Position paper of the Italian Association of Medical Oncology on the impact of COVID-19 on Italian oncology and the path forward: the 2021 Matera statement.

The coronavirus disease 2019 (COVID-19) pandemic has severely affected cancer care and research by disrupting the prevention and treatment paths as well as the preclinical, clinical, and translational research ecosystem. In Italy, this has been particularly significant given the severity of the pandemic's impact and the intrinsic vulnerabilities of the national health system. However, whilst detrimental, disruption can also be constructive and may stimulate innovation and progress. The Italian Association of Medical Oncology (AIOM) has recognized the impact of COVID-19 on cancer care continuum and research and proposes the '2021 Matera statement' which aims at providing pragmatic guidance for policymakers and health care institutions to mitigate the impact of the global health crisis on Italian oncology and design the recovery plan for the post-pandemic scenario. The interventions are addressed both to the pillars (prevention, diagnosis, treatment, follow-up, health care professionals) and foundations of cancer care (communication and care relationship, system organization, resources, research, networking). The priorities to be implemented can be summarized in the MATERA acronym: Multidisciplinarity; Access to cancer care; Telemedicine and Territoriality; Equity, ethics, education; Research and resources; Alliance between stakeholders and patients.

TRPM7 and MagT1 regulate the proliferation of osteoblast-like SaOS-2 cells through different mechanisms.

A correct magnesium (Mg2+) intake is essential for bone health. In particular, Mg2+ deficiency inhibits the proliferation of osteoblast-like SaOS-2 cells by increasing nitric oxide (NO) production through the upregulation of inducible NO synthase. At the moment, little is known about the expression and the role of TRPM7, a channel/enzyme involved in Mg2+ uptake, and MagT1, a Mg2+ selective transporter, in SaOS-2 cells. Here, we demonstrate that TRPM7 is not modulated by different extracellular concentrations of Mg2+ and its silencing exacerbates growth inhibition exerted by low Mg2+ through the activation of inducible NO synthase and consequent accumulation of NO. Moreover, MagT1 is upregulated in SaOS-2 cultured in high Mg2+ and its silencing inhibits the growth of SaOS-2 cultured in media containing physiological or high Mg2+, without any modulation of NO production. We propose that TRPM7 and MagT1 are both involved in regulating SaOS-2 proliferation through different mechanisms.

Use of an angiographic catheter in place of the Racz epidural catheter in the lysis of epidural space adhesions. A technical note.

This technical note describes lysis of adhesions in the epidural space with the use of a 5F vascular catheter inserted on a 0.35-inch guide passed through the sacral foramen. Commonly employed in the administration of anesthetics, a vascular catheter can be advantageously used in place of the Racz epidural catheter, with a potential reduction in damage to the nerve structures of the sacral canal.

Modulating mesenchymal stromal cell function with cholesterol synthesis inhibitors.

There is increasing evidence that statins, inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, can effectively be used not only in the treatment of hypercholesterolemia, but also in other human disorders; indeed, statins have strong anti-inflammatory and immunomodulatory effects, so that they can influence the onset and outcome of inflammation and autoimmunity. On the other hand, it has been shown that statins can affect growth and survival of solid tumour and leukemic cells, thus they have been proposed in the treatment of neoplasias as multiple myeloma, in association with drugs, as thalidomide, known to act on the cancer microenvironment. In the current view, tumor microenvironment include many cell types that interact with tumor cells: among them, stromal and endothelial cells, macrophages and dendritic cells, the various types of lymphocytes such as NK cells, B and T cells. The interplay between all these cell populations, and the balance between these, determines whether there is a tumour cell growth promotion or inhibition. In haematological malignancies, such as multiple myeloma, chronic lymphocytic and myeloid leukemias and follicular lymphomas, the survival, drug-resistance and proliferation of leukemic cells have been shown to be largely dependent on a supportive microenvironment, so that some cellular components of it, mainly mesenchymal stromal cells, cancer associated fibroblasts and macrophages, are now proposed as targets of new therapies. Herein, we analyze the effects that statins can exert on cancer cells, stromal cells and human natural killer cells, to discuss whether they can be proposed as anti-cancer drugs.

MF-59 adjuvant influence on the functions of gammadelta T cells in HIV-1+ adults immunized with influenza seasonal vaccine.

INTRODUCTION: We previously reported that in HIV-1 infected patients circulating Vdelta1 T lymphocytes (Vdelta1) increase and proliferate in vitro in response to Candida albicans (Ca). Herein, we analysed the effects of MF59 adjuvant on the Vdelta1 T cell responses to hemagglutinin (HA) and Ca in HIV-1 seropositive and seronegative adults after influenzal vaccine, to clarify th molecular mechanisms triggered in vivo by an adjuvanted vaccine against influenza virus. MATERIALS AND METHODS: 58 seropositive (HIV-1+) and 48 seronegative (HIV-1-) subjects received influenzal vaccines containing or not the MF59 adjuvant. The follow-up of in vitro T cell proliferation and cytokine production (IL-17A, IL-22, IL-23, IL-6) to HA and Ca antigens were performed at different time points (at basal time and after 30 and 90 days from vaccination) by cytofluorimetric approaches. RESULTS: We confirmed that in HIV-1 infected individuals the Vdelta1 T cell subset is expanded in HIV-1 infected individuals and moreover the number of circulating Vdelta1 Tcells significantly enhanced in all HIV-1+ subjects on day 90 after influenza vaccination. Regard the follow-up of proliferative responses, the increments of CD3+ response to HA and Vdelta1 T cells to Ca in HIV-1+ individuals were detectable earlier on day 30 for MF59-vaccinated patients, instead on day 90 post-vaccination in HIV(+)-vaccinated without MF59 adjuvant. Of note, production of lL-17A and IL-22, two cytokines with anti-fungal activity, in response to Ca was enhanced (for IL-17A) or restored (for IL-22) by vaccination in HIV-1+ donors, mainly using the MF59-adjuvanted vaccine. Moreover, after vaccination IL-23 and IL-6 production increased in response to HA in the HIV+ and HIV- groups vaccinated with MF59 adjuvant. CONCLUSIONS: We suggest that in HIV-1 infected patients the circulating Vdelta1 T lymphocytes reactive to Ca upon challenge with influenza virus vaccine receive an activating/enhancing signal mediated by cytokines triggered by the boost with HA antigen particularly in presence of MF59 adjuvant.

Treatment of a Symptomatic Epidural Gas Cyst Using an Angiographic 5F Catheter in the Epidural Space of the Spinal Cord through the Sacral Hiatus. A Case Report.

An 85-year-old woman arrived at our institution because of left lumbar sciatica of about two years duration unrelieved by conventional oral pain therapy. A computed tomography scan obtained at the second visit showed an epidural gas cyst, with compression and dislocation of the left spinal nerve root L5. The common treatment of an epidural gas cyst is either a direct surgical approach or a CT-guided needle aspiration. We describe an alternative method to mechanical lysis of epidural gas cysts with the use of an 5F angiographic catheter inserted on a 0.035-inch guidewire. This procedure is less invasive than a surgical approach and safer than a CT-guided needle aspiration. Remission of symptoms was maintained at control visits at three and five months.

Rupture of a left internal jugular vein. A rare case.

A 60-year-old woman with neurofibromatosis type 1 presented with a nonpainful swelling in the left laterocervical region that had suddenly arisen after mild exertion the previous evening. Computed tomography with and without contrast enhancement revealed a rupture of the wall of the left internal jugular vein, with a diffuse subcutaneous hematoma. Postoperative histopathologic examination reported diffuse proliferation of plexiform neurofibromatous tissue within the vessel wall.

Gammadelta T lymphocytes producing IFNgamma and IL-17 in response to Candida albicans or mycobacterial antigens: possible implications for acute and chronic inflammation.

T lymphocytes bearing the gammadelta T cell receptor are known to play an important role in the first-line defense against viral, bacterial and fungal pathogens. Two main subsets of gammadelta T cells are known, showing distinct functional behaviour: Vdelta2 T lymphocytes, circulating in the peripheral blood, are involved in the response to mycobacterial infections and certain viruses, including coxsakie virus B3 and herpes simplex virus type 2. Vdelta1 T cells are resident in the mucosal-associated lymphoid tissue and are reported to participate in the immunity against Listeria monocytogenes and cytomegalovirus. Vdelta2 T lymphocytes recognize non-peptidic phosphorylated metabolites of isoprenoid biosynthesis, expressed by mycobacteria, while Vdelta1 T cells mainly interact with MHC-related antigens (MIC-A and MIC-B) and with receptors, called UL-16 binding proteins, for the UL-16 protein produced by cytomegalovirus-infected cells. Both Vdelta1 and Vdelta2 T cells can produce interferon-gamma in response to MIC-A(+) cells or non-peptide antigens, respectively. Moreover, production of TNF-alpha by human Vgamma9/Vdelta2 T cells has been demonstrated in response to bacterial products and non-peptidic molecules. Recently, it has been reported that gammadelta T lymphocytes can produce IL-17 during Escherichia coli or Mycobacterium tuberculosis infections in mice. This is of interest as IL-17 is emerging as a cytokine crucial in the control of intracellular pathogens and fungi. In this review, we will discuss the possible role of IL-17 producing gammadelta T cells in the regulation of acute and chronic inflammation, focusing on the different response of the two subsets to mycobacterial, viral or fungal antigens.

Effective in vivo induction of NKG2D ligands in acute myeloid leukaemias by all-trans-retinoic acid or sodium valproate.

Engagement of NKG2D by their ligands (NKG2D-L), as the human major histocompatibility complex class I-related molecules MIC-A and the UL16-binding proteins, on cytolytic lymphocytes leads to the enhancement of antitumour effector functions. These ligands are missing or expressed at very low levels on leukaemic cells; furthermore, they can be shed by tumour cells and inhibit cytolytic activity of lymphocytes. Herein, we show that in vivo administration of all-trans-retinoic acid (ATRA) or the histone deacetylase inhibitor sodium valproate (VPA) to patients affected with acute myeloid leukaemia (AML) M3 or M1 respectively, leads to the induction of transcription and expression of NKG2D-L at the surface of leukaemic cells. Apparently, no detectable shedding of the soluble form of these molecules was found in patients' sera. Conversely, AML blasts from patients treated with chemotherapy not including ATRA or VPA did not show any induction of NKG2D-L transcription. Furthermore, upon therapy with ATRA or VPA, leukaemic blasts become able to trigger lytic granule exocytosis by autologous CD8(+) T and natural killer lymphocytes, as shown by CD107a mobilization assay, followed by leukaemic cell lysis. These findings indicate that ATRA and VPA may contribute to the activation of cytolytic effector lymphocytes in vivo, possibly enhancing their anti-leukaemic effect.

Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division.

In this study, we analysed 30 patients with B-cell chronic lymphocytic leukaemia (CLL), compared with 10 healthy donors, for the expression and function of the leukocyte-associated Ig-like receptor-1 (LAIR-1). LAIR-1 is an inhibitory receptor containing a cytoplasmic tyrosine-based inhibitory motif (ITIM) that binds to the SH2 domain of phosphatases, leading to dephosphorylation of different kinases. Constitutive activation of c-Jun aminoterminal kinase (JNK), p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, has been reported in CLL. We show that LAIR-1 is absent in high-risk (HR) CLL and differently expressed on intermediate- and low-risk CLL and the intensity of expression, which is always significantly lower than in healthy donors, correlates with disease stage and progression. Interestingly, both constitutive and sIgM-induced phosphorylation of p38 and JNK is inhibited by LAIR-1 through an ITIM-dependent signal, as demonstrated by the use of specific ITIM-binding peptides; importantly, this inhibitory signal is missing when LAIR-1 is not expressed as occurs in HR CLL. Moreover, engagement of LAIR-1 blocks constitutive and sIgM-induced Akt phosphorylation, besides nuclear factor kappa-B nuclear translocation, and prevents CLL division. These results suggest that CLL lacking LAIR-1 may miss one of the molecular mechanisms controlling B-cell activation and proliferation.

Bicompartmental breast lipostructuring.

The techniques of additive mastoplasty described over the years require the use of alloplastic materials (silicon), which often are poorly tolerated by the body and need access paths that could leave visible, unaesthetic residual scars. Furthermore, the controversy over silicone gel-filled breast implants, which in the early 1990s restricted their clinical use for primary cosmetic breast augmentation, still raises concerns in some patients. The authors therefore felt encouraged to search for alternatives to breast implants and reconsider fat transfer. In fact, for almost a century, autologous adipose tissue has been used safely and with success in many other surgical fields for the correction of volumetric soft tissue defects. Its natural, soft consistency, the absence of rejection, and the versatility of use in many surgical techniques have always made autologous adipose tissue an ideal filling material. In the past, the authors used this technique, as originally described by Fournier (intraparenchymal, en bloc injection), for 41 patients. However, disappointed by a very high rate of complications and the almost complete reabsorption of the grafted fat, they quit using the procedure. An extensive literature review indicated that the complications observed were related only to technical errors and to the anatomic site of harvesting and implantation. The authors therefore developed a new method incorporating recent contributions in functional anatomy and fat transfer. Fat is harvested in a rigorously closed system, minimally manipulated, and reimplanted strictly in two planes only: into the retroglandular and prefascial space and into the superficial subcutaneous plane of the upper pole of the breast (bicompartmental grafting). Any intraparenchymal placement is carefully avoided. Since 1998, 181 patients (300 breasts) have undergone this procedure. Grafted fat volume has ranged from 160 to 685 ml (average, 325 ml) per breast. Complications have been minimal and temporary. All patients have been carefully monitored with preoperative and serial postoperative mammograms and ultrasonograms. This strict follow-up assessment allowed the authors to clarify the controversial aspect of microcalcifications, the main point of criticism for this procedure over the years. Microcalcifications can occur in response to any trauma or surgery of the breast, but are very different in appearance and location. Thus, they can be discriminated easily from those appearing in the context of a neoplastic focus. Probably the most important point is that the fat survival ranged from 40% to 70% at 1 year. The volume is maintained because when the authors transplant living fat tissue, they also transfer a consistent amount of adult mesenchymal stem cells that spontaneously differentiate into preadipocytes and then into adipocytes, compensating for the partial loss of mature adipocytes reabsorbed through time. This theory has been well demonstrated via advanced research performed by the authors and by many other prominent medical institutes worldwide. The findings show that adipose tissue has the same potential for growth of adult mesenchymal totipotential stem cells of bone marrow and can eventually be differentiated easily by the use of specific growing factors and according to the needs and applications in other cellular lines (osteogenic, chondrogenic, myogenic, epithelial). In summary, the authors wish to highlight a formerly controversial procedure that, thanks to recent technical and clinical progress, has become a safe and viable alternative to the use of alloplastic materials for breast augmentation for all cases in which additive mastoplasty with implants is either unsuitable or unacceptable by the patient herself. However this method cannot be considered yet as a complete substitute for augmentation with implants because the degree of augmentation and projection still is limited.

Catheterization via Caudal Puncture of the Epidural Space with a 5F Angiography Catheter and a Coaxial Steerable 0.038" Guidewire for Delivery of Drugs and Adhesiolysis.

UNLABELLED: We describe a technique for epidural medication delivery with angiographic catheters and guidewires inserted via caudal puncture and advanced cephalad under fluoroscopic guidance in the treatment of painful spinal diseases. METHODS: From November 2005 to September 2006 a total of 18 consecutive patients underwent adhesiolysis by an angiographic 5 French hockey-stick tip catheter and a coaxial 0.038" steerable guidewire inserted at the sacral hiatus and advanced cephalad under fluoroscopic guidance up to the site of adhesion. We obtained pain relief for more than three months in 61% of patients. There were no periprocedural/postprocedural complications. Our system of accessing the epidural space provides a safe means of delivering epidural medication, performing mechanical adhesiolysis and may be useful in the treatment of selected patients with painful spinal diseases.

Effects of balance exercises on people with multiple sclerosis: a pilot study.

OBJECTIVE: To evaluate the effects of balance retraining in a sample of people with multiple sclerosis. DESIGN: Randomized controlled trial. SETTING: Rehabilitation unit. SUBJECTS: A consecutive sample of 44 subjects was randomized into two experimental groups and one control group. The inclusion criteria were: ability to stand independently more than 30 seconds, ability to walk for 6 m. INTERVENTIONS: Group 1 received balance rehabilitation to improve motor and sensory strategies. Group 2 received balance rehabilitation to improve motor strategy. Group 3 received treatments not specifically aimed at improving balance. MAIN OUTCOME MEASURE: Berg Balance Scale, Dynamic Gait Index and fall frequency were used to assess balance impairments. Dizziness Handicap Inventory and Activities-specific Balance Confidence were used to assess handicap and the level of balance confidence. RESULTS: Frequency of falls post treatment was statistically different among groups (P=0.0001); The Berg Balance Scale showed an overall statistically significant difference (P=0.0008) among groups. Change pre-post scores were 6.7, 4.6 and 0.8 points for groups 1, 2 and 3. Dynamic Gait Index showed an overall near statistically significant difference among groups (P=0.14), with change pre-post scores of 3.85, 1.6 and 1.75 points for groups 1, 2 and 3; after the exclusion of drop-outs a statistically significant difference was observed (P=0.04). The self-administered tests (Activities-specific Balance Confidence and Dizziness Handicap Inventory) did not show clinically relevant improvements. CONCLUSIONS: Balance rehabilitation appeared to be a useful tool in reducing the fall rate and improving balance skills in subjects with multiple sclerosis. Exercises in different sensory contexts may have an impact in improving dynamic balance.

Migratory pathways of gammadelta T cells and response to CXCR3 and CXCR4 ligands: adhesion molecules involved and implications for multiple sclerosis pathogenesis.

Gammadelta T lymphocytes are thought to be involved in multiple sclerosis (MS) pathogenesis. In this work, we discuss the characteristics of these cells and possible implications in the pathogenesis of MS, focusing on the mechanism(s) underlying extravasation and tissue localization. Phenotype and transendothelial migration of gammadelta T cells from healthy donors and patients with relapsing-remitting MS were studied. In MS patients the V delta 2 T cell subset, expressing NKRP1A/CD161 adhesion molecule, is expanded and capable of transendothelial migration. V delta 1/V delta 2 subsets use distinct signal transduction pathways: V delta 1 cells lack NKRP1A and express PECAM-1/CD31, which drives transmigration, while V delta 2 cells are PECAM-1 negative and use NKRP1A. V delta 2 migration is coupled with CAMKII, whereas V delta 1 depend on PI-3K. NKRP1A and PECAM-1 selectively activate the two pathways: indeed, oligomerization of NKRP1A on V delta 2 T cells leads to CAMKII activation, occupancy of PECAM-1 on V delta 1 cells triggers the PI-3K-dependent Akt/PKB pathway. Moreover, V delta 2 T cells are CXCR3(bright)CXCR4(dull), while V delta 1 are mostly CXCR4(+). V delta 1 and V delta 2 cells transmigrate in response to IP-10/CXCL10 and SDF-1/CXCL12 according to the expression of their specific receptors. In a fraction of V delta 1 T cells coexpressing CXCR3 and CXCR4, the homeostatic chemokine 6Ckine/SLC/CCL21 is more effective. IP-10/CXCL10 or 6Ckine/SLC/CCL21 and SDF-1/CXCL12-induced transmigration is coupled to PI-3K/Akt/PKB, but only CXCR3 is capable of inducing CAMKII activation. We suggest that both subsets of gammadelta T lymphocytes may migrate to the site of lesion in MS using two different signaling pathways to extravasate and responding to different chemokines.

Protected carotid stenting: the usefulness of filter protection devices.

We report our experience in carotid artery stenting using a filter protection device. From July 2003 to September 2006 we treated 62 patients by internal carotid stenting using a filter protection device. Procedural success was achieved in 100% of cases. There were five periprocedural complications: one dissection of the internal carotid artery, two TIAs and two groin haematomas at the site of needle access. Neurological examination performed after the procedure and during the 30 days of follow-up did not reveal major neurological complications. Cerebral protection with a filter during carotid artery stenting seemed feasible and safe.

In vivo apoptosis of CD8(+) lymphocytes in acute myeloid leukemia patients: involvement of soluble HLA-I and Fas ligand.

In this study, we show that high serum levels of soluble human leukocyte antigens (HLA) class I molecules (sHLA-I, range: 0.7-1.7 micro g/ml) and soluble Fas ligand (FasL, range: 0.4-1.9 ng/ml) are detected in patients with acute myeloid leukemia (AML) at diagnosis, compared with healthy donors (HD) (sHLA-I, range: 0.1-0.6 micro g/ml; sFasL, range: 0.1-0.4 ng/ml). Patients' sera were able to induce transcription and secretion of FasL in CD8(+) T cells, followed by apoptosis in vitro; this apoptosis was inhibited by anti-HLA-I-specific monoclonal antibodies, suggesting that sHLA-I is responsible for cell death. These findings closely relate to the in vivo upregulation of FasL transcription observed in peripheral blood (PB) lymphocytes from AML patients; in the same cells, mRNA for the antiapoptotic proteins Bcl-2 and Bcl-x(L) was downregulated. Interestingly, caspase-8 and caspase-3, both downstream mediators of death receptor-induced apoptosis, were activated in CD8(+) cells of AML patients; one-third of these cells were already apoptotic in vivo, at variance with lymphocytes of HD. These data strongly suggest that in AML, increased levels of sHLA-I molecules may contribute to the elimination of potentially anti-tumor effector cells through a FasL/Fas interaction.

ZAP-70 is expressed by normal and malignant human B-cell subsets of different maturational stage.

ZAP-70 tyrosine kinase is involved in signalling pathways following T-cell receptor stimulation and was originally described only in T cells and natural killer cells. ZAP-70 expression has been reported in normal mouse B lineage cells and in human malignant B lymphocytes, mainly in chronic lymphocytic leukemia (CLL) where it correlates with clinical outcome. We analyzed several B-cell lines and ex vivo malignant B cells, ranging from acute lymphoblastic leukemia to multiple myeloma and reflecting different stages of B-cell differentiation, and they showed ZAP-70 expression regardless their maturation stage. We then analyzed by Western blot and flow cytometry different human normal B-lymphocyte subpopulations: naïve, germinal center and memory B cells from tonsils, CD19+ CD5+ cells from cord blood and CD19+ lymphocytes from peripheral blood. All expressed ZAP-70 protein, though at different levels depending on their differentiation, activation and tissue localization. In addition, ZAP-70 expression levels could be modulated following stimulation via the B-cell receptor. These findings implicate a potential role of ZAP-70 in the signalling pathway of B lymphocytes at different maturational stages, indicate that ZAP-70 expression is not a CLL-specific feature among B-cell malignancies and suggest that the absence of ZAP-70 rather than its presence should be considered abnormal for malignant B lymphocytes.

Short, medium and long term efficacy of epidurally injected anaesthetic-corticosteroid mixture in lumbocruralgia and lumbosciatalgia.

We assessed the efficacy of an epidural sited anaesthetic-corticosteroid mixture with transforaminal or interlaminar/interspinous access, in subjects with chronic lumbocruralgia or lumbosciatalgia caused by discal pathology or degenerative foraminal stenosis. From September 2003 to June 2005, 84 patients were treated in the transforaminal region and 32 in epidural space through back access (interlaminar or interspinous) with 2 ml cortisone (megacort) and 2ml anaesthetic (naropine 7.5mg/ml). All 116 patients underwent a minimum of two and a maximum of three treatment sessions. The results were evaluated for a follow-up period of ten months by comparing the answers given by the patients with the Visual Analogic Score. This was done prior to and after every single injection and during the follow-up period. Out of 142 spaces treated, improvement of symptoms for a period varying from one to three months was recorded in 74 cases (52%), for a period of more than three months in 53 (37%) cases, while in the remaining 15 (11%) cases no sufficient regression of pain was reported. In many cases of chronic lumbago/lumbosciatalgia, the percutaneous injection of an anaesthetic-cortisone mixture can be useful in relieving or even killing pain for a period of more than three months. No major complication was reported.

Pertussis toxin (PTX) B subunit and the nontoxic PTX mutant PT9K/129G inhibit Tat-induced TGF-beta production by NK cells and TGF-beta-mediated NK cell apoptosis.

We show that the pertussis toxin B oligomer (PTX-B), and the PTX mutant PT9K/129G, which is safely administered in vivo, inhibit both transcription and secretion of TGF-beta elicited by HIV-1 Tat in NK cells. Tat-induced TGF-beta mRNA synthesis is also blocked by the ERK1 inhibitor PD98059, suggesting that ERK1 is needed for TGF-beta production. Moreover, Tat strongly activates the c-Jun component of the multimolecular complex AP-1, whereas TGF-beta triggers c-Fos and c-Jun. Of note, treatment of NK cells with PTX-B or PT9K/129G inhibits Tat- and TGF-beta-induced activation of AP-1. TGF-beta enhances starvation-induced NK cell apoptosis, significantly reduces transcription of the antiapoptotic protein Bcl-2, and inhibits Akt phosphorylation induced by oligomerization of the triggering NK cell receptor NKG2D. All these TGF-beta-mediated effects are prevented by PTX-B or PT9K/129G through a PI3K-dependent mechanism, as demonstrated by use of the specific PI3K inhibitor, LY294002. Finally, PTX-B and PT9K/129G up-regulate Bcl-x(L), the isoform of Bcl-x that protects cells from starvation-induced apoptosis. It is of note that in NK cells from patients with early HIV-1 infection, mRNA expression of Bcl-2 and Bcl-x(L) was consistently lower than that in healthy donors; interestingly, TGF-beta and Tat were detected in the sera of these patients. Together, these data suggest that Tat-induced TGF-beta production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G.