Stress Injuries in the Athlete.

Stress fractures are a common injury that present in athletes because of the high intensity and repetitive nature of many sports. These injuries require a high index of suspicion in the treating clinician to allow for timely management. Though most low-risk fractures heal well with conservative management, high-risk stress fractures as well as any fracture in the elite athlete may warrant surgical intervention as well as an augmented treatment and rehabilitation regimen.

High-Throughput Binder Confirmation Using Affinity Selection Mass Spectrometry.

Affinity selection mass spectrometry (AS-MS) was recently applied to a new high-throughput binder confirmation (HTBC) platform. The HTBC-AS-MS platform can assess target engagement for hundreds of chemical series per target and is used at GSK to prioritize synthesis decisions for follow-up organic synthesis of DNA-encoded library technology (ELT) hits.

Discovery of 1'-(1-phenylcyclopropane-carbonyl)-3H-spiro[isobenzofuran-1,3'-pyrrolidin]-3-one as a novel steroid mimetic scaffold for the potent and tissue-specific inhibition of 11β-HSD1 using a scaffold-hopping approach.

11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 11β-HSD1, particularly in adipose tissues, has been associated with metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11β-HSD1 with a small nonsteroidal molecule is therapeutically desirable.

DNA-Encoded Library Hit Confirmation: Bridging the Gap Between On-DNA and Off-DNA Chemistry.

DNA-encoded library (DEL) technology is a powerful platform for hit identification in academia and the pharmaceutical industry. When conducting off-DNA resynthesis hit confirmation after affinity selection, PCR/sequencing, and data analysis, one typically assumes a "one-to-one" relationship between the DNA tag and the chemical structure of the attached small-molecule it encodes. Because library synthesis often yields a mixture, this approximation increases the risk of overlooking positive discoveries and valuable information.

Half-Life Extension of BMP1/TLL Metalloproteinase Inhibitors Using Small-Molecule Human Serum Albumin Binders.

Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer half-lives are highly desirable. One of the most promising approaches to extend the half-life of drugs is conjugation to human serum albumin (HSA).

First Metatarsophalangeal Joint Space Area Decreases Within 1 Month After Implantation of a Polyvinyl Alcohol Hydrogel Implant: A Retrospective Radiographic Case Series.

In 2016, the U.S. Food and Drug Administration approved the first and only polyvinyl alcohol hydrogel implant for the treatment of hallux rigidus.

Two-phase equation of state for lithium fluoride.

We present an equation of state for the solid and liquid phases of lithium fluoride that covers a wide range of conditions from ambient pressure and temperature to the high pressures and temperatures exhibited in shock- and ramp-compression studies. The particular solid phase we have focused on in this work is the B1 phase. We have followed an approach where the pressure and heat-capacity functions of both phases are fit to experimental data and our own quantum molecular dynamics simulations and are then integrated in a thermodynamically consistent way to obtain the corresponding free-energy functions.

Lateral Column Lengthening for Revision Triple and Double Arthrodesis and Severe End-Stage Flatfoot Deformity.

Few options exist for the treatment of revision and severe cases of end-stage flatfoot deformity. Triple arthrodesis or medial-approach double arthrodesis have been the standard but often do not provide enough correction of the deformity. Lateral column lengthening is a powerful procedure performed either with an Evans calcaneal osteotomy or calcaneocuboid distraction arthrodesis that can be used as an adjunct in realigning the flatfoot.

Outcomes of Wound Healing and Limb Loss After Transmetatarsal Amputation in the Presence of Peripheral Vascular Disease.

Transmetatarsal amputation (TMA) is the procedure of choice in treating forefoot gangrene and infection. Foot and ankle and vascular surgeons work closely together in limb salvage, but little is known about the timing of vascular intervention to achieve a healed amputation site. This study retrospectively looked at 153 patients with peripheral vascular disease who underwent TMA with a minimum of a 3-year follow-up.

Comparative Nonunion Rates in Triple Arthrodesis.

The contemporary literature is unclear regarding the joint that is most "at risk" to yield a nonunion in the performance of triple arthrodesis of the foot. There is also a debate regarding the best methods of joint preparation. A retrospective radiographic review was conducted of all primary triple arthrodeses performed within in a Northern California health maintenance organization between January 2007 and June 2013.

Comparison of Medial Malleolar Fracture Healing at 8 Weeks After Open Reduction Internal Fixation Versus Percutaneous Fixation: A Retrospective Cohort Study.

Unstable medial malleolar fractures are treated with either standard open reduction internal fixation (ORIF) or a percutaneous approach. The percutaneous approach avoids the potentially excessive soft tissue dissection associated with an open approach but can also result in inadequate anatomic reduction. No studies have compared the incidence of radiographic healing of medial malleolar fractures between an open approach and percutaneous fixation.

Arthroscopic Medial Approach for Modified Double Arthrodesis of the Foot.

The single medial incision subtalar joint and talonavicular joint arthrodesis has been shown to be a useful alternative for the correction of hindfoot valgus deformity. We describe an arthroscopic method of joint preparation using this approach. The present case report included 6 consecutive patients aged 35 to 72 (mean ± standard deviation 55.

Maggot debridement therapy: a systematic review.

Maggot debridement therapy is used extensively in the UK in both community and hospital situations, but remains a potentially under-used modality in many wound care markets. It promotes wound healing by performing three key processes: debridement, disinfection and growth-promoting activity. It can be used for the debridement of non-healing necrotic skin and soft tissue wounds, including pressure ulcers, venous stasis ulcers, neuropathic foot ulcers and non-healing traumatic of post-surgical wounds.

Synuclein gamma protects HER2 and renders resistance to Hsp90 disruption.

Hsp90 is an important driver of stabilization and activation of several oncogenic proteins in many key pathways in oncogenesis, including HER2. The present study demonstrated that synuclein gamma (SNCG) prevents the protein degradation and protects the function of HER2 in the condition when the function of Hsp90 is blocked. Disruption of Hsp90 resulted in a significant degradation of HER2 and the loss of activity.

Expression of synuclein gamma indicates poor prognosis of triple-negative breast cancer.

Synuclein gamma (SNCG), previously identified as breast cancer-specific gene 1, is highly expressed in malignant cells but not in normal epithelium. Studies have demonstrated that the expression of SNCG is an independent predictive marker for recurrence and metastasis in breast cancer. Triple-negative breast cancer (TNBC) is characterized by a lack of expression of both the estrogen receptor and progesterone receptor proteins as well as HER-2 and is often associated with particularly poor outcomes, early development of chemotherapy resistance, and ineffectiveness of targeted therapy.

Synuclein gamma predicts poor clinical outcome in colon cancer with normal levels of carcinoembryonic antigen.

Background: Synuclein gamma (SNCG), initially identified as a breast cancer specific gene, is aberrantly expressed in many different malignant tumors but rarely expressed in matched nonneoplastic adjacent tissues. In this study, we investigated the prognostic potential of SNCG in colon cancer particularly in the patients with normal carcinoembryonic antigen (CEA) levels.

Methods: SNCG levels were assessed immunohistochemically in cancer tissues from 229 colon adenocarcinoma patients with a mean follow-up of 44 months.

Vitexins, nature-derived lignan compounds, induce apoptosis and suppress tumor growth.

Purpose: Lignans such as secoisolariciresinol diglucoside in flaxseed, are metabolizes to bioactive mammalian lignans of END and ENL. Because mammalian lignans have chemical structural similarity to the natural estrogen, they are thought to behave like selective estrogen receptor modulators and therefore have anticancer effect against hormone-related cancers. We isolated a series of lignan compounds, named as Vitexins, from the seed of Chinese herb Vitex Negundo.

Discovery of novel selective HER-2 sheddase inhibitors through optimization of P1 moiety.

A novel series of carbamates was discovered as potent and selective HER-2 sheddase inhibitors. Significant enhancement in potency and selectivity was achieved through attenuating the P1 moiety, which was conventionally believed to be exposed to solvent.

Compelling P1 substituent affect on metalloprotease binding profile enables the design of a novel cyclohexyl core scaffold with excellent MMP selectivity and HER-2 sheddase inhibition.

A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core that exhibited excellent HER-2 potency and unprecedented MMP-selectivity that we believe would not have been possible via conventional P1' perturbations.

Design and identification of selective HER-2 sheddase inhibitors via P1' manipulation and unconventional P2' perturbations to induce a molecular metamorphosis.

In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.

Activation of Stat5 and induction of a pregnancy-like mammary gland differentiation by eicosapentaenoic and docosapentaenoic omega-3 fatty acids.

The protective effect of early pregnancy against breast cancer can be attributed to the transition from undifferentiated cells in the nulliparous to the differentiated mature cells during pregnancy. Considerable evidence suggests strongly that the n-3 polyunsaturated fatty acid (PUFA) content of adipose breast tissue is inversely associated with an increased risk of breast cancer. Here, we report that there was a decrease in the n-6/n-3 PUFA ratio and a significant increase in concentration of n-3 PUFA docosapentaenoic acid and eicosapentaenoic acid in the pregnant gland.

Discovery of a potent, selective, and orally active human epidermal growth factor receptor-2 sheddase inhibitor for the treatment of cancer.

The design, synthesis, evaluation, and identification of a novel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of human epidermal growth factor receptor-2 (HER-2) sheddase is described. Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decrease tumor size, cleaved HER-2 extracellular domain plasma levels, and potentiate the effects of the humanized anti-HER-2 monoclonal antibody (trastuzumab) in vivo in a HER-2 overexpressing cancer murine xenograft model.

Expression of neuronal protein synuclein gamma gene as a novel marker for breast cancer prognosis.

Synucleins are emerging as central players in the fundamental neural processes and in the formation of pathologically insoluble deposits characteristic of neurodegenerative diseases. However, synuclein gamma (SNCG), previously identified as a breast cancer specific gene (BCSG1), is also highly expressed in breast carcinomas, but not expressed in normal or benign breast tissues. We analyzed SNCG gene expression in 93 clinical breast specimens and associated it with clinical outcome.

Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells.

Overexpression and activating mutations of ErbB family members have been implicated in the development and progression of a variety of tumor types. Cleavage of the HER2 receptor by an as yet unidentified ectodomain sheddase has been shown to liberate the HER2 extracellular domain (ECD) leaving a fragment with constitutive kinase activity that can provide ligand-independent growth and survival signals to the cell. This process is clinically relevant since HER2 ECD serum levels in metastatic breast cancer patients are associated with a poorer prognosis.