Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation

Anabolic biosynthesis requires precursors supplied by the Krebs cycle, which in turn requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and glutamine, which require the activity of pyruvate carboxylase (PC) and glutaminase 1 (GLS1), respectively. Due to their rapid proliferation, cancer cells have increased anabolic and energy demands; however, different cancer cell types exhibit differential requirements for PC- and GLS-mediated pathways for anaplerosis and cell proliferation. Here, we infused patients with early-stage non–small-cell lung cancer (NSCLC) with uniformly ¹³C-labeled glucose before tissue resection and determined that the cancerous tissues in these patients had enhanced PC activity. Freshly resected paired lung tissue slices cultured in ¹³C₆-glucose or ¹³C₅,¹⁵N₂-glutamine tracers confirmed selective activation of PC over GLS in NSCLC. Compared with noncancerous tissues, PC expression was greatly enhanced in cancerous tissues, whereas GLS1 expression showed no trend. Moreover, immunohistochemical analysis of paired lung tissues showed PC overexpression in cancer cells rather than in stromal cells of tumor tissues. PC knockdown induced multinucleation, decreased cell proliferation and colony formation in human NSCLC cells, and reduced tumor growth in a mouse xenograft model. Growth inhibition was accompanied by perturbed Krebs cycle activity, inhibition of lipid and nucleotide biosynthesis, and altered glutathione homeostasis. These findings indicate that PC-mediated anaplerosis in early-stage NSCLC is required for tumor survival and proliferation.     

Natural killer-like T-cell lymphomas: aggressive lymphomas of T-large granular lymphocytes [see comments]

Natural killer (NK)-like T cells are major histocompatibility complex- unrestricted cytotoxic T cells that are surface CD3-positive, express NK-cell antigens, and rearrange their T-cell receptor. Most neoplasms arising from this T-cell subpopulation have been a chronic lymphoproliferative disease referred to as T-large granular lymphocyte (LGL) leukemia. Only 10 NK-like T-cell lymphomas have been described in detail previously; this study presents the clinicopathologic features of six others and distinguishes these lymphomas from T-LGL leukemia. All patients presented with B-symptoms and often had marked hepatosplenomegaly without significant peripheral lymphadenopathy. Four of the six patients were immunosuppressed. All had CD3, CD8, CD56- positive tumors, presumably of hepatosplenic (n = 3), intestinal (n = 1), pulmonary (n = 1), or nodal (n = 1) origin. Three patients had lymphomatous bone marrow infiltrates, and four had peripheral blood involvement by neoplastic large lymphocytes, some of which had a blastic appearance or resembled virocytes. Azurophilic granules, ultrastructurally corresponding to cytoplasmic dense core and/or double density granules, were seen in all cases. T-cell clonality was shown in five tumors by Southern blot analysis, and three had abnormal karyotypes. Two untreated patients died 20 days after presentation, and three patients who received combination chemotherapy died within 5 months of presentation. One patient remains in complete remission 22 months after treatment. These findings suggest NK-like T-cell lymphomas are aggressive, are clinicopathologically distinct from T-LGL leukemia, and should be in the differential diagnosis of extranodal T-cell lymphoproliferations, including those in immunosuppressed patients. Furthermore, the LGL morphology, phenotype, and tissue distribution of some NK-like T-cell lymphomas suggest they arise from thymic- independent T cells of the hepatic sinusoids and intestinal mucosa.     

3D printable SiO2 nanoparticle ink for patient specific bone regeneration

Sodium alginate and gelatin are biocompatible & biodegradable natural polymer hydrogels, which are widely investigated for application in tissue engineering using 3D printing and 3D bioprinting fabrication techniques. The major challenge of using hydrogels for tissue fabrication is their lack of regeneration ability, uncontrolled swelling, degradation and inability to hold 3D structure on their own. Free hydroxyl groups on the surface of SiO₂ nanoparticles have the ability to chemically interact with alginate–gelatin polymer network, which can be explored to achieve the above parameters. Hence validating the incorporation of SiO₂ nanoparticles in a 3D printable hydrogel polymer network, according to the patient''s critical defects has immense scope in bone tissue engineering. In this study, SiO₂ nanoparticles are loaded into alginate–gelatin composite hydrogels and chemically crosslinked with CaCl₂ solution. The effect of SiO₂ nanoparticles on the viscosity, swelling, degradation, compressive modulus (MPa), biocompatibility and osteogenic ability were evaluated on lyophilized scaffolds and found to be desirable for bone tissue engineering. A complex irregular patient-specific virtual defect was created and the 3D printing process to fabricate such structures was evaluated. The 3D printing of SiO₂ nanoparticle hydrogel composite ink to fabricate a bone graft using a patient-specific virtual defect was successfully validated. Hence this type of hydrogel composite ink has huge potential and scope for its application in tissue engineering and nanomedicine.

3D printing of a complex and irregular virtual defect using SiO₂ nanoparticle and hydrogel composite ink for patient specific defect fabrication.     

Incidence and Predictors of Permanent Pacemaker Requirement after Transcatheter Aortic Valve Implantation with a Self‐Expanding Bioprosthesis

Background: Previous reports have suggested the occurrence of cardiac conduction disorders and permanent pacemaker (PPM) requirement after transcatheter aortic valve implantation (TAVI). Based on a single‐center experience, we aim to assess the incidence of postprocedural conduction disorders, need for PPM, and its determinants after TAVI with a self‐expanding bioprosthesis. Methods: From August 2007 to October 2009, 32 consecutive patients underwent TAVI with the Medtronic CoreValve (MCV) System (Medtronic Inc., Minneapolis, MN, USA). Three patients paced at baseline and two cases of procedure‐related mortality were excluded. We analyzed the 12‐lead electrocardiogram at baseline, immediately after procedure and at discharge. Requirements for PPM were documented and potential clinical, electrophysiological, echocardiographic, and procedural predictors of PPM requirement were studied. Results: After TAVI, eight patients (29.6%) required PPM implantation due to high‐grade atrioventricular (AV) block. The prevalence of left bundle branch block increased from 13.8% to 57.7% directly after implantation (P = 0.001). Need for PPM was correlated to the depth of prosthesis implantation (r = 0.590; P = 0.001). At a cutoff point of 10.1 mm, the likelihood of pacemaker could be predicted with 87.5% sensitivity and 74% specificity and a receiver operator characteristic curve area of 0.86 ± 0.07 (P = 0.003). Of the seven patients with preexisting right bundle branch block (RBBB), four (57.1%) required PPM implantation after TAVI. Conclusions: High‐grade AV block requiring PPM implantation is a common complication following TAVI and could be predicted by a deeper implantation of the prosthesis. Patients with preexisting RBBB also seem to be at risk for the development of high‐grade AV block and subsequent pacemaker implantation. (PACE 2010; 1364–1372)     

Validity of Clinically Derived Cumulative Somatosensory Impairment Index

Deshpande N, Metter EJ, Ferrucci L. Validity of clinically derived Cumulative Somatosensory Impairment Index.

Objective

To develop a Cumulative Somatosensory Impairment Index for the lower limbs and evaluate its construct validity for discriminating relevant groups and predictive validity for predicting global postural control over time.

Design

Prospective cohort study.

Setting

Population-based cohort.

Participants

InCHIANTI (“Invecchiare in Chianti” or aging in the Chianti area) study participants (N=960; age, 21-91y, 51.8% women).

Interventions

Not applicable.

Main Outcome Measures

The Cumulative Somatosensory Impairment Index was derived from baseline performance on clinical tests of pressure sensitivity, vibration sensitivity, proprioception, and graphesthesia. Global postural control was assessed using Frailty and Injuries Cooperative Studies of Intervention Techniques (FICSIT) balance test, time to complete 5 repeated chair stands, and fast walking speed, at baseline and at 3-year follow-up.

Results

In participants without neurologic conditions (n=799), the Cumulative Somatosensory Impairment Index was significantly different in age groups classified by decades (P<.001). Compared with participants without prevalent conditions, the Cumulative Somatosensory Impairment Index was significantly higher in persons with diabetes (P=.017), peripheral arterial disease (P=.006), and a history of stroke (P<.001). In the overall population (N=960), in the fully adjusted multiple regression models, the Cumulative Somatosensory Impairment Index independently predicted deterioration in FICSIT scores (P=.002), time for 5 repeated chair stands (P<.001), and fast gait speed (P=.003) at 3-year follow-up.

Conclusions

The Cumulative Somatosensory Impairment Index is a valid measure that detects relevant group differences in lower limb somatosensory impairment and is an independent predictor of decline in postural control over 3 years.     

Hepatic tuberculosis in absence of disseminated abdominal tuberculosis

Liver involvement in tuberculosis in absence of miliary tuberculosis is rare. This study was performed to analyse the spectrum and response to treatment of hepatic tuberculosis in the absence of miliary abdominal tuberculosis. Retrospective analysis of seven cases of hepatic tuberculosis without miliary abdominal tuberculosis who presented at the single tertiary referral center were analyzed. All patients presented with fever and hepatomegaly. Five of them had pain in upper abdomen and vomiting. HIV serology was positive in one patient. All patients had normocytic normochromic anaemia, raised erythrocyte sedimentation rate (Mean 65). Mild elevation of liver enzymes and low albumin (Mean 2.4 gm%) with reversal of albumin globulin ratio (Mean 0.6) were seen in all. Two had jaundice. Prothrombin time was normal in all and lactate dehydrogenase values were elevated in all (Mean 794 IU/L). On ultrasonography, 2 had multiple hypodense lesion, 1 had coarse echotexture of liver, 1 had hyperechoic pattern and 3 had just hepatomegaly. Complete resolution of liver lesions on treatment with 4-drug anti-tuberculosis drug chemotherapy was seen. In conclusion, liver tuberculosis has protean manifestations with nonspecific alteration of liver function tests and is best diagnosed on liver biopsy. Overall response to therapy is satisfactory.     

Asian paralysis syndrome

We report 20 children admitted to the paediatric ward of a public general hospital for acute flaccid paralysis, which was bilaterally symmetrical in all cases and was associated with bulbar involvement in eight of them. Recovery was partial. Nerve conduction studies showed motor axonal neuropathy. This new disease, variously termed as non-inflammatory neuropathy/Chinese paralysis syndrome must be differentiated from Guillain-Barré syndrome (GBS) and poliomyelitis. Both GBS and Asian paralysis syndrome have bilaterally symmetrical flaccid paralysis but GBS tends to have sensory involvement, full recovery occurs in 90% of cases and nerve conduction shows demyelinating neuropathy. Asian paralysis syndrome and poliomyelitis are pure motor lesions without sensory changes and partial recovery, but poliomyelitis differs in that paralysis is asymmetrical and unequal, muscle spasm is always present in the initial stage and there are prodromal symptoms. Nerve conduction studies show anterior horn cell disease. This new entity, common in Asian populations, assumes public health importance when it mimics poliomyelitis in a country that has tried to eliminate poliomyelitis by universal immunization. To the best of our knowledge, this is the first report of Asian paralysis syndrome in children in our area.