Synthesis and biological evaluation of EGFR binding peptides for near-infrared photoimmunotherapy.

Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that involves photoimmunotherapy drug injection and NIR light exposure. In NIR-PIT, antibodies are commonly used as target-directed molecules carrying IRDye700DX (IR700). However, antibodies have disadvantages, such as high cost, complex development strategies, and poor tumor penetration. In contrast, peptides have lower production costs, can be easy to chemically synthesize and modify, and can also be used for tumor-targeting like antibodies. In this study, we developed a novel PIT drug using a peptide as the target-directed molecule. Epidermal growth factor receptor (EGFR) was selected as the target, and monovalent and bivalent EGFR-binding peptides were synthesized. The bivalent peptide showed sufficient binding to EGFR-positive cells, and a bivalent peptide-IR700 conjugate with a long linker induced morphological changes in EGFR-positive cells. Additionally, the drug significantly reduced cell viability in vitro in an NIR light-dose- and drug-concentration-dependent manner. These results indicate the feasibility of NIR-PIT in treating cancer using peptide-based drugs.

A Modified Modular Stem in Primary Total Hip Arthroplasty for Developmental Dysplasia of the Hip: Average 11-year Follow-Up in Cases With Previously Reported 3-year Clinical Results.

BACKGROUND: Modular stems require careful follow-up, especially after any design modification. This study investigated the mid- to long-term outcomes of total hip arthroplasty in patients with developmental dysplasia of the hip using the S-ROM-A stem, a modified S-ROM stem for Asians. METHODS: We previously reported short-term outcomes for all 220 dysplastic hips that underwent primary total hip arthroplasty with the S-ROM-A stem. Here, we followed the clinical and radiological outcomes of 201 of the 220 hips (91%) for a mean 11.4 years postoperatively. We also performed multivariate analysis to determine whether large anteversion angle adjustment was associated with increased osteolysis. RESULTS: The cumulative survival rate of the stem at 168 months postoperatively was 97.4%. Two hips underwent revision surgery, including 1 due to neck trunnionosis. Characteristic distal stem fracture occurred in 3 hips (1.5%). Most partial radiolucent lines observed around the sleeve early postoperatively disappeared by 7 years, postoperatively. Mild osteolysis occurred relatively frequently (20%), but a multivariate model adjusted for polyethylene type showed no significant association between the occurrence of osteolysis and anteversion adjustment of the modular stem (stem anteversion decreased ≤-20°, P = .829; stem anteversion increased ≥+20°, P = .619). CONCLUSION: Partial radiolucent lines early postoperatively do not affect long-term outcomes. The clinical benefits of actively adjusting the stem anteversion angle outweigh the mechanical risks. Mild osteolysis, stem fracture, and trunnionosis were relatively frequent complications. Analysis with longer follow-up and more cases are necessary to clearly determine if these complications are associated with the design modification.

Revision Total Hip Arthroplasty Using the Modular Proximal Stem Modified for Asians: Medium-Term Clinical Results and Perioperative Complications.

BACKGROUND: This study aimed to examine the medium-term clinical and radiological outcomes of revision THA using the S-ROM-A stem, a modification of the S-ROM stem intended for Asians. METHODS: Femoral reconstruction using the S-ROM-A stem was performed in 126 hips that underwent revision THA. All patients were followed for perioperative complications. In addition, clinical and radiographic outcomes at a mean of 8 (range 5-14) years postoperatively were evaluated in 96 hips of 86 patients (76%). RESULTS: The most common perioperative complication was a femoral fracture, occurring in 16 hips (13%), including 11 intraoperative and 5 postoperative fractures. Dislocation occurred in five hips (4.0%), infection in three hips (2.4%), and trunnionosis in two hips (1.6%), including late complications. The total second stem revision was performed in two hips while stem only second revision preserving the bone ingrown sleeve was performed in four hips. With a second revision for aseptic loosening as the endpoint, the 13-year stem survival rate was 100%. Hip function as assessed by the Japanese Orthopedic Association score improved from a mean of 48 points preoperatively to 87 points 8 years postoperatively (P < .05). Radiological evaluation at the final follow-up showed that 95 hips (99%) achieved bone ingrowth fixation and one hip (1%) achieved fibrous stable status. CONCLUSION: Revision THA using the S-ROM-A stem resulted in good medium-term outcomes. Although modifications of the stem length and shape may be effective in preventing fractures in Asians with relatively small body sizes, attention should be paid to the occurrence of trunnionosis, which may be associated with the decreased taper size.

Do radiological findings around the Fitmore stem change over time? : radiolucency around the short hip stem disappears within a few years: a retrospective study.

AIMS: Although the short stem concept in hip arthroplasty procedure shows acceptable clinical performance, we sometimes get unexplainable radiological findings. The aim of this retrospective study was to evaluate changes of radiological findings up to three years postoperatively, and to assess any potential contributing factors on such radiological change in a Japanese population. METHODS: This is a retrospective radiological study conducted in Japan. Radiological assessment was done in accordance with predetermined radiological review protocol. A total of 241 hips were included in the study and 118 hips (49.0%) revealed radiological change from immediately after surgery to one year postoperatively; these 118 hips were eligible for further analyses. Each investigator screened whether either radiolucent lines (RLLs), cortical hypertrophy (CH), or atrophy (AT) appeared or not on the one-year radiograph. Further, three-year radiographs of eligible cases were reviewed to determine changes such as, disappeared (D), improved (I), stable (S), and progression (P). Additionally, bone condensation (BC) was assessed on the three-year radiograph. RESULTS: CH was observed in 49 hips (21.1%), AT was observed in 63 hips (27.2%), and RLLs were observed in 34 hips (14.7%) at one year postoperatively. Among 34 hips with RLLs, 70.6% showed change of either D or I on the three-year radiograph. BC was observed in younger patients more frequently. CONCLUSION: The Fitmore stem works well in a Japanese population with favourable radiological change on hips with RLLs. Longer-term follow-up is required to determine clinical relevance. Cite this article: Bone Jt Open 2022;3(1):20-28.

Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure.

Based on the X-ray crystallography of recombinant BACE1 and a hydroxyethylamine-type peptidic inhibitor, we introduced a cross-linked structure between the P1 and P3 side chains of the inhibitor to enhance its inhibitory activity. The P1 and P3 fragments bearing terminal alkenes were synthesized, and a ring-closing metathesis of these alkenes was used to construct the cross-linked structure. Evaluation of ring size using P1 and P3 fragments with various side chain lengths revealed that 13-membered rings were optimal, although their activity was reduced compared to that of the parent compound. Furthermore, the optimal ring structure was found to be a macrocycle with a dimethyl branched substituent at the P3 ß-position, which was approximately 100-fold more active than the non-substituted macrocycle. In addition, the introduction of a 4-carboxymethylphenyl group at the P1' position further improved the activity.

A Five-Year-Old Slipped Capital Femoral Epiphysis Treated With Dynamic Single Screw Fixation.

Slipped capital femoral epiphysis (SCFE) commonly occurs during puberty. Onset of SCFE at either less than 10 years old or over 16 years is defined as atypical. As in our patient, atypical onset at less than 10 years occurred in 9%, and the age of onset has been decreasing in recent years and that the probability of concomitant obesity is particularly high in young patients without obvious underlying disease or background factors. In the treatment of SCFE, preventing further slipping and permitting femoral bone growth by physeal closure is difficult, especially for young patients. We adopted 'dynamic single screw fixation' using SCFE short thread screw for continuous fixation without disturbing the growth of proximal femur or damaging to growth plate. Refixation was necessary once. The screw worked for 7 years 4 months while physeal closure was avoided. At the 10-year follow-up, her growth had stopped. She had no problem clinically, no increase in the posterior sloping angle (PSA), and no obvious growth disturbance of the femur.

Improving MiniHip femoral prosthesis positioning using a cross-laser projection system in total hip arthroplasty by an anterolateral supine approach.

BACKGROUND: The authors developed a cross-laser projection system (CLP) to place a femoral neck-sparing short stem using the minimally invasive anterolateral supine approach in total hip arthroplasty. This study aimed to verify the utility of CLP. METHODS: Thirty joints were assessed with the MiniHip (Corin). The authors compared femoral component implantation with a patient-specific femoral osteotomy guide (PSG) for the femoral neck-cut (PSG group), with the CLP attached to the rasp handle to irradiate the cross-laser to the target of PSG (CLP group), and without PSG or CLP (control group). RESULTS: In the CLP group, the positional deviation of anteversion, anterior/posterior tilt and varus/valgus placement of the stem postoperatively were 1.8° ± 0.2°, 2.0° ± 2.0° and 2.0° ± 0.1°, respectively. The positional deviation of anteversion (p < 0.001) and anterior/posterior tilt (p = 0.036) were significantly smaller than those in the other groups. CONCLUSIONS: CLP improves the accuracy of MiniHip femoral prosthesis placement.

Clinical results of a short stem with flat tapered wedge design in primary total hip arthroplasty for hip dysplasia in Asians.

BACKGROUND: Cementless femoral reconstruction is challenging in hip dysplasia due to deformity of the proximal femur causing insufficient stem fixation and/or inadequate neck anteversion. Strategies to address these problems include the use of a modular stem or a distal fixation stem, but both stems have some characteristic disadvantages. METHODS: We studied the postoperative clinical outcomes in primary total hip arthroplasty in 257 hips using the flat tapered wedge short femoral stem for hip dysplasia in an Asian population (postoperative follow-up period: 2 years to 6 years and 11 months; mean 4 years and 5 months). We took advantage of the characteristic of high flexibility in stem placement because of its low volume, positioning it while performing some varus/valgus and rotational alignment adjustments. RESULTS: Favorable clinical functional outcomes were obtained, including the radiographic outcome of biological fixation achieved in all stems. Regarding complications, there was no case of split fracture of the femoral calcar region during stem insertion, and the rate of postoperative dislocation was also low at 0.4% (1 case). In the pre- and postoperative computed tomography measurements, the variability in stem anteversion postoperatively was significantly reduced compared to preoperative anatomical anteversion. CONCLUSION: This flat-shaped short low-volume stem likely has high flexibility in positioning in cases of hip dysplasia and can be easily positioned to avoid fractures while still achieving secure fixation.

Long-term assessment of morphological, functional, and quantitative parameters of skeletal muscle in older patients after unilateral total hip arthroplasty.

Total hip arthroplasty (THA) is performed for pain relief in patients with osteoarthritis of the hip joint. After THA, patients may recover muscle mass and physical function. Muscle quality is the main parameter used to indicate intramuscular fat content, and it is related with muscle function in older individuals. However, how THA affects muscle quality, as determined by echo intensity (EI), is not well understood. The purpose of this study was to determine the long-term characteristics of EI, muscle quantity, muscle function, and physical functions in the patients with THA surgery. In order to achieve the purpose, we performed two comparison. First, we compared muscle EI, quantity and function in operated leg with unoperated legs in the same patients and with the legs of healthy adults (i.e., both unoperated legs). Second, we compared physical functional tests between THA patient and age and body composition matched controls. Twenty-two older individuals (age: 67.1 ± 5.3 years, height: 160.9 ± 7.1 cm, body mass: 62.6 ± 16.1 kg) who underwent unilateral THA several (5.2 ± 3.1) years ago (THA group) and 22 healthy controls with matching age and body composition (age: 68.3 ± 4.4 years, height: 160.3 ± 7.9 cm, body mass: 61.7 ± 7.8 kg) (CON group) participated in this case-control study. EI, an index of muscle quality, and muscle thickness (MT), an index of muscle quantity, were measured from B-mode transverse images of the rectus femoris obtained through ultrasound. The maximal isometric knee extension torque was measured in both the operated and unoperated legs in the THA group and in the right leg in the CON group (control leg); physical function tests, such as sit-to-stand, walking speed, hip adduction, and abduction torque assessments, were performed in both groups. MT and maximal isometric knee extension torque in operated leg were not different with unoperated, and control legs; the EI in the operated leg was significantly higher than that in the control leg (106.9 ± 16.9 vs. 92.4 ± 21.0 a.u., P < 0.05). The THA group demonstrated slower walking speed and lower hip abduction torque than the CON group (walking speed: 1.3 ± 0.2 vs. 1.5 ± 0.2 m/s; hip abduction torque 1.2 ± 0.3 vs. 1.5 ± 0.5 Nm/kg, P < 0.05). Several years after THA, the operated legs completely recovered the same level of muscle quantity as that in healthy participants but with lower muscle quality and hip joint function. These defects may be associated with locomotive dysfunction in older THA patients.

Allosteric regulation accompanied by oligomeric state changes of Trypanosoma brucei GMP reductase through cystathionine-ß-synthase domain.

Guanosine 5'-monophosphate reductase (GMPR) is involved in the purine salvage pathway and is conserved throughout evolution. Nonetheless, the GMPR of Trypanosoma brucei (TbGMPR) includes a unique structure known as the cystathionine-ß-synthase (CBS) domain, though the role of this domain is not fully understood. Here, we show that guanine and adenine nucleotides exert positive and negative effects, respectively, on TbGMPR activity by binding allosterically to the CBS domain. The present structural analyses revealed that TbGMPR forms an octamer that shows a transition between relaxed and twisted conformations in the absence and presence of guanine nucleotides, respectively, whereas the TbGMPR octamer dissociates into two tetramers when ATP is available instead of guanine nucleotides. These findings demonstrate that the CBS domain plays a key role in the allosteric regulation of TbGMPR by facilitating the transition of its oligomeric state depending on ligand nucleotide availability.

Treatment of periprosthetic hip infection with retention of a well-fixed stem: six to 13-year outcomes.

BACKGROUND: Treatment of periprosthetic joint infection (PJI) is challenging, generally requiring complete implant removal. However, recently reported treatments involve partial retention of implants because of the severe local and systemic burden on the patients and difficulties in functional preservation. Long-term results should be evaluated because of the risk of residual biofilm on the retained implant and late infection recurrence. We evaluated 6 to 13-year clinical outcomes of two-stage treatment of chronic PJI retaining well-fixed cementless stems. METHODS: Among 36 surgeries for deep infection following hip arthroplasty performed from 2004 to 2011, six hips had a well-fixed and well-functioning cementless stem. These six hips were all chronic PJI and were treated without stem removal. The first-stage surgery involved acetabular cup removal and reconstruction by filling the acetabular defect with antibiotic-loaded acrylic cement, creating a socket-like hemispherical dent, and reducing the retained femoral head to this dent. After confirming infection eradication the second-stage acetabular reconstruction was performed. One patient died of an unrelated noninfective cause 1 year after the operation. Clinical outcomes of the remaining five patients were followed for 6 to 13 years. RESULTS: Between the two surgeries (range; 2-5 months), patients underwent active range-of-motion and ambulation exercises. No dislocation was found during the interval. No recurrence of infection was found and good functional outcomes and radiographic findings were observed during the average follow-up of 109 months in all five patients. CONCLUSIONS: Two-stage treatment with retention of a well-fixed stem may minimize local and systemic burden of the patient and enhance functional preservation while obtaining long-term infection control. Although further study could establish the effectiveness and indications for this treatment option, currently used indications should be carefully evaluated considering factors including local and systemic conditions of the patient, implant fixation status, and type of bacteria.

Treatment for unstable slipped capital femoral epiphysis: Current status and future challenge in Japan.

BACKGROUND: Treatment for unstable slipped capital femoral epiphysis (SCFE) is challenging and controversial. For many years, the debate centered around closed treatments and especially the pros and cons of manual reduction and its concrete procedure. However, recent studies reported on open treatments such as open reduction through an anterior approach and modified Dunn procedure. Being in a period of such transition, we investigated the current status and future challenge of treatment for unstable SCFE. METHODS: A questionnaire survey of medical institutions specializing in pediatric hip disorders across Japan was conducted. Survey items were the accurate diagnosis of physeal stability, the pre- and intra-operative evaluation of epiphyseal hemodynamics, and current treatment strategy. RESULTS: Survey responses returned from 29 out of 40 participant institutions (response rate: 73%) revealed that 55% of the institutions evaluated physeal stability based on clinical findings of ambulation capability in accordance with the Loder classification. Another 38% diagnosed physeal stability comprehensively by combining the Loder classification and imaging findings. Epiphyseal hemodynamics was assessed preoperatively in 18% of the institutions, effectively using angiography, contrast-enhanced magnetic resonance imaging (MRI), and bone scintigraphy. Intraoperative assessment was performed in 13% based on the bleeding through a drilling hole on the articular surface and observation of the cancellous bone color during open surgeries. As a treatment strategy, 52% of the institutions used in-situ fixation, while another 38% used manual reduction and internal fixation. On the other hand, open reduction was used at 3 institutions (the remaining 10%): the modified Dunn procedure at 2 institutions and arthrotomy at 1 institution. CONCLUSION: Treatment for unstable SCFE remains controversial, but closed treatments without hemodynamic monitoring is no longer the center of the controversy. Today, the topic of the discussion is shifting toward how to correlate hemodynamic findings with treatment procedures and the indications for open treatments.

Cementless Total Hip Arthroplasty in Hip Dysplasia with an Extensively Porous-Coated Cylindrical Stem Modified for Asians: A 12-Year Follow-Up Study.

Long-term outcomes of primary cementless total hip arthroplasty were examined for 198 hips of Asian patients with developmental dysplasia of the hip. AML stems were modified for patients' relatively small physique. Stable fixation was achieved despite various proximal femoral deformities. At follow up (mean 12.1 years), radiographs demonstrated fixation in all hips, with 100% stem survivorship. Radiographic changes revealed that the severity of stress-shielding was mild in 55% of hips, moderate in 26%, and severe in 19%. Longer follow up is needed to determine whether these changes will develop into clinical manifestations. A distal fixation stem can be a useful reconstruction option when application of a proximal fixation stem in primary total hip arthroplasty is difficult for various reasons.

A modified S-ROM stem in primary total hip arthroplasty for developmental dysplasia of the hip.

This study examined the clinical outcome of 220 hips in 196 Asian patients who underwent primary total hip arthroplasty (THA) for treatment of developmental dysplasia of the hip (DDH) using a modified S-ROM modular (S-ROM-A) stem designed for Asians, after 2-5 years (mean, 3.3 years) of follow-up. The stem was placed so that the anteversion angle of the neck was decreased against the sleeve in 56% of the hips and increased in 18% of the hips. Bone ingrown fixation was achieved in 99.5% of the hips on X-ray at final follow-up. There were 2 (0.9%) dislocations postoperatively. In primary THA for treatment of DDH accompanied by femoral rotational deformity, the freely-rotatable modular stem provided favorable short-term outcomes by affording both morphological and functional advantages.