One trial (63 participants) provided very low quality evidence of a short-term, but not persisting, benefit of accelerated compared with usual rehabilitation after volar plate fixation.For trials testing single interventions applied post-immobilisation, there was very low quality evidence of no clinically significant differences in outcome in patients receiving passive mobilisation (69 participants, two trials), ice (83 participants, one trial), PEMF (83 participants, one trial), PEMF plus ice (39 participants, one trial), whirlpool immersion (24 participants, one trial), and dynamic extension splint for patients with wrist contracture (40 participants, one trial), compared with no intervention. This finding applied also to the trial (44 participants) comparing PEMF versus ice, and the trial (29 participants) comparing manual oedema mobilisation versus traditional oedema treatment. There was very low quality evidence from single trials of a short-term benefit of continuous passive motion post-external fixation (seven participants), intermittent pneumatic compression (31 participants) and ultrasound (38 participants). AUTHORS' CONCLUSIONS: The available evidence from RCTs is insufficient to establish the relative effectiveness of the various interventions used in the rehabilitation of adults with fractures of the distal radius. Further randomised trials are warranted. However, in order to optimise research effort and engender the large multicentre randomised trials that are required to inform practice, these should be preceded by research that aims to identify priority questions.

Suppressors of cytokine signaling 2 and 3 diametrically control macrophage polarization.

Suppressors of cytokine signaling (SOCS) are important regulators of lipopolysaccharide (LPS) and cytokine responses but their role in macrophage polarization is unknown. We have shown here that myeloid-restricted Socs3 deletion (Socs3(Lyz2cre)) resulted in resistance to LPS-induced endotoxic shock, whereas Socs2(-/-) mice were highly susceptible. We observed striking bias toward M2-like macrophages in Socs3(Lyz2cre) mice, whereas the M1-like population was enriched in Socs2(-/-) mice. Adoptive transfer experiments showed that responses to endotoxic shock and polymicrobial sepsis were transferable and macrophage dependent. Critically, this dichotomous response was associated with enhanced regulatory T (Treg) cell recruitment by Socs3(Lyz2cre) cells, whereas Treg cell recruitment was absent in the presence of Socs2(-/-) macrophages. In addition, altered polarization coincided with enhanced interferon-gamma (IFN-γ)-induced signal transducer and activator of transcription-1 (STAT1) activation in Socs2(-/-) macrophages and enhanced interleukin-4 (IL-4) plus IL-13-induced STAT6 phosphorylation in Socs3(Lyz2cre) macrophages. SOCS, therefore, are essential controllers of macrophage polarization, regulating inflammatory responses.

A new polycythaemia vera-associated SOCS3 SH2 mutant (SOCS3F136L) cannot regulate erythropoietin responses.

Recently several different JAK2 exon12 mutations have been identified in V617F negative polycythaemia vera (PV) or idiopathic erythrocytosis (IE) patients. The patients present with erythrocytosis, ligand-independent cell growth and low serum erythropoietin (EPO) levels. Within this group, a deletion of amino acids 542-543 (N542-E543del) of JAK2 is most prevalent. We have previously shown that in the presence of JAK2(V617F), suppressor of cytokine signalling 3 (SOCS3) is unable to negatively regulate EPO signalling and proliferation of V617F-expressing cells. Here we report a PV patient heterozygous for the somatic JAK2(N542-E543del) mutation and a previously unreported germline mutation within the SH2 domain of SOCS3 (F136L). Interestingly, the SOCS3(F136L) mutation was detected in a Japanese myeloproliferative disorder patient cohort at double the frequency of healthy controls. Cells expressing SOCS3(F136L) had markedly elevated EPO-induced proliferation and extended EPO-induced JAK2 phosphorylation. Additionally, compared to wild-type SOCS3, mutant SOCS3 had an extended half-life in the presence of JAK2 and JAK2(N542-E543del). Our findings suggest that this loss-of-function SOCS3 mutation may have contributed to disease onset by causing deregulated JAK2 signalling in the presence of a constitutively active JAK2(N542-E543del) mutant.

SOCS3 tyrosine phosphorylation as a potential bio-marker for myeloproliferative neoplasms associated with mutant JAK2 kinases.

JAK2 V617F, identified in the majority of patients with myeloproliferative neoplasms, tyrosine phosphorylates SOCS3 and escapes its inhibition. Here, we demonstrate that the JAK2 exon 12 mutants described in a subset of V617F-negative MPN cases, also stabilize tyrosine phosphorylated SOCS3. SOCS3 tyrosine phosphorylation was also observed in peripheral blood mononuclear cells and granulocytes isolated from patients with JAK2 H538QK539L or JAK2 F537-K539delinsL mutations. JAK kinase inhibitors, which effectively inhibited the proliferation of cells expressing V617F or K539L, also caused a dose-dependent reduction in both mutant JAK2 and SOCS3 tyrosine phosphorylation. We propose, therefore, that SOCS3 tyrosine phosphorylation may be a novel bio-marker of myeloproliferative neoplasms resulting from a JAK2 mutation and a potential reporter of effective JAK2 inhibitor therapy currently in clinical development.

The suppressors of cytokine signalling E3 ligases behave as tumour suppressors.

Many studies have suggested that E3 ubiquitin ligases can behave as either oncogenes or tumour suppressor genes and, recently, it has become clear that the SOCS (suppressor of cytokine signalling) E3 ligases fit this mould. While most cancer-associated E3s regulate the cell cycle or DNA repair, the SOCS proteins inhibit growth factor responses by degrading signalling intermediates such as JAKs (Janus kinases) via the SOCS-box-associated ECS (Elongin-Cullin-SOCS) E3 ligase. Clinical studies have found that (epi)genetic (mutation or methylation) phenomena can occur in many solid tumours and a growing number of clinical findings reveal post-translational modifications that disrupt SOCS function in haematological malignancy. In the present review, we provide a summary of the functions of the SOCS E3s and propose the potential use of members of this family as diagnostic markers and therapeutic targets in cancer.

SOCS3 in liver regeneration and hepatocarcinoma.

Cytokine responses are stringently controlled by a family of proteinsSTAT3 termed the suppressors of cytokine signaling (SOCS), and deregulation of SOCS function is associated with many diseases, including several cancers, disorders in hematopoiesis, and autoimmune diseases. Our current understanding of the divergent roles of SOCS3 has recently improved and indicates that SOCS3 is critical in modulating cytokine-mediated and neoplastic-proliferative responses in the liver. The generation of hepatocyte-specific Socs3 knockout mice suggests that loss of SOCS3 expression encourages hepatocyte proliferation, survival, and hepatocellular carcinoma formation. By elucidating the regulation of pathways leading to liver regeneration we may gain useful insights to control liver disease and tumor growth.

Substitution of pseudokinase domain residue Val-617 by large non-polar amino acids causes activation of JAK2.

Explaining the uniqueness of the acquired somatic JAK2 V617F mutation, which is present in more than 95% of polycythemia vera patients, has been a challenge. The V617F mutation in the pseudokinase domain of JAK2 renders the unmutated kinase domain constitutively active. We have performed random mutagenesis at position 617 of JAK2 and tested each of the 20 possible amino acids for ability to induce constitutive signaling in Ba/F3 cells expressing the erythropoietin receptor. Four JAK2 mutants, V617W, V617M, V617I, and V617L, were able to induce cytokine independence and constitutive downstream signaling. Only V617W induced a level of constitutive activation comparable with V617F. Also, only V617W stabilized tyrosine-phosphorylated suppressor of cytokine signaling 3 (SOCS3), a mechanism by which JAK2 V617F overcomes inhibition by SOCS3. The V617W mutant induced a myeloproliferative disease in mice, mainly characterized by erythrocytosis and megakaryocytic proliferation. Although JAK2 V617W would predictably be pathogenic in humans, the substitution of the Val codon, GTC, by TTG, the codon for Trp, would require three base pair changes, and thus it is unlikely to occur. We discuss how the predicted conformations of the activated JAK2 mutants can lead to better screening assays for novel small molecule inhibitors.

The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3.

The somatic JAK2 valine-to-phenylalanine (V617F) mutation has been detected in up to 90% of patients with polycythemia and in a sizeable proportion of patients with other myeloproliferative disorders such as essential thrombocythemia and idiopathic myelofibrosis. Suppressor of cytokine signaling 3 (SOCS3) is known to be a strong negative regulator of erythropoietin (EPO) signaling through interaction with both the EPO receptor (EPOR) and JAK2. We report here that JAK2 V617F cannot be regulated and that its activation is actually potentiated in the presence of SOCS3. Instead of acting as a suppressor, SOCS3 enhanced the proliferation of cells expressing both JAK2 V617F and EPOR. Additionally, although SOCS1 and SOCS2 are degraded in the presence of JAK2 V617F, turnover of SOCS3 is inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation of SOCS3 protein. We also observed constitutive tyrosine phosphorylation of SOCS3 in peripheral blood mononuclear cells (PBMCs) derived from patients homozygous for the JAK2 V617F mutant. These findings suggest that the JAK2 V617F has overcome normal SOCS regulation by hyperphosphorylating SOCS3, rendering it unable to inhibit the mutant kinase. Thus, JAK2 V617F may even exploit SOCS3 to potentiate its myeloproliferative capacity.

CD33 responses are blocked by SOCS3 through accelerated proteasomal-mediated turnover.

CD33 is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family of inhibitory receptors and a therapeutic target for acute myeloid leukemia (AML). CD33 contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM), which can recruit SHP-1 and SHP-2. How CD33 expression is regulated is unclear. Suppressor of cytokine signaling 3 (SOCS3) is expressed in response to cytokines, LPS, and other PAMPs, and competes with SHP-1/2 binding to ITIMs of cytokine receptors, thereby inhibiting signaling. In this study, using peptide pull-down experiments, we found that SOCS3 can specifically bind to the phosphorylated ITIM of CD33. Additionally, following cross-linking SOCS3 can recruit the ECS E3 ligase resulting in accelerated proteasomal degradation of both CD33 and SOCS3. Our data suggest that the tyrosine motifs in CD33 are not important for internalization, while they are required for degradation. Moreover, SOCS3 inhibited the CD33-induced block on cytokine-induced proliferation. This is the first receptor shown to be degraded by SOCS3 and where SOCS3 and its target protein are degraded concomitantly. Our findings clearly suggest that during an inflammatory response, the inhibitory receptor CD33 is lost by this mechanism. Moreover, this has important clinical implications as tumors expressing SOCS3 may be refractory to alpha-CD33 therapy.

Anabolic neuropeptides.

The hypothalamus and other brain regions that control energy homeostasis contain neuronal populations that produce specific neuropeptides which have experimental effects on feeding behavior and body weight. Here, we describe examples of neuropeptides that exert 'anabolic' effects, notably stimulation of feeding and increased body weight. Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) are inhibited by leptin and insulin, and thus are stimulated in states of energy deficit and fat loss, e.g., underfeeding. NPY neuronal overactivity contributes to enhanced hunger and food-seeking activity under these conditions. The lateral hypothalamic area (LHA) contains specific neuronal populations that affect feeding in different ways. Neurons expressing the appetite-stimulating peptide orexin A are stimulated by starvation (but not food restriction) and by hypoglycemia, but only if food is withheld. Orexin neurons are apparently activated by low glucose but are promptly inhibited by visceral feeding signals, probably mediated via vagal sensory pathway and the nucleus of the solitary tract (NTS); a short-term role in initiating feeding seems most likely. Other LHA neurons express melanin-concentrating hormone (MCH), which transiently increases food intake when injected centrally. MCH neurons may be regulated by leptin, insulin and glucose. Glucose-sensing neurons in the hypothalamus and elsewhere are sensitive to other cues of nutritional state, including visceral satiety signals (transmitted via the vagus) and orexin A. Thus, long- and short-term humoral and neural signals interact with each other to meet diverse nutritional needs, and anabolic neuropeptides are important in the overall integration of energy homeostasis. Clarifying the underlying mechanisms will be essential to understanding normal energy balance and the pathogenesis and treatment of disorders, such as obesity and cachexia.